Unit 2

Differentiate myeloblasts from lymphoblasts based on immunophenotype.

CD13, CD33, MPO

Discuss the pathogenesis of sarcoidosis.

CD4+ TH1 cells secrete IL-2 and IFN-ɣ which lead to T cell proliferation (IL-2) and macrophage activation polyclonal hypergammaglobulinemia familial and HLA components

Which lymphomas/leukemias are CD5+?

CLL/SLL (CD23+) caused by a clonal rearrangement in the Ig genes; and Mantle cell lymphoma (CD23-) caused by t(11;14)

t(9;22), Philadelphia

CML, B-ALL (poor prognosis); BCR-ABL

Describe the role of telomerase in maintaining tumor cell proliferation.

Cancer cells reactive telomerase activity to retain functional telomeres after multiple rounds of cell division beyond that normally permissible nay human cells (Hayflick limit)

A 76 yo man presents to your clinic complaining of ringing in both ears that has been present over the past month. He also tells you that he seems to be having trouble hearing during this period as well. His past medical history is significant for bladder cancer, for which he is currently being treated with chemotherapy. You suspect that his hearing loss is related to one of his medications. Which of the following is a drug that is used for this patient and also associated with ototoxicity?

Ciplastin

A 72 yo woman presents to the emergency room complaining of the onset of pain and bleeding with urination over the past 24 hrs. She denies any fever, flank pain, or history of kidney stones. Her past medical history is significant for breast cancer, for which she is currently receiving chemotherapy. Urinalysis is significant for copious amounts of blood and RBCs. You admit the patient for a urology work-up and you begin to wonder if the symptoms might be related to her chemotherapeutic regimen which involves?

Cyclophosphamide

A patient is being treated for ovarian cancer with a drug that cross-links DNA. She notices blood in her urine. What is the causative agent and what could have helped prevent this?

Cyclophosphamide; Mesna and hydration

The patient is a 20-year-old college student who presented to the emergency room at a community hospital with general malaise, low-grade fever, and purplish discoloration on his face. The facial discoloration developed rapidly during the time from when he left his house to the time he arrived at the emergency room. Blood cultures were drawn and he was admitted to the intensive care unit. He was given IV antibiotics, fresh frozen plasma, cryoprecipitate, fluid resuscitation and dopamine. He was transferred to a university medical center hospital where he expired 18 hours after initial presentation. ↑PT/PTT, ↓PLT, gram stain of rare gram+ cocci in pairs and clusters inside PMNs

DIC

Alkylating agents

DNA cross-linkers; cell cycle non-specific; bone marrow suppression 1. Cyclophosphamide- hemorrhagic cystitis 2. Busulfan- pulmonary fibrosis 3. mechlorethamine 4. Nitrosoureas (Carmustine, Lomustine)- highly lipophilic; can cross BBB 5. Isofamide- bladder toxicity 6. Decarbazine 7. Chlorambucil 8. Mephlan

Describe the organization of the human genome.

DNA is organized as chromatin plus histones and non-histone proteins packed into compact chromosomal units; 23 pairs of chromosomes (22 autosomes + XY sex chromosome pair) with a small portion of the genome (2%) encoding expressed gene sequences (mRNA, tRNA, rRNA, snRNA, miRNA etc.)

A patent receiving a combination of 5-FU, leuvocorin, and oxaloplatin for his colorectal cancer experiences significant toxicity in the form of myelosupression, diarrhea, and altered mental status. What is the most likely explanation for this increased toxicity?

DPD deficiency; genetic testing is not required

A 2-year-old boy is brought to your oncology clinic after having been recently diagnosed with Wilms tumor. Physical examination is significant for a palpable left-sided flank mass. You explain to the child's mother that the best course of treatment will include surgical excision of the tumor and chemotherapy. You recommend the sue of at lease two drugs, one of which acts by interfering with RNA synthesis through the inhibition of DNA-dependent RNA polymerase. Since this drug can also cause bone marrow suppression, the child's blood cell counts, especially his platelets and leukocytes, will have to be monitored closely. What is the name of this drug?

Dactinomycin = Actinomycin D

Define "differentiation" as it applies to neoplasms, and describe what loss of differentiation implies to the function of tumor cells. What is high and low grade?

Differentiation is the extent to which a tumor resembles its normal cell counterpart. Loss of differentiation usually also implies loss of function. Low grade (well/moderately differentiated)= I/II; high grade (poorly/undifferentiated)= III/IV

t(14;21)

Down syndrome

Define dysplasia and describe its clinical significance.

Dysplasia is loss of maturation without invasion of underlying stroma. It may spontaneously regress or eventually progress to invasive cancer.

Recognize significance of reactive granulocytic changes (toxic granulation and Döhle bodies).

Döhle bodies are sky-blue cytoplasmic patches representing dilated endoplasmic reticulum. Toxic granules are coarser and darker than the normal Neutrophils containing coarse purple cytoplasmic granules (toxic granulations) and blue cytoplasmic patches (Döhle bodies, arrow) are observed in this peripheral blood smear from a patient with bacterial sepsis.

What do MCV, MCH, MCHC, and RDW measure?

MCV: normocytic, microcytic, macrocytic MCH/MCHC: hypochromic or normochromic (32-36 g/dL) RDW: red cell distribution width; the range of variation in RBCs

Identify representative cancer associated genes involved in DNA repair.

MLH1 & MSH2: DNA mismatch repair; associated with hereditary nonpolyposis colon carcinoma

Methotrexate/pemetrexed..

MOA: Anti-folates; Inhibits DHFR Leucovorin is used in conjunction with high does MTX to rescue normal cells from toxicity adverse effects: hand-foot syndrome (for pemetrexed)- painful erythema and swelling of hands and feet; dexamethasone reduced incidence and severity

Cepecitabine.

MOA: Capecitabine hydrolyzed to 5-FU in tumor. Therapeutic uses: oral drug used in metastatic breast cancer either as a single agent or in combination; adjuvant therapy of stage III and high-risk stage II colon cancer; mono therapy for metastatic colorectal cancer; XELOX (capecitabine/oxaliplatin) first line treatment for metastatic colorectal cancer

Cytarabine (Ara C).

MOA: S-phase specific deoxycytosine analog; inhibits DNA polymerase, inhibits DNA synthesis and repair, incorporated into RNA and DNA (interferes with chain elongation) Therapeutic uses: hematologic malignancies (AML, non-Hodgkin's lymphoma); NOT active in solid tumors A/E: myelosupression, mucositisis, N/V, neurotoxicity

hydroxyurea

MOA: S-phase specific ribonucleoside reductase inhibitor used to treat CML

Gemcitabine.

MOA: fluorine-substituted deoxycytidine analog; inhibits DNA polymerase, inhibits DNA synthesis and repair Therapeutic uses: advanced pancreatic cancer, non-small cell lung, bladder, ovarian, soft-tissue, sarcoma, non-hoskins lymphoma A/E: myelosupression (neutropenia: dose limiting), N/V, flu-like, rare HUS or TTP

5-fluropyrimidine (5-FU).

MOA: pro-drug metabolized to FdUMP that forms a covalent complex with thimidylate synthase, incorporation of FuTP into RNA, incorporation of FdUTP into DNA. therapeutic uses: most widely used in colorectal cancer; active against solid tumors (breast, stomach, pancreas, esophagus, liver, head & neck, anus) adverse effects: 5-FU is catabolized by dihydropyrimadine dehydrogenase (DPD); 5% of cancer patients lack DPD= severe toxicity

Fludarabine.

MOA: purine antagonist; triphosphate form interferes w/ DNA synthesis and repair through inhibition of DNA polymerase-a &b, directly incorporated into DNA, inhibits ribonucleotide reductase, induces apoptosis Therapeutic uses: low grade non-Hodgkin's lymphoma, CLL A/E: myelosupression (dose-limiting); potent immunosuppressant- increased risk for opportunistic infections (fungi, herpes, PJP)

t(11, 14)

Mantle cell lymphoma; Cyclin D to IgHC (G1→S)

Which lymphoma is associated with H. pylori?

Marginal cell lymphoma → MALT

Define metastasis and describe its effect on prognosis.

Metastasis is when implants of the tumor are not contiguous with the primary mass. If a tumor has metastasized then it is malignant and almost all malignant tumors have the capacity to metastasize (excepts are unoperated gliomas and most basal cell carcinomas)

Compare and contrast B12 and folate deficiency

Metformin can also cause B12 deficiency

Describe the processes of DNA replication and cell division - mitosis and meiosis.

Mitosis: interphase- decondensed chromosomes replicate prophase- chromatin condenses into chromosomes prometaphase- nuclear envelope disappears metaphase- chromosomes align at the equatorial plate anaphase- sister chromatids separate & centromeres divide telophase- chromatin expands, cytoplasm divides Meiosis: MI- reductional division (diploid to haploid) P1- choosing over may occur MI- homologous chromosomes align at equatorial plate AI- homologous chromosomes separate MII- equatorial division, same as mitosis

Explain the application of genetic studies in medical practice.

Most, if not all, human diseases have a genetic component. A complete family genetic history can provide information that can be used to determine and individual's risk of future disease and thus enable development of preventative medicine strategies.

Granulomas in Crohn disease

Noncaseating

Discuss the mechanism of anemia of renal failure and how this differs from all other forms of anemia.

Normocytic normochromic anemia in CKD is caused by decreased synthesis of erythropoietin (EPO) by interstitial fibroblasts within the kidneys.

Recognize the clinical manifestations of sudden infant death syndrome (SIDS).

Occurs during presumed sleep (peak between 2 and 3 months); not familial, associated with young maternal age or unmarried, short intergestational intervals, low socioeconomic groups, smoking, drug abuse (methadone), African Americans, premature or low birth weight, males, not the first sibling or SIDS in a prior sibling

Explain how to differentiate polycythemia vera from reactive polycythemia due to chronic lung disease or paraneoplastic syndrome.

PV: ↓ erythropoietin (EPO); normal O2 saturation (SaO2) CLD: ↑ EPO; ↓SaO2 Renal cell carcinoma: ↑EPO; normal SaO2

Define penetrance & expressivity; give examples of each.

Penetrance: Some mutations may not be expressed in individuals carrying the mutation, although the presences of the mutation may be confirmed by the reappearance of the phenotype in the next generation; a population measure. E.g. neuroblastoma (Rb gene), breast cancer (BRCA1 gene) Expressivity: the same mutation may exhibit different phenotypes in different individuals; acts at the level of the individual and is likely due to modifying contributions of other genes and environments. E.g. holoprosencephaly

Outline the BASIC processes that produce primary and secondary hemostasis

Primary hemostasis: local neurohumor factors at injury site results in platelet adhesion, activation, and aggregation (platelet plug). Secondary hemostasis: synthesis of tissue factor results in initiation of clotting cascade, thrombin activation, and fibrin polymerization to strengthen the platelet plug.

Distinguish among the different causes of amyloidosis and the contexts in which they occur.

Primary: AL (amyloid light chain) protein produced by plasma cells; associated with multiple myeloma Secondary: AA (amyloid-associated) protein derived from SAA (serum amyloid-associated) protein that is synthesized in liver as part of acute phase response; associated with long-standing inflammation (TB, bronchiectasis, osteomyelitis, RA, inflammatory bowel, "skin-popping" narcotics) in those with an enzyme defect that results in incomplete breakdown of SAA or those with Familial Mediterranean fever

Compare the circulating life spans of red blood cells, neutrophils and platelets.

RBC: 120 days Neutrophils: 6-7 days circulating; 1-4 days in tissue Platelets: 7-10 days circulating

Discuss the role of reactive oxygen species and antioxidant defense system in cell injury.

Reactive oxygen species (free radicals) cause cellular injury via per oxidation of lipids and oxidation of DNA. Elimination of of free radicals occurs via antioxidants (e.g. glutathione, Vitamins A, C, & E), enzymes (superoxide dismutase in mitochondria, glutathione peroxidase in mitochondria, catalase in peroxisomes), or metal carrier proteins (transferrin and ceruloplasmin)

Compare the similarities and differences between regeneration and healing and offer examples.

Regeneration: proliferation of residual (uninjured cells) of labile tissues (HSCs, surface epithelia, exocrine gland ducts, columnar epithelium of the GI tract, uterus and fallopian tubes, and the transitional epithelium of the urinary tract)- residual epithelial cells produce growth factors, newly generated cells migrate to till the defect and tissue integrity is restored. Healing: Deposition of connective tissue to form a scar in tissue that cannot regenerate (permanent tissues i.e. cardiac, neurons)

Describe the genetic cause and clinical characteristics of Angelman syndrome.

Results from a pathogenic *loss of the maternal alleles* (through deletion, inversion, uniparental disomy) at 15q11-13. Because the paternal genes of the homologous chromosome are imprinted in this region (and thus normally silenced), the deletion of the maternal alleles gets rid of the only functional copies of the necessary genes. clinical characteristics: severe intellectual disability, developmental delay, speech impairment, gait, ataxia, *happy demeanor*, microcephaly and seizures may be present diagnosis may not occur until after first year or much later

How do you differentiated hemolytic anemia from anemia of diminished erythropoiesis?

Reticulocyte count; ↑RC ( > 3% corrected)= hemolytic, ↓RC= diminished erythropoiesis

Name and describe some important diseases that exhibit an X-linked dominant pattern of inheritance.

Rett syndrome- caused by mutations in the methyl CpG binding protein 2 (MECP2) gene at Xq28 with a small number of cases associated with the FOXG1 gene at 14q13 (locus heterogeneity); neurodevelopment disorder almost exclusively seen in females; characterized by *hand-wringing*, loss of speech, microcephaly, seizures, and mental retardation

Explain/describe the term cell cycle specificity and be able to classify anticancer drugs based on the cell cycle specificity.

S phase: Antimetabolites, Dactinomycin, & 5-FU (RNA synthesis inhibitors) G2-S phase: Epipodophyllotoxin & Camptothecins (topoisomerase inhibitors) G2-M phase: bleomycin M phase: taxanes, vinca alkaloids, Ixabepilone (microtubule inhibitors)

Antimetabolites

S-phase specific; 1. Anti-folates (methotrexate, pemetrexed): inhibit DHFR 2. Pyrimidine analogs (5-FU, Capecitabine): Inhibit TS 3. Cytidine analogs (Cytarabine, Gemcitabine): Inhibit DNA elongation/DNA synthesis and repair 4. Purine antagonist (6-MP, Fludarabine, Thioguanine): inhibits de novo purine nucleotide synthesis

Describe the Y chromosome - structure and function.

SRY= sex-determining region

Define paraneoplastic syndromes, and list six examples.

Symptoms not explained by local effects, metastasis or indigenous hormone production: 1. Endocrine: ectopic hormone production (e.g. Cushing syndrome or SIADH due to small cell carcinoma of the lung, hypercalcemia due to PTHrP secretion by squamous cell carcinoma of the lung) 2. Neuromuscular: myasthenia, peripheral neuropathies, CNS disorders 3. Dermatologic: acanthosis ngricans (maligna), dermatomyositis 4. Vascular/hematologic: thrombosis (Trousseau sign), anemia, polycythemia, thrombocytosis, DIC 5. Nephrotic syndrome- damage to renal BVs; protein in urine, edema of feet 6. Clubbing

Large granular lymphocytic leukemia

T cell and NK cell variants, both occur mainly in adults lymphocytes in the peripheral blood and bone marrow with abundant blue cytoplasm containing scattered coarse granules patients present with neutropenia and anemia NK-cell tumors are more aggressive

Discuss the clinical features, causes, and lab results seen in thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.

TPP is an inherited autoimmune disorder of the vWF cleavage enzyme ADAMTS13. ↓ADAMTS13 → accumulation of vWF-vWF-vWF → microthrombi → RBC schistocyte HUS is due to drug or infection classicaly in children w/ E coli O157:H7 dysentery → toxin damage endothelial cells → micro thrombi →RBC schistocyte Lab findings: thrombocytopenia with ↑ bleeding time, normal PT/PTT, anemia with schistocytes, ↑ megs on BM

Describe the extracellular matrix and explain it's role in tissue repair.

The ECM consist of the interstitial matrix between cells (made up of collagens and several glycoproteins), basement membranes underlying epithelia and surrounding vessels (made up of non fibrillar collagen and laminin). The ECM provides mechanical support to tissues (collagen & elastin); acts as a substrate for cell growth and the formation of tissue microenvironments; regulates cell proliferation and differentiation (proteoglycans bind growth factors and display them at high concentrations; fibronectin and laminin stimulate cells through their cellular intern receptors). An intact ECM is required for tissue regeneration, and if the ECM is damaged, repair can be accomplished only by scar formation

Discuss the mechanisms of liver regeneration.

The liver is an example of a stable tissue in which the cells are quiescent (G0) but can reenter the cells cycle to regenerate tissue when necessary.

Describe the mechanisms underlying triplet expansion disorders. Give examples of such disorders.

These disorders are characterized by expansion of triplet repeats in specific genes that affect the expression and/or function of the gene; expansion occurs during DNA replication (polymerase slippage or unequal crossing-over) resulting in progressive increases in triplet numbers; all of these genes have short, non-pathogenic repeat numbers in non-affected individuals; repeat numbers tend to increase with successive generations and severity of symptoms seems to increase with increasing numbers of repeats (genetic anticipation) Fragile X syndrome (expansion in meiosis I of female gametes), Huntington's disease (male meiosis), Myotonic dystrophy

A 25 year old man was admitted for hernia repair. Admission laboratory data were as follows: CBC and platelet count normal, ↑APTT, Factors VIII, IX, XI and XII are in the normal range.

This patient was deficient for prekallikrein; Contact system deficiencies (factor XII, HMWK, prekallikrein) do not pose any hemorrhagic risk.

Richter syndrome

Transformation of CLL/SLL to diffuse large B cell lymphoma

A 50-year-old woman returns to your oncology clinic for a follow-up visit. She is currently on a multidrug regimen for metastatic breast cancer. She appears to be responding well after the addition of a chemotherapeutic agent aimed at the HER-2/neu receptors within her cancer cells. While she is in the office, you schedule her for an imaging study to evaluate her heart. She asks why this test needs to be done and you remind her that, although the new medication is highly effective against her type of breast cancer, it can also cause cardiac dysfunction in up to 10% of patients.

Trastuzumab (Herceptin®)

Describe Histiocytoses.

Uncommon proliferative lesions of macrophages and dendritic cells. A special type of immature dendritic cell, the Langerhans cell, gives rise to a spectrum of neoplastic disorders referred to as the Langerhans cell histiocytoses.

Which coagulation factors are not synthesized in the liver? Where are they synthesized?

VIII and vWF; endothelial cells and megakaryocyes

A 12 year old boy underwent tooth extraction. Persistent bleeding followed. The history was remarkable for bruising and frequent epistaxis. The patient's mother also experienced easy bruising and menorrhagia. Physical examination revealed medium sized ecchymotic lesions on the lower extremities. Laboratory findings were as follows: ↑APTT, ↑BT, normal platelets, ↓FVIII, ↓vWF

Von Wildebrand disease

Describe the mechanism of action for Warfarin (Coumarin). What drug is used to reverse it?

Warfarin: Inhibits epoxide reductase; blocks the ɣ-carboxylation of factors II (prothrombin), VII, IX, X, and Protein C & S, thus rendering them inactive Protamine sulfate is used to reverse it's actions

Explain the mechanisms of gene dosage on the human X chromosome.

X chromosome inactivation- a random epigenetic event (no change in primary DNA sequence) dependent on the XIST gene which synthesizes a non-coding RNA that coats one X chromosme and blocks gene expression; results in the formation of a barr body (darkly staining heterochromatic region observed in interphase nuclei from female cells; the number of Barr bodies= # X chromosomes - 1 the X and Y chromosomes contain a homologous region (the pseudoautosomal region [PAR]) which escapes X chromosome inactivation

Which factor deficiency does not prolong the PT or PTT but may result in severe bleeding?

XIII (13)

Amyloidosis

a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar (misfolded) proteins are responsible for tissue damage and functional compromise diagnosed by Congo red dye and red-green birefringence

Recognize the clinical presentation of sarcoidosis and propose treatment for this disorder.

a multi system disease of unknown etiology characterized by noncaseating granulomas in many tissues and organs Bilateral hilar lymphadenopathy or lung involvement without smoking Eye & skin involvement occurs in 25% of cases treatment: steroid therapy

Adult T-Cell Leukemia/Lymphoma

a neoplasm of CD4+ T cells observed in adults infected by human T cell leukemia virus type 1 (HTLV-1); commonly in Japan and Caribbean characterized by skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and hypercalcemia PBS: "cloverleaf" or "flower cells"

Lofgren syndrome

a type of sarcoidosis found primarily in Danish and Swedish populations or African Americans in US presents as erythema nodosum with fever and lymphadenopathy; no granulomas present, just reactive inflammation

Name and describe the myeloid neoplastic proliferations of white cells

a. acute myeloid leukemias (AML): blasts accumulate in the bone marrow( > 20% blasts) b. myelodysplastic syndromes (MDS, tMDS): dysmaturation and ineffective hematopoiesis resulting in peripheral blood cytopenias ( < 20% blasts); may progress to AML c. myeloproliferative disorders (CML, PV, ET, myelofibrosis): increased production of differentiated myeloid elements (< 20% blasts) leading to elevated peripheral blood counts; may progress to AML

Recognize, compare, and contrast the patterns of acute and chronic inflammation.

acute inflammation is the immediate, limited (innate immunity) response that arises due to infection or tissue necrosis and is characterized by the presence of edema and neutrophils in tissue. chronic inflammation is the delayed, specific response (adaptive immunity) that arises due to persistent infection, viruses, mycobacteria, parasites, fungi, autoimmune disease, foreign material, and some cancer; characterized by lymphocytes and plasma cells in tissue

Describe the outcomes of acute and chronic congestion.

acute: pulmonary- alveolar septal edema and intra-alveolar hemorrhage; hepatic- central vein and sinusoids distended, reversible fatty change chronic: pulmonary- septa thickened, fibrotic, hemosiderin laden macrophages (heart failure cells); hepatic- central lobules red-brown (nutmeg liver) and slightly depressed, hemorrhagic necrosis, hemosiderin laden macrophages

Name the adult cancers curable by chemo alone and the curable cancers in children.

adult: Hodgkin's and non-Hodgkin's, AML, germ cell cancer, choriocarcinoma children: ALL, Burkitt's, Wilm's, embryonal rhabdomyosarcoma

Differentiate alkaline and acid hemoglobin electrophoresis.

alkaline: useful in screening for a sickle cell disease acid: used to diagnose sickle cell; can differentiate HbS and HbC

Differentiate allelic heterogeneity and locus heterogeneity.

allelic heterogeneity is when a range of clinical presentations exist due to the variety of possible mutations at different alleles in the *same gene*; often observed in recessively-inherited diseases where the mutations lead to LOF e.g. CFTR gene locus hetogeneity is when a particular clinical presentation can occur due to mutation in *two different genes*. e.g thalassemias and hemoglobin subunit genes

Describe the clinical presentation and morphology of Acute promyelocytic leukemia (AML-M3).

anemia: fatigue neutropenia: infections, fever thrombocytopenia: mucosal and cutaneous bleeding

Discuss the difference between arterial and venous thrombi and embolism.

arterial (mural thrombus): site of injury or turbulence; characterized by lines of Zahn; embolism is retrograde venous: sites of stasis; emboli in the direction of blood flow

Describe the clinical presentation and treatment of selected complications of cancer and cancer treatment d. Cancer-associated thrombosis

arterial thrombosis (stroke, MI) or venous thromboembolism (DVT, PE)- dyspnea, cough, wheezing, chest pain, tachycardia, limb swelling increased risk in cancer due to hypercoaguable state stimulated by neoplastic cells commonly seen in cancers of the pancreas, lung, stomach and lymphoma as well as chemotherapy (especially tamoxifen for breast cancer) DIC is seen with leukemia treatment/prevention: heparins or warfarin (outpatient)

Recognize specific morphologic features of dysgranulopoiesis.

atypical granulocytes with hypolobated nucle (Pseudo-pelger-huet cells), pelgeroid features, increased size, and hypo granular cytoplasm

Recognize specific morphologic features of dysmegakaryocytopoiesis.

atypical hypolobulated megakaryocytes

Recognize specific morphologic features of dyserythropoiesis.

atypical, multinucleate and bizarre red cell precursors; ringed sideroblasts

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: b. Lambert-Eaton myasthenic syndrome

autoantibodies attacj presynaptic voltage gated Ca channels of the NM junction; usually small cell lung cnacer presentation: weakness (proximal muscles most affected), lower extremity, difficulty rising from chair, climbing stairs, waddling gait, elevating arms, less respiratory and ocular involvement than MG treatment: treat underlying cancer, then immunosuppressive agents if necessary

Differentiate autosomal dominant vs autosomal recessive inheritance and name diseases that illustrate these patterns of inheritance.

autosomal recessive disorders are typically caused by loss-of-function mutations in genes encoding proteins with enzymatic activity. e.g. cystic fibrosis, phenylketonuria, alkaptonuria, homocystinuria, sickle cell anemia, tay-sachhs autosomal dominant disorders generally involve a gain-of-function mutation so that affected proteins acquire new functions or are deregulated. e.g. achondroplasia

Correctly name neoplasms based on tissue of origin and whether they are benign vs. malignant.

benign tumors: usually add suffix "-oma" malignant: epithelial tumors add "-carcinoma"; mesenchymal tumors add "-sarcoma"

Eosinophilic granuloma

benign unifocal and multifocal unisystem langerhans cell histocytosis found in older children (> 3 yo) and adults; associated with smoking; commonly spontaneously regresses upon cessation of smoking

A 69-year-old man presents to your clinic complaining of shortness of breath that has become progressively worse over the past month. He tells you that he was diagnosed with testicular cancer 4 months ago, for which he is currently on chemotherapy. Physical examination is significant for decreased oxygen saturation at 89% on room air and decreased air movement on lung examination. When imaging studies reveal pulmonary fibrosis, you begin to suspect that this patient's symptoms are likely related to (this drug) that is part of his chemotherapeutic regimen.

bleomycin

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: a. Hypercalcemia

both a complication of cancer AND the most common paraneoplastic syndrome; cancer complication: osteolysis induced by cancer- multiple myeloma or metastatic to bone paraneoplastic: production of parathyroid hormone related protein (PTHrP)- breast, lung (squamous cell carcinoma), renal, and ovary carcinomas presentation: constipation, nausea, anorexia, polydipsia, polyuria, bone pain, volume depletion, altered mental status; severity depends on time course, rapidly rising suspicious for malignancy treatment: STOP calclium supplements, vit D and diuretics; agressive fluid resuscitation, bisphosphates to inhibit osteoclasts and bone resorption

Name the cytokine most directly responsible for cancer cachexia.

cachexia= loss of body fat and lean body mass with anorexia, weakness, and anemia. mediated through TNF; NOT due to increased nutritional demands of tumor

TB granuloma

caseating with central necrosis

Differentiate a caseating and noncaseating granuloma

caseating: central necrosis (very pink center with no cells)

Describe the mechanism of apoptosis and give examples.

caspases activate proteases and endonucleases; proteases break down the cytoskeleton, endonucleases break down DNA. e.g. endometrial shedding during menstrual cycle, removal of cells during embryogenesis, CD8 T cell-mediated killing of virally infected cells

Discuss the pathophysiology of cystic fibrosis.

caused by mutations in the CFTR gene on chromosome 7 (commonly ΔF508)

Characterize the causes, laboratory diagnosis, and clinical significance of anemia of chronic disease.

causes: most common form of anemia in hospitalized patients; associated with chronic inflammation due to high levels of hepcidin (Il-6 → hepicidin) which surpassed erythropoietin synthesis by kidney (osteomyelitis, bacterial endocarditis, lung abscess, RA, regional enteritis, neoplasms, Hodgkin's lymphoma, carcinomas of lung and breast) lab diagnosis: ↓serum iron, ↑ferritin (Fe stores are high) ↓TIBC

Discuss the clinical features, causes, and lab results seen in disorders characterized by increased vascular fragility.

causes: nonthrombocytopenic purpuras caused by Acquired: Ag-Ab complexes to blood vessel wall (infection & drugs), scurvy, senile collagen atrophy, cushion's, amyloidosis, scleroderma, Henoch-Sconlein purpura Inherited: Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia., Marfan, osteogenesis imperfect, psuedoxanthoma elasticum lab results: normal PT/PTT. platelet count, and bleeding time

Lead poisoning

causes: older houses; more common in northern midwest to was coast in central cities symptoms: abdominal pain, learning disabilities (lower IQ), delayed growth and development, impaired hearing, seizure and coma lab findings: ↑serum Fe, ↑ferritin, ↓TIBC, ↑ZPP (FEP) treatment: Dimercaptosuccine acid (succimer; DMSA) or IM British anti-Lewisite (BAL)

Anaplastic large cell lymphoma

characterized by large anaplastic cells, some of which contain horse-shoe shaped nuclei strong association with rearrangements involving the ALK gene t(2;5); associated with children and young adults, better prognosis

Compare and contrast Trisomy 13, 18, and 21. Why are these compatible with life?

chromosome 13, 18, and 21 are gene poor, allowing for 3 copies to be compatible with life trisomy 13 (Patau syndrome): 50% die by 1 mo., 75% die by 6 mo.; patients characterized by cleft lip/palate, polydactyly, microphthalmia trisomy 18 (Edwards syndrome): 90% die by 1 year; characterized by rocker bottom feet, micrognathia, overlapping clenched fingers, large occiput trisomy 21 (Down syndrome): mental retardation, epicanthal folds, simian crease, ASD, ALL, duodenal actress, celiac

Identify the pathologic features of Wilm's tumors.

classic triphasic pattern with blastemal, stromal and epithelial cell types; if blastemal is predominant, the prognosis is good; if anaplasia, the prognosis is bad

Discuss the clinical features, causes, and lab results seen in DIC.

clinical presentation: microangiopathic hemolytic anemia, dyspnea, respiratory failure, convulsions, oliguria, acute renal failure, progressive circulatory failure, shock causes: acute- infection, obstetric complications, trauma, transfusion of ABO incompatible RBCs, liver disease; chronic- malignancy, retained dead fetus, liver disease, severe localized intravascular coagulation lab: ↓platelet count, ↓fibrinogen, ↑PT/PTT, ↑D-dimer

Compare myeloblast (AML) and lymphoblasts (ALL).

compared to myeloblast, lymphoblasts have: 1. condensed chromatin 2. inconspicuous nucleoli 3. scant granular cytoplasm

Describe normal/reactive lymph node histology.

cortex: follicles → naive B cells; mantle zone → small naive B cells, marginal zone paracortex between follicles → T cells medulla: plasma cells and few lymphocytes

Anti-tumor antibiotics

create oxygen free radicals, causing single and double-stranded DNA breaks 1. Bleomycin- accumulation in G2, treats germ cell cancer (testicular) 2. Doxorubicin 3. Daunorubicin 4. Idarubicin- AML (1st line w/ Cytarabine) A/E: cardiotoxicity in anthracyclines (-ubicin's); pulmonary fibrosis in Bleomycin

Describe (generally) the maturation of myelocytes.

decreasing N:C ratio, diminishing nucleolus (erythrocyte loses nucleus) , condensing chromatin

A 66 year old man with a diagnosis of amyloidosis was admitted to the hospital with severe gastrointestinal bleeding. Admission laboratory data included: Anemia due to chronic blood loss, ↑PT, ↑APTT, normal factors II, V, IX, and XI

deficiency factor X; common in amyloidosis; prolonged PT and PTT because X is part of common pathway

A 79 y.o. female was admitted for minor surgery. She had no bleeding problems and had no personal or family history of bleeding problems. Routine pre operative testing revealed: ↑PTT, TT corrected by mixing studies

deficiency in the contact system; no need to stop surgery

Describe the biological features of neuroblastoma.

deletion in the short arm of chromosome 1 (1p) that causes N-myc amplification (double minutes); the more amplification, the worse the prognosis

Identify the pathologic features neuroblastomas.

derived from primitive neural crest cells; sheets, nodular aggregates of uniform small cells (small round blue cell tumors of childhood); homer-wright pseudorosettes (pictured); ganglion cells= ganglioma neuroblastoma

Identify the pathologic features of cystic fibrosis.

diagnostic tests: sweat test- increased [Cl > 60 mmol/L]; baby tastes salty; false positive in severe malnutrition, glycogen storage disease, mucopolysaccharidoses, ectodermal dysplasia, diabetes insidious and hypothyroidism genetic testing- prenatal, neonatal, postnatal

Who should you prophylax with iron?

dialysis patients

Auer rods

differentiate myeloblasts from lymphoblasts; commonly associated with AML

Peripheral T-cell lymphoma (unspecific)

diffuse effacement of the lymph node architecture by a pleomorphic picture of small and large malignant T cells that express CD2, CD5, CD3, and α:β or ɣ:δ T cells, +/- CD4 or CD8, lack TdT presents clinically as generalized lymphadenopathy, sometimes eosinophilia, pruritus, fever, and weight loss

Megaloblastic anemia

diminished erythropoiesis ( ↓RC) cause: impaired DNA synthesis due to B12 (cobalamin) and folate deficiency; alcoholics, pregnancy + gastrectomy, tapeworms, chrohns for B12 clinical presentation: pancytopenia PBS: dyserythropoiesis, hypersegmented neutrophils, anisocytosis, macroovalocytosis

Aplastic anemia.

diminished erythropoiesis ( ↓RC) cause: often idiopathic, the rest of the ages are known etiologies as exposure to drugs, irradiation, viral infections, and inherited as Fanconi anemia marrow aspirate yields a "dry tap", ABSENT splenomegaly treatment: immunosuppressive therapy to stop T cell attack or bone marrow transplant

Characterize the causes, laboratory diagnosis, and clinical significance of iron deficiency anemia.

diminished erythropoiesis ( ↓RC) causes: dietary, chronic blood loss, impaired absorption, increased requirement laboratory diagnosis: ↓ferritin; ↑TIBC; ↓serum iron, ↑ free protoporphyrin microcytic, hypochromic (increased central pallor)

Describe the mechanisms underlying mitochondrially-inherited disorders. Give examples of such disorders.

disorders associated with mutations in mitochondrial genes display almost exclusive maternal inheritance due to the high ratio of mitochondria from the egg; all mitochondrial genes may be identical (homoplasmy) or they may vary due to mutations (heteroplasmy); the severity of the phenotype of a particular mitochondrial mutation can vary depending on the relative proportion of mutant vs non-mutant mitochondria Leber's hereditary optic neuropathy (LHON), Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Myoclonic epilepsy ragged red fibers (MERRF)

A 14-year-old boy presents to your office for initiation of chemotherapy to treat his acute lymphoblastic leukemia. You explain to the boy and his mother that you will be using several different chemotherapy agents to treat his disease. One of the agents you will be administering acts by blocking DNA and RNA synthesis; however, this drug also causes the production of oxygen free radicals, which can damage cardiac tissue when given at high doses. In order to avoid this rather serious side effect, you will carefully monitor levels of the drug so as to avoid cardiac toxicity if possible

doxorubicin

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: c. Cushing syndrome

due to ectopic production of ACTH or ACTH-like peptide commonly due to small-cell lung cancer, bronchial carcinoid tumors presentation: hypertension, glucose intolerance, central obesity, buffalo hump, moon face, thin extremities treatment: remove or reduce tumor mass, removal of adrenal glands may help

Discuss the concept of anticipation.

earlier onset of disease and more severe phenotypes in successive generations. e.g. triple repeats

Define and differentiate edema, hyperemia and congestion.

edema: accumulation of fluid within tissue. hyperemia: redness of tissue due to arteriolar dilation and increased blood flow (active) congestion: systemic or local diminished outflow of venous blood resulting in cyanosis (passive)

Define genomic imprinting.

epigenetic modification (methylation) of specific genome regions that modulate gene expression based on parental origin of chromosomes so that only one chromosome's (the NON-imprinted) allele's are expressed; maternally imprinted means that maternal genes are not expressed, paternally imprinted means that paternal genes are not expressed.

Myelophthisic anemia

expensive replacement of marrow by tumor or other lesions; commonly metastatic breast, lung, prostate , TB, lipid storage disorders, osteosclerosis PBS: anemia, thrombocytopenia, leukoerythroblastosis (immature cells-myelocytes and nucleated RBCs) and tear drop cells

Differentiate exudate from transudate.

exudate: cellular (cloudy), high protein content, may contain some white and red cells due to inflammation/infection (vasodilation & stasis, increased interendothelial spaces); specifically gravity > 1.020 transudate: hypocellular (clear) low protein content, few cells due to increased hydrostatic pressure (venous outflow obstruction like in CHF) or decreased colloid osmotic pressure (decreased protein synthesis due to liver disease, increased protein loss due to kidney disease, or malnutrition); specific gravity < 1.012

Contact system

factors of the intrinsic pathway- factors XII (Hageman factor), prekallikrein, high molecular weight kininogen (Fitzgerald factor); all made in the liver; decreased activity with liver disease, newborns, antiphospholipid syndrome, asian descent (XII); homozygous deficiencies are rare (AR); cause prolonged PTT but no bleeding disorders or hyper coagulability; do NOT need to measure or monitor for surgery

How do you measure total body stores of iron vs that found in the blood.

ferritin= total body stores TIBC= measures transferrin (carrier of blood iron)

Which lymphomas/leukemias are CD10+?

follicular lymphoma caused by t(14;18) and Burkitt's lymphoma (aggressive) caused by t(8;14)

Describe the formation of granulomas and name some causative agents.

form of chronic inflammation in which macrophages present Ag via MHC II to CD4 T cell leading macrophages to secrete IL-12 which induces TH1 differentiation and IFN-g which converts macrophages to epitheliod histiocytes (macrophages with abundant pink cytoplasm); usually surrounded by giant cells and rim of lymphocytes; noncaseating lack central necrosis (e.g. rxn to foreign material, cat-scratch disease, sarcoidosis, crohn disease); caseating with central necrosis (e.g. TB, leprosy, fungi, syphilis)

Mixed cellularity Hodgkins lymphoma

form of classical HL more common in males and strongly associated with EBV, older age, and systemic symptoms diffuse effacement by a heterogeneous cellular infiltrate which includes small lymphocytes, *Eosinophils*, and benign macrophages with neoplastic cells

Marginal zone lymphoma

group of small B cell tumors that arise within the lymph nodes, spleen, or extra nodal sites associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis (may regress with treatment of H pylori)

Define extramedullary hematopoiesis and discuss its significance.

hematopoiesis occurring outside of the medullary cavities of bone when the marrow can't keep up; often in embryonic sites such as the liver, spleen & thymus; may lead portal hypertension (ascites, esophageal varcies) or splenomegaly

Describe the role of hepcidin in the regulation of iron.

hepcidin works on ferroportin receptors in: 1. hepatocytes- prevents release of iron from stores (ferritin) 2. ernterocytes- prevents iron uptake 3. macrophages- prevents iron recycling from phagocytosed RBCs

Vorinostat

histone deacetylase inhibitor used in cutaneous T cell lymphoma

Describe the differences among hyperplasia, hypertrophy, atrophy, and metaplasia.

hypertrophy: an increase in cell size (mass) due to increased stress; involves gene activation, protein synthesis, and production of organelles. hyperplasia: an increase in cell number; production of new cells from stem cells. atrophy: a decrease in organ size due to decreased stress; decrease in the number of cells via apoptosis; decrease in the size of cells via ubiquitin-proteasome degradation of cytoskeleton and autophagy of cellular components. metaplasia: a change in the stress on an organ leads to a *reversible* change in cell type; may progress to dysplasia and eventually cancer (EXCEPT apocrine metaplasia of the breast)

Recognize hyperplasia, hypertrophy, atrophy, and metaplasia and give examples.

hypertrophy: permeant tissues (cardiac muscle, skeletal muscle, nerves) can ONLY undergo hypertrophy and NOT hyperplasia. i.e. growth of cardiac myocytes in response to hypertension, skeletal muscle in weight lifting hyperplasia: hormonal (e.g. glandular epithelium of breast during puberty, HPV wart, gingival overgrowth), compensatory (e.g. liver regrowth) may progress to dysplasia and eventually cancer (i.e endometrial hyperplasia) EXCEPT benign prostatic hyperplasia (BPH) which does NOT increase the risk of prostate cancer. atrophy: decreased hormonal stimulation, disease, or decreased nutrients/blood supply (e.g. menopause, fracture healing, testicular) metaplasia: Barrets esophagus- squamous epithelium to columnar epithelium to better handle the stress of acid in the esophagus; Vitamin A deficiency- the thin squamous lining of the conjunctiva undergoes metaplasia into keratinizing squamous epithelium (keratomalacia); smokers- ciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratified squamous cells

Describe the mechanism of the tumor suppressor RB. In what state does it activate or inhibit the cell cycle?

hypophosphorylation= inhibition of cell cycle hyperphosphorylation= activation of the cell cycle

A 9-year-old boy has developed prominent bruises on his extremities over the past week. On physical examination, he has ecchymoses and petechiae on his arms and legs. Laboratory studies show hemoglobin 13.8 g/dL, hematocrit 41.9, MCV 93, platelet count 22,300/mm3, and WBC count 7720/mm3. He had respiratory syncytial virus pneumonia 3 weeks ago. His condition improves with corticosteroid therapy. What is the most likely cause of his problem?

immune thrombocytopenia purpura (ITP)

Be familiar with some of the ancillary techniques used in tissue diagnosis, such as immunohistochemistry, flow cytometry, cytogenetics, and molecular methods.

immunochemistry: special stains of tissue sections using monoclonal Abs to detect cell-specific Ag. Used for characterizing lymphomas and poorly differentiated tumors, identifying source of metastatic tumor or presence of antigens of therapeutic significance molecular pathology: for detection of gene rearrangements to aid diagnosis or predict prognosis, detection of minimal residual disease, or familial predisposition to certain cancers cytogenetics: certain chromosomal abnormalities can aid in diagnosis or have prognostic significance flow cytometry: monoclonal Abs detect surface cytoplasmic cell-specific Ags to aid in diagnosis, especially for leukemias and lymphomas *cytogenetics and flow cytometry require fresh, non-fixed tissue

Describe the clinical presentation and treatment of selected complications of cancer and cancer treatment c. Anorexia/cachexia

in patients with cancer, the basal metabolic rate is increased despite reduced food intake; due to TNF-α; no treatment besides removal of tumor

Describe the effects of inbreeding on allele distribution.

inbreeding increases the chance that offspring will inherit common alleles from both parents

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: e. Polycythemia

increased RBC mall caused by tumor secretion of erythropoietin (EPO) as seen in renal carcinomas presentation: plethora, splenomegaly (uncommon) diagnosis: elevated EPO levels treatment: treat underlying disease

Monoclonal gammopathy of undetermined significance (MUGS)

increases serum protein with M spike on SPEP; other features of multiple myeloma are absent (no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteins) common in elderly 1% progress to MM per year

Discuss the clinical indications of bone marrow biopsy and aspirate examination. What information can each show you?

indications: 1. unexplained cytopenias 2. atypical circulating cells 3. hematological neoplasias biopsy: immunohistochemistry aspirate: morphology, iron stain, myeloid: erythroid (M:E) ratio, flow cytometry for markers, cytoplasm

Recognize infectious and noninfectious etiologies of granulomatous reactions

infectious: 1. TB (caseating) 2. leprosy (noncaseating) 3. syphilis (caseating Gumma) 4. cat-scratch disease non-infectious: 1. Autoimmune (RA, SLE, Chrohns)- noncaseating 2. Sarcoidosis (noncaseating) 3. Prolonged exposure to toxic substances (silica, atherosclerosis lipids) 4. Foreign body rxn 5, Pyogenic (pregnancy tumor)- richly vascular lobular capillary hemangioma

Mitochondrial inheritance pedigree analysis.

inheritance from mothers only

G6PD deficiency

intracorpuscular hemolytic disorder cause: X-linked recessive resulting in reduced half life of G6PD; hemolysis due to oxidant stress PBS: bite cells & Heinz bodies (diagnostic)

Paroxysmal nocturnal hemoglobinuria (PNH)

intracorpuscular hemolytic disorder cause: acquired defect in myeloid stem cells resulting in absent GPI → No DAF, rendering cells suceptible to compliment (especially at night due to ↓pH) clinical presentation: hemoglobinuria (especially in morning) Diagnosis: sucrose screening and Ham's test; lack of CD55 & CD59 on flow cytometry

Intrinsic pathway

involves factors XII (Hageman factor), XI, IX, VIII, prekallikrein, high molecular weight kininogen merges with extrinsic pathway to form common pathway activated when factor XII ends negatively charged "foreign" surface exposed to blood sequentially activates factors XI, IX, X, then factor II (prothrombin to thrombin) which converts fibrinogen to fibrin

Describe how to differentiate iron deficiency anemia from anemia of chronic disease.

iron deficiency: ↓ferritin, ↑TIBC chronic disease: ↑ferritin, ↓TIBC (trying to sequester iron, thus ↑ stored iron and decrease bound)

Lymphocyte-depletion Hodgkins lymphoma

least common form of HL (classical) characterized by a paucity of lymphocytes and a relative abundance of RS cells predominantly in older patients, HIV +, and often EBV associated most aggressive

Describe the classic peripheral blood findings in patients with CML, and how they are different from reactive processes.

leukocytosis ( often > 100,000); predominantly neutrophils, band forms (left shift), metamyelocytes, myelocytes, eosinophils and basophils

Recognize the peripheral blood and BM findings in the fibrotic stage of primary myelofibrosis.

leukoerythroblastosis- release of nucleated erythroid and early granulocyte progenitors teardrop-shaped red cells (dacrocytes)

Differentiate leukemia and lymphoma.

lymphoma: confined to a mass lesion without any or minimal evidence of blood or marrow involvement leukemia: extensive blood or marrow involvement

What mediates the outcomes of acute inflammation? Describe the possible outcomes.

macrophages: 1. resolution and healing- anti-inflammatory cytokines (IL-10 & TGF-β) 2. continued inflammation (IL-8 mediated pus) 3. abscess 4. chronic inflammation (present Ag to CD4 T cells)

Lymphocyte predominant Hodgkin lymphoma

males < 35 yo present with cervical or axially lymphadenopathy NOT associated with EBV more likely to recur but prognosis is excellent characterized by a nodular infiltrate of lymphohistocytic (L&H) variants, small lymphocytes with variable numbers of histiocytes

Letterer-Siwe disease

malignant multifocal multisystem Langerhans cell histiocytosis occurs before 2 years of age a rapidly fatal disease involving cutaneous lesions resembling seborrheic eruption, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and eventually osteolytic bone lesions

Multiple myeloma

malignant proliferation of plasma cells in the bone marrow punched-out bone lesions (especially in vertebrae & skull) → hypercalcemia, monoclonal Igs (IgG, IgA) detected by abnormal spike in serum urine → recurrent infections, renal failure, Bence jones proteinuria, AL amyloidosis BM: ↑plasma cell # PBS: rouleaux formation

Histological changes in an alcoholic liver

mallory body: intracellular accumulations of fibrillar material steatosis- fatty change

Describe chromosome nondisjunction in mitosis, Meiosis I, and Meiosis II.

mitosis- during the first cell division of the embryo (zygote)= full Down syndrome; during the second cell division= three different cell types (monosomic, normal, trisomic). The monosomic cells don't survive and a mosaic individual results. Clinical consequences are dependent on the proportion of normal and trisomic cells. No risk for future offspring. Meiosis I- all gametes abnormal Meiosis II- 50% gametes normal

Describe the PTT mixing study. What two conditions does it help distinguish?

mix the patients plasma with normal plasma; if the PTT ratio is 1:1 (corrected), this indicates a factor deficiency that was corrected by the factor found in the normal plasma. If the ratio is not corrected, this indicates an inhibitor effect (antibody/anticoagulant)

Precursor B-cell leukemia/lymphoblastic lymphoma

more common than T cell; typically manifest as childhood leukemias characterized by lymphoblasts (TdT+) that express CD10, CD19, and CD20 excellent response to chemo; prophylaxis to scrotum and CSF t(12;21) has a good prognosis; t(9;22) has a poor prognosis

von Willebrand's disease

most common bleeding disorder; 3 main types type I- most common; AD; Quantitative decrease in vWF; mild with excessive bleeding after surgery or trauma Type II- rare, AD, Qualitative (normal levels of vWF but dysfunctional Type III- AR, Quantitative ↓ vWF, ↑PTT (type I and III due to association with VIII), normal platelet count, ↑ bleeding time ; ristocetin test is diagnostic

Recognize the clinical manifestations of neuroblastomas.

most common childhood extra cranial solid tumor: 50% abdominal (25-35% adrenal); 14% thoracic (posterior mediastinum) younger children: large abdominal mass, fever, weight loss, localized disease often asymptomatic older children: 1/3 present with metastases

Follicular lymphoma

most common form of indolent NHL in US neoplastic proliferation of B cells that express CD19, CD20, CD10, BCL-2 driven by t(14;18) that leads to over expression of BCL-2 (inhibits apoptosis in follicle) → painless lymphadenopathy

Extranodal NK/T-cell lymphoma

most commonly present as a destructive midline mass involving the nasopharynx or less commonly the skin or other extranodal sites such as the testis tumor cell infiltrate surrounds and invades small vessels, leading to extensive ischemic necrosis most tumor cells express NK cell markers and are EBV related agressive and respond poorly to therapy

Distinguish similarities and differences among necrosis, apoptosis, and cellular aging.

necrosis is cell murder caused by some underlying pathological process that results in death of large groups of cells followed by acute inflammation. apoptosis is cell suicide by an ATP dependent, genetically dependent mechanism involving single cells, NOT followed by inflammation. cellular aging: Accumulation of mutations in DNA compromises functional activities and cell survival; decreased cellular replication - cells reach replicative senescence after a fixed number of divisions due to progressive shortening of telomeres which ultimately results in cell cycle arrest.

Hodgkin lymphoma

neoplastic proliferation of Reed-Sternberg cells, which are large B cells with multi lobed nuclei and prominent nucleoli (owl's eye)

Acute leukemia

neoplastic proliferation of blasts; >20% blasts crowd out normal hematopoiesis, resulting in abrupt anemia (fatigue), neutropenia (fever, infection), thrombocytopenia (bleeding), bone pain, lymphadenopathy, splenomegaly, testicular and CNS involvement (ALL)

Burkitt lymphoma

neoplastic proliferation of intermediate-sized B cells that express CD19, CD20, CD10, BCL6 & LACK TdT; 3 forms: 1. African (endemic)- involves the jaw; latent EBV 2. Sporatic (non endemic)- abdomen 3. HIV associated PBS: high mitotic index → "starry sky" driven by t(8;14); c-myc to IgHC promotes cell growth

Diffuse large B cell lymphoma

neoplastic proliferation of large B cells that express CD19 and CD20 with variable expression of germinal center markers CD10 and BCL6 presents in late adulthood as rapidly enlarging, often symptomatic mass at single node or extra nodal site diffuse sheets of large cells on PBS poorly differentiated/ aggressive

Mycosis Fungoides/Sézary Syndrome

neoplastic proliferation of mature CD4 T cells that infiltrate the skin producing localized skin rash, plaques, and nodules infiltration of the epidermis and upper dermis by neoplastic T cells (Sezary cells), which have nuclei with a cerebriform appearance due to marked infolding of the nuclear membrane

Mantle cell lymphoma

neoplastic proliferation of small B cells (CD20, CD19, CD5, LACKS CD23) that expands into the mantle zone presents in late adulthood with a painless lymphadenopathy driven by t(11;14); Cyclin D1 to IgHC promotes G1/S transition in cell cycle, facilitating neoplastic proliferation poor prognosis mnemonic: 14-11=3

Describe the techniques for detecting chromosome aneuploidies.

non-invasive: prenatal screening (ultrasound, nuchal translucency), NEW cell free DNA screening in maternal plasma invasive (isolate cells by amniocentesis or chorionic villus sampling)

Identify the histololgy of sarcoidosis.

noncaseating epithelia granulomas with a thin layer of laminated fibroblasts peripheral to the granuloma; eventually replaced with a hyalinized scar; Schumann bodies (laminated concretions of Ca and proteins) Asteroid bodies (pictured)- stellate inclusions within giant cells

Explain how one person can get 5 X chromosomes.

nondisjunction in both maternal Meiosis I and Meiosis II

Describe the clinical presentation and treatment of selected complications of cancer and cancer treatment e. Tumor lysis syndrome

occurs in malignancies with a high proliferative rate (i.e. aggressive lymphomas or leukemias) usually after initiation of cytotoxic therapy; oncologic emergency massive tumor cell lysis releases large amounts of potassium, phosphate, and nucleic acids into the blood; rapidly increases uric acid production; uric acid precipitates in renal tubules leading to acute renal insufficiency diagnosis: hyperuricemia, hyperkalemia, hyperphosphatemia, HYPOcalcemia treatment/prevention: aggressive hydration, allopurinol or rasburicase (to prevent renal insufficiency)

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: d. SIADH

occurs in small-cell lung cancer or thyme (secretes ADH) presentation: asymptomatic if chronic; acute can result in brain swelling, lethargy, weakness, seizures, coma, and death (Na < 125) diagnosis: hyponatremia ( < 135), normotensive, euvolemic (no edema, dry mouth or reduced skin turgor) treatment: fluid restriction, vasopressin receptor antagonist if refractive

Name the common etiologies of basophilic leukocytosis

often indicative of myeloproliferative disease (CML)

Identify representative cancer associated oncogenes.

oncogenes: growth factors, growth receptors (RET, MET) proteins involved in signal transduction (RAS, ABL, JAK, NOTCH) or nuclear regulatory proteins (cyclin-CDKs, MYC)

Name the specific treatment for iron deficiency anemia. What are some adverse side effects of treatment?

oral iron (ferrous gluconate, ferrous sulfate); absorption can increase with Vitamin C; stools can turn black IV iron can be given as a backup if orly does not work but watch out for anaphylaxis (give a test dose)

Use the Hardy-Weinberg principle (HWP) to calculate allele and genotype frequencies.

p + q = 1; where p is the frequency of the dominant allele and q is the frequency of the recessive allele p² + 2pq + q² = 1; where p²= the frequency of homozygous dominant genotype, 2pq= heterozygous, and q²= heterozygous recessive

Discuss the physiologic and pathological mechanisms of free radical generation. Which free radical is most damaging?

physiologic: cytC oxidase (complex IV in ETC) transfers electrons to oxygen → partial reduction of O2 yields superoxide, hydrogen peroxide, and hydroxide (most dangerous) radicals pathogenic: 1. ionizing radiation (OH radicals), 2. inflammation (NADPH ox. generates superoxide ions during O2 dependent killing by neutrophils), 3. metals (Fenton rxn- Fe generates hydroxyl free radicals), 4. drugs and chemicals (liver metabolism of carbon tetrachloride & acetaminophen), 5. reperfusion injury (increased troponin after MI)

Plasmacytoma

plasma cell neoplasms presenting as a solitary lesion of either bone or soft tissue; bony lesions occur in the same locations as multiple myeloma (progression to multiple myeloma is common), extra osseous lesions in lungs, oronasopharynx, or nasal sinuses

Lines of Zahn

platelet and fibrin deposits alternating with RBC-rich layers; form ONLY in flowing blood (arterial); distinguishes premortem from postmortem clots

Discuss the major causes of thrombocytopenia and give examples.

platelets < 100,000 1. Decreased production (defective DNA synthesis): aplastic anemia, leukemias, B12 & folate deficiencies 2. Decreased survival: autoimmune (ITP) or mechanical injury 3. Sequestration (hypersplenism) 4. Dilutional (massive transfusion)

Leber's hereditary optic neuropathy (LHON)

presentation: bilateral, painless visual loss usually during young adult life. Blurry vision followed by loss of central vision in one eye, followed by a similar process in the other eye. Antioxidant therapy may slow progression. mutation in mtDNA genome in components of NADPH dehydrogenase complex (subunit 1) gender bias 4:1 male:female

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)

presentation: multisystem disorder with typical onset in childhood. initial symptoms- generalized tonic-clonic seizures, recurrent headaches, anorexia, recurrent vomiting Mt-TL1 mutation encoding tRNA-Leu

Myoclonic epilepsy ragged red fibers (MERRF)

presentation: myoclonus (involuntary muslce twitching), followed by ataxia, epilepsy, weakness and demtia, muscle biopsy reveals "ragged red fibers" when stained with Gomori Trichome. Onset is early in childhood mutation in Mt-TK gene encoding tRNA-Lys

Hairy cell leukemia

primarily a disease of middle-aged Caucasian males neoplastic proliferation of mature B cells (CD19, CD20, CD25, CD103, Κ or λ light chain) characterized by hairy cytoplasmic processes PBS: round or reniform nuclei and modest amounts of pale blue cytoplasm, often with web like extensions (hair) BM: diffuse interstitial infiltrate (dry tap) splenomegaly; splenic red pulp is infiltrated lymphadenopathy usually absent

Describe the untreated natural progression of primary myelodysplastic syndromes.

primarily a disease of the elderly (70 yo); normally asymptomatic symptomatic: weakness, infections, hemorrhages The more blasts, the higher the risk of progression to AML; t-MDS have more severe progression

Differentiate the clinical presentation and prognosis of primary and secondary amyloidosis.

primary (AL): more often involves the heart, GI & respiratory tract secondary (AA): secondary to chronic inflammatory disorders, involves the kidneys, liver, spleen, and lymph nodes; worse prognosis in both: organs appear gray, waxy, and firm

Compare the similarities and differences between wound healing by first intention and wound healing by second intention and relate examples.

primary intention: wound edges are brought together leading to minimal scar formation (e.g. surgical incision) secondary intention: edges are not approximated; granulation tissue fills the defect; myofibroblasts then contract the wound, forming a scar (requires collagen-vitamin C, copper, zinc) e.g. contracture

Describe a histologic feature which favors primary tumor from a metastatic lesion.

primary tumor is normally found as 1 large tumor vs metastatic lesion which is normally discovered as multiple tumors at once

Immune thrombocytopenic purpura (ITP).

primary: 1. acute- children; post viral; self-limiting 2. chronic- IgG autoantibodies against GPIb or GPIIb/IIIa; adult females, treat w/ corticosteroids and/or splenectomy; lab findings- ↓platelets, ↑megs in MB, normal PT/PTT, large platelet on PBS secondary: SLE, HIV, post viral, drug (Quinidine,quinine, Rifampin, Oral, antidiabetics, sulfonamides drugs)

Differentiate disorders of primary hemostasis from secondary hemostasis.

primary: due to platelet deficiency or dysfunction; characterized by immediate bleeding or petechiae normally superficial at single sites; PT/PTT will be normal secondary: due to coagulation cascade or its regulation; characterized by late deep bleeding (hematoma or hemarthrosis), normally at multiple sites; PT/PTT will decrease according to which coagulation pathway is effected

Name and describe plasma cell disorders.

proliferation of a B cell clone that synthesizes and secretes a single homogenous Ig or its fragments; the monoclonal Ig in blood= M component 1. Multiple Myeloma- IgG/IgA 2. Plasmacytoma 3. Monoclonal gammopathy of undetermined significance (MGUS)- M-spike 4. Lymphoplasmacytic lymphoma (Waldenstrom)- IgM

Bortezomin

protease inhibitor used to treat multiple myeloma as combination therapy

Describe what happens to the nucleus leading to cell death.

pyknosis (condensation) → karyorrhexis (fragmentation) → karyolysis (fading)

Describe the clinical presentation, diagnosis, and treatment of selected paraneoplastic syndromes: f. Acromegaly

rarest type of paraneoplastic syndrome growth hormone releasing hormone more than growth hormone; seen in carcinoid tumors (neuroendocrine origin) hands, feet, and face increase in size- protruding jaw, enlarged nose, thicker lips

Define cellularity. What is normal percent cellularity in bone marrow and what does increase or decrease in % cellularity indicate?

ratio of cells to fat in BM; 65% cellularity is normal but varies by age (100% at birth, 30% in elderly); In response to anemia, there is hyperplasia which can increase the % cellularity to a certain extend. A % percent cellularity can indicate a defect in production (aplastic anemia)

Understand the pathophysiology of hypercoagulable states.

recurrent DVT's or DVT's at a young age due to excess procoagulant proteins or defective anticoagulant proteins (proteins C or S); may be inherited or acquired.

Describe the clinical presentation and treatment of selected complications of cancer and cancer treatment b. Superior vena cava syndrome

results from obstruction of blood blow by compression or invasion of the SVC; usually due to metastatic disease in adjacent lymph nodes; lung cancer is a major cause followed by lymphomas mediastinal widening and pleural effusion seen on chest x-ray treatment: cure cancer, head elevation, glucocorticoids, diuretics

Describe the genetic cause and clinical characteristics of Prader-Willi syndrome.

results from the combination of the normally imprinted and inactive maternal genes in the 15q11-13 region along with a *loss of the paternal* homologues (through deletion, inversion, or uniparental disomy) in the same region. Imprinting of the maternal alleles along with loss of the same paternal alleles means there is no functional copy of specific genes in that region, leading to the syndrome. early signs: failure to thrive (hypotonia affects ability to suck); later signs (1-6 years old): increased interest in food (obesity), hypogonia, mild intellectual disabilities, behavioral issues such as tantrums and stubbornness, distinctive facies (narrow, almond-shapped eyes, mall mouth, thin upper lip, full cheeks)

Describe the phases of cellular injury.

reversible: the initial phases of cellular injury marked by *cellular swelling*; cytosol swelling results in loss of microvilli and membrane blebbing; ribosomal detachment & decreased protein synthesis irreversible: eventually the damage becomes great enough to cause *membrane damage*; PM damage results in enzyme leaking and Ca entering cell; mitochondrial damage results in loss of ETC and cytC activates apoptosis; lysosomal damage results in hydrolytic enzymes leaking into the cytosol which are in turn activated by Ca; all of these lead to cell death

Use the Hardy-Weinberg principle (HWP) to calculate risk.

risk of having an affected child= the mother's risk (1 if she is a carrier) X the father's risk (=frequency of heterozygote in pop. if unknown) X risk of the child (punnet square)

Discuss population-wide screening processes, including ethical aspects of such screens.

screening was designed to identify adults at risk of developing diseases such as cancer: 1. colonoscopy- colon cancer 2. mammography- breast cancer 3. Pap smear- cervical cancer 4. Digital rectal exam & PSA- prostate cancer such tests seek to catch dysplasia before it becomes carcinoma or carcinoma before clinical symptoms arise.

What is the PTT test useful for? What prolongs it?

screens the activity of proteins in the intrinsic pathway; useful to monitor the efficacy of heparin therapy for acute thrombosis or embolism prolonged in: 1. common pathway defect 2. heparin use 3. factor deficiency 4. DIC

Describe the clinical presentation and treatment of selected complications of cancer and cancer treatment a. Cord compression

second most common neurological complication after brain metastases; breast, lung, prostate, multiple myeloma back pain, gradually worsening around the level of involvement (70 % thoracic, 20% lumbosacral, 10% cervical); neurological signs- motor weakness, sensory deficit less common, bowel and bladder incontinence and urinary retention are late findings treatment: corticosteroids, surgery, radiation, or both

Differentiate sensitivity & specificity in regards to genetic testing.

sensitivity: the number of *affected* individuals who test positive for a disease out of the total number of *affected* individuals. specificity: the number of *unaffected* individuals who have a negative test out of the total number of *unaffected* individuals

Define serous, fibrinous, suppurative, and ulcerative inflammation.

serous: exudation of cell-poor fluid into spaces created by injury to surface epithelia (blisters) or body cavities lined by the peritoneum, pleura, or pericardium (effusion); usually no organisms or leukocytes fibrinous inflammation: when vascular leaks are large or there is a local procoagulant stimulus; higher MW proteins such as fibrinogen pass out of the blood with fibrin formation and deposition in extracellular space (e.g fibrinous pericarditis) purulent (suppurative) inflammation: localized collection of purulent inflammatory tissue (neutrophils, liquefactive necrosis, edema fluid); aka pus; frequently seen in infections w/ pyogenic bacteria (staph and enteric gram-negatives) that cause liquefactive tissue necrosis (e.g. acute appendicitis); abscesses are localized collections of pus in a tissue, organ, or confined space. ulcerative inflammation: local excavation of surface of organ or tissue produce by sloughing of inflamed necrotic tissue; commonly the mouth, stomach, intestines, or GI tract, venous ulcers in older people

Describe the structure and function of mitochondrial genes and explain the concept of heteroplasty.

small genome (16,600bp), circular, encodes 37 genes, 13 of which encode proteins and the rest encode tRNAs and rRNAs replicated by DNA pol-g heteroplasmy: each cell may contain mitochondrial genomes that carry mutations in specific genes in a background of wt genomes; the expression of a mutant phenotype depends on the relative proportion of mutated vs. wt genomes

Describe the conceptual bases of cell and gene therapies and the available techniques for introducing genes into patient cells.

somatic cell gene therapy: 1. Ex vivo- cells are removed from the body, incubated with a vector, and returned to the body (e.g. blood cells) 2. In situ- vector is placed directly into the affected tissues (e.g. infusion of adenoviral vectors into trachea and bronchi of CF patients, injection of tumor mass with vector carrying gene for a cytokine or toxin, injection of a vector carrying dystrophin gene into muscle of patient with MD) 3. In vivo- vector is directly injected into the blood stream and is delivered to the target tissue

Secondary hemostasis

stabilizes the weak platelet plug via the coagulation cascade: 1. Tissue factor elaborated at sites of injury initiates cascade 2. Thrombin converts fibrinogen to fibrin 3. fibrin is cross-linked yielding a stable platelet-fibrin thrombus

Describe the staging of neuroblastoma.

stage 1- tumor restricted to organ or structure of origin stage 2- tumor extends in continuity beyond site of origin but not across midline; ipsilateral nodes may be positive stage 3- tumor extends across the midline; ipsilateral and contralateral lymph nodes may be positive stage 4- distant metastases to bone, liver, soft tissues, brain, and distant lymph node groups

Describe prenatal screening and diagnostic procedures.

standard non-invasive screening: 1. ultrasonography- detects gross abnormalities & nuchal translucency (abnormal excess of fluid at back of neck) 2. maternal serum screening (triple of quadruple test)- alpha fetoprotein, free beta chorionic gonadotropin, unconjugated estriol, inhibin A invasive prenatal diagnostic techniques: 1. amniocentesis- amniotic fluid removed from the abiotic sac at around 15-16 wks; fluid contains fetal cells that can be cultured for genetic, cytogenetic, and/or biochemical analysis 2. chorionic villus sampling (CVS)- biopsy of tissue from the villus are of chorion (derived from trophoblast) at 10-12 wks; tests for PKU, homocystinuria, glycogen storage, Niemann-Pick, Tay-Sachs, ADA deficiency

Name the anemias due to diminished erythropoiesis. Differentiated stem cell defects vs. mature erythroblast defects.

stem cell: 1. Aplastic anemia 2. Pure red cell aplasia 3. renal failure 4. endocrine disorders mature erythroblasts: 1. ↓ Heme synthesis- hypochromic, microcytic (iron deficiency, thalassemias, sideroblastic) 2. ↓ DNA synthesis- megaloblastic (B12 or folate deficiency)

Understand the possible complications of anemia treatments, especially of iron poisoning.

symptoms: 1st stage (30 m- 12 hr): GI toxicity 2nd stage (8-12 hr): latent period 3rd stage (12- 48 hr): systemic toxicity including hepatic failure, hypoglycemia, metabolic acidosis, bleeding, shock, coma, convulsions, death 4th stage (4-8 wk): pyloric/antral stenosis, CNS sequelae diagnosis: determine serum iron 2-6 hours after ingestion; may be normal even in presence of posining treatment: IV *deferoxamine* and fluids

Name the translocation which is practically always present in chronic myeloid leukemia (CML).

t (9:22); Philadelphia; BCR-ABL

Name the chromosomal abnormality associated with Acute promyelocytic leukemia (AML-M3) and its clinical significance.

t(15;17); tumors with this translocation respond to all-trans retinoid acid (ATRA)

Recognize the diagnostic features of Langerhans cell histiocytosis and the spectrum of diseases in which it presents.

tennis racket-like Birbeck granules in cytoplasm on EM Letterer-Siwe disease (malignant) or Eosinophilic granuloma (benign)

Define teratoma and hamartoma.

teratoma: derived from multiple germ cell layers. hemartoma: masses of disorganized but mature tissues that are normal at that site

Your patient has anemia of chronic disease. Why can you not give them oral iron?

the actions of hepcidin prevent uptake in gut

Nodular sclerosis Hodgkin lymphoma

the most common form of HL (classical) classical presentation is enlarging of vertical or mediastinal lymph node in young adult characterized by the presence of *lacunar cells* and collagen bands that divide the lymphoid tissue in to circumscribed nodules

Chronic lymphocytic leukemia (CLL)/small cell lymphoma (SLL)

the most common leukemia of adults in the western world proliferation of naive B cells that co-express CD19, CD20, CD5, CD23 PBS: increased # of small, round lymphocytes with scant cytoplasm and smudge cells BM: non-paratrabecular aggregates of small lymphocytes lymph node architecture is diffusely effaced by a predominant population of small lymphocytes cytogenetics: deletions of 13q12-14, 11q, 17p; trisomy 21 clinical manifestation: often asymptomatic or non specific (fatigue, weight loss, anorexia); hypogammaglobulinemia (infection); autoimmune hemolytic anemia prolymphocytic transformation to diffuse B cell lymphoma (Richter syndrome)

A patient with acute lymphoblastic leukemia is being treated with 6-mercaptopurine when she begins to have attacks of gouty arthritis. Allopurinol is added to her regimen, but she does not seem to improve. What other factors need to be considered?

thipurine methyltransferase (TPMP) deficiency

Recognize the common clinical presentations and hematologic findings of essential thrombocythemia.

thrombosis and hemorrhage ABSENT splenomegaly

Define and differentiate thrombosis, hemorrhage, and shock.

thrombosis: formation of clot within vessel; components include vascular wall, platelets, and coagulation cascade hemorrhage: extravasation of blood shock: severe hemorrhage that results in hypoperfusion of tissues due to reduced CO or effective circulating blood volume.

Epipodophyllotoxins & Camtothecins

topoisomerase inhibitors 1. Etoposide (VP-16)- topoisomerase II 2. Topetecan- topoisomerase I inhibitor 2nd line for ovarian cancer; reduce dose in renal impairment 3. Irinotecan- topoisomerase I inhibitor used in the treatment of colorectal cancer; prodrug converted to SN38 by liver macrophages; reduce dose in liver dysfunction

Discuss stem cells. Differentiate totipotent and multipotent; myeloid and lymphoid precursors.

totipotents stem cells (TPSC) are capable of unlimited renewal and differentiation; express CD34; dysfunction can lead to anemia or leukemia; used for chemo multipotent stem cells are derived from TPSCs and are capable of extended self-reneal and differentiation based on type → lymphoid stem cells and myeloid stem cells (aka CFUs)

Describe how to predict the pattern of hematogenous metastasis.

tumor emboli follow the normal route of drainage; tumors in the portal circulation usually metastasize to liver and those in system circulation go to the lungs first.

Describe the two-hit hypothesis and give an example.

tumor supressor gene function is lost through a two-hit process, where the first hit may be inherited or sporadic, while the second allele is lost via a mechanism termed "loss of heterozygosity" (LOH) e.g retinoblastoma

Describe how to predict the pattern of lymph node metastasis.

tumors metastasize to regional lymph nodes-nodes that drain the area of the primary mass

Precursor T-cell leukemia/lymphoblastic lymphoma

typically manifests in *T*eenage males as lymphomas, often with *T*hymic involvement characterized by lymphoblasts (TdT+) that express CD2-CD8

Lymphocyte-rich Hodgkins lymphoma

uncommon form of classical HL in which reactive lymphocytes make up the cast majority of cellular infiltrate distinguished from lymphocyte predominant type by CD15+, CD30+, CD45- associated with EBV very good prognosis

Explain how gene/allele frequencies can be calculated in a human population.

use PCR to count alleles of a known genotype and thus determine the genotypic frequency. e.g. CCR5 allele not feasible for all genes and alleles due to the large number of genes in the genome and allelic heterogeneity

Define the international normalized ration (INR).

used to standardize PT results in nations taking warfarin (Coumadin); goal is a value of 2 to 3

Discuss the significance of Vitamin K deficiency and Coumarin therapy as acquired bleeding disorders.

vitamin K carboxylates factors II, VII, IX, X and proteins C; carboxylation is necessary for function deficiency occurs in newborns (lack of GI bacteria), antibiotic therapy, malabsorption vitamin K is activated by epoxide reductase in the liver; Coumarin works by inhibiting epoxide reductase and thus vitamin K activation; leading to anticoagulation

Autoimmune hemolytic anemia; warm vs cold

warm: IgG binds at 37°C; compliment activation, splenic destruction; SLE, CLL, drugs (penicillin) cold: IgM in extremities; Reynaud's, mycoplasma, mono diagnosis: postive direct Coombs test

A 55 yo man present with increasing fatigue, 15 lbs weight loss, and a microcytic anemia. Colonoscopy identifies a mass in the sending colon, and biopsy specimens reveal well-differentiated colorectal cancer (CRC). He undergoes surgical resection and is found to have high-risk stage III CRC with five positive lymph nodes. After surgery, he feels entirely well with no symptoms. No comorbid illness. Should he receive adjunct chemotherapy?

yes; no symptoms after surgery or comorbidities

What is zinc protoporhyrin and how does it effect heme synthesis?

zinc protoporhyrin (ZPP) is an intermediate in heme synthesis, thus iron deficiency can lead to ↑ZPP. Also, lead (Pb2+) is a divalent cation that can inhibit products of ZPP, thus ↑ZPP and also inhibit heme synthesis

Describe the primary feature of polycythemia vera (PV) which differentiates it from other myeloproliferative syndromes.

↑RBCs (polycythemia) → abnormal blood flow → cyanosis, bleeding, and thrombosis

A 44-year-old asian woman (non-smoker) had been well until approximately 1 year before this evaluation, when pain in her right shoulder and scapula developed, followed by cough and an episode of hemoptysis. A chest radiograph that was obtained at another hospital reportedly showed findings suggestive of pneumonia. Antibiotic agents were administered, but the pain and radiographic abnormalities persisted. CT of the chest revealed an irregular mass in the anterior right upper lobe, along with multiple pleural nodules (most <1 cm in diameter). What is the probable cause of her condition and what therapy should be initiated?

EGFR mutation; therapy with erlotinib should be initiated

Describe the impact of epigenetic modifications on gene expression and chromatin function.

Epigenetic modifications of the genome and products may include DNA methylation, histone acetylation, and translational regulation of mRNAs by microRNAs; nucleotide modifications occur in DNA, mRNAs, and tRNAs; only cytosine can be methylated, occurs in the context of CpG dinuclotide; consequences of DNA methylation include alteration of chromatin structure, alteration of binding of proteins to DNA, and alteration of gene expression patterns (genomic imprinting); methylation of imprinted alleles inhibits their activity

HbC

Extravascular hemolytic anemia cause: AR mutation in β chain of Hb (G to L)

Alpha thalassemia

Extravascular hemolytic anemia cause: Hb alpha gene deletion (↓α, ↑β) 1 gene deleted- asymptomatic 2 genes deleted- alpha thal trait 3 genes deleted- HbH (severe anemia) 4 genes deleted- hydrops fetalis (fatal in utero)

Beta thalassemia

Extravascular hemolytic anemia cause: Hb beta gene mutation (↓β, ↑α); highest frequency in Mediterranean, African, Southeast Asia; minor, intermedia, major clinical presentation: hepatosplenomegaly, skeletal deformities (crewcut appearance) due to expansion of hematopoiesis, hemochromatosis (iron overload) PBS: microcytic; hypochromic; target cells, nucleated RBCs, anisocytosis treatment: blood transfusions diminish the anemia and its complications but also add to the systemic iron overload

Hereditary spherocytosis

Extravascular hemolytic anemia cause: Inherited (AD) cell skeleton defect clinical presentation: anemia, jaundice, splenomegaly, gall stones PBS: normocytic; hyperchromic (loss of central pallor); anisocytosis/↑RDW diagnosis: osmotic fragility test, which reveals increased fragility in hypotonic solution treatment: splenectomy (Howell-Jolly bodies)

Sickle cell anemia

Extravasuclar hemolytic anemia cause: Hereditary (AR) mutation in β chain of Hb (E6V); homozygous= ALL HbS, heterozygous 50% HbS; more prevalent in AA (P Falciparum resistance) clinical presentation: deoxygenation results in sicking which can be vasocclusive (leg ulcers), autosplenectomy (infarcted spleen) increases risk of infection with encapsulated bacteria (S. pneumoniae, H. inflienzae, Salmonella) PBS: anisocytosis, poikilocytosis, target cells diagnosis: Hb electrophoresis- screen with alkaline; diagnose with acidic treatment: hydroxyurea- DNA inhibitor that ↑HbF, anti-inflammatory

Contrast the nature of hematopoietic sites in the fetus versus those of the adult.

Fetus: Mesoblastic period (1st trimester)- yolk sac, primary erythroid (ε, ζ ) → hepatic period (2nd trimester)- fetal liver, primary erythroid → Myeloid period (3rd trimester)- bone cavities of central & peripheral skeleton; erythroid & myeloid; HbF replaced after 6 mo. w/ HbA Adult sites: central skeleton ONLY; vertebral bodies, sternum, ribs, pelvis

Summarize the mechanisms of fibrosis development and give examples.

Fibrosis describes the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation or in the myocardium after infarction. Fibrosis that develops in a tissue space occupied by an inflammatory exudate is called organization (e.g. organizing pneumonia)

t(14;18)

Follicular lymphoma; BCL-2

A 17-year-old girl has had frequent nosebleeds since childhood. Her gums bleed easily, even with routine tooth brushing. She has experienced menorrhagia since menarche at age 14. On physical examination, there are no abnormal findings. Laboratory studies show hemoglobin 14.1 g/dL, hematocrit 42.5, MCV 90, platelet count 277,400mm3, and WBC count 5920/mm3. Her platelets fail to aggregate in response to ADP, collagen, epinephrine, and thrombin. The ristocetin agglutination test result is normal. There is a deficiency of glycoprotein IIb-IIIa. Her prothrombin time is 12 sec and her partial thromboplastin time is 28 sec. What is the most likely diagnosis?

Glanzmann's disease

Differentiate cancer grading and cancer staging and explain which is most useful in determining therapy and prognosis.

Grade is degree of histological differentiation: grades 1-3/ or 4 (well, moderate, or poor differentiation) correlate with increasing cellular anaplasia. Need supplementary testing to help with prediction of tumor aggressiveness and/or response to tailored therapy Stage is extent of tumor size and spread (T and N and M): T= primary Tumor, N is lymph Node metastasis (N0-3), M is for hematogenous, M is for hematogenous Metastasis (M0-1); Stage I- T variable; N0, M0 Stage IV- M1, T and N variable Stages II-III- varies by organ *STAGE TRUMPS GRADE anytime*

Differentiate HUS/TTP from DIC.

HUS & TPP are both problems primarily involving *platelets*; TPP with vWF polymers due to ↓ADAMTS13 and HUS with E coli toxin activation of platelets DIC is primarily a problem involving pathological activation of *coagulation* due to release of TF (sepsis, endothelial injury)

Compare and contrast Hemophilia A, Hemophilia B, and von Willebrand's disease.

Hemophilia A: X-linked recessive deficiency in factor VIII; presents with deep tissue, joint, and postsurgical bleeding; ↑PTT; normal PT, ↓ FVIII, normal platelet count and bleeding time; avoid aspirin, prophylaxis with DDAVP (desmopressin), factor VIII replacement Hemophilia B (Christmas disease): similar to A except FIX decreased instead of FVIII von WIllebrand's disease: most common inherited bleeding disorder; ↓ vWF; AD; normal platelet count, ↑ bleeding time, ↑PTT; ristocetin test is diagnostic

Describe the mechanism of action for Heparin. What drug is used to reverse it?

Heparin: Activates anticlotting factors (antithrombin) which inactivates prothrombin, and factor X Vitamin K and fresh frozen plasma used to reverse it

Discuss acquired and hereditary hypercoagulable states.

Hereditary: 1. Factor V Leiden (activated protein C resistance) 2. Mutation in prothrombin gene (fibrinolysis) 3. Deficiencies- Protein C or S (inactivate factor VIII); Antithrombin III deficiency Acquired: 1. Antiphospholipid antibody syndromes (anticardiolipin antibodies, lupus-like anticoagulants)- increased thrombi with paradoxical ↑PTT 2. DIC 3. HIT

Describe the difference between non-Hodgkin and Hodgkin lymphoma.

Hodgkin is characterized by Reed-Sternberg cells ignore the third one

What is the treatment for vitamin B12 deficiency anemia?

Hydroxocobalamin (aka aquacobalamin) or cyanocobalamin; start with oral, resort to IV if neural signs

A patient with severe acute myeloid leukemia is being treated with chemotherapy. She goes into A-fib and is brought into the hospital for observation. What chemotherapeutic agent creates oxygen free radicals that can result in cardiotoxicity? What agent could have been used to help reduce the amount of oxygen free radicals?

Idarubicin; Dexrazoxane

A 64-year-old man with chronic myelogeneous leukemia is being seen in your oncology clinic. He has been treated with α-interferon and cytarabine with no improvement. He asks you if there are any other options to treat his disease. You tell him that you would like to try a different agent that acts by inhibiting a tyrosine kinase on a mutated gene product, Bcr-Abl, which has been shown to be associated with this disease.

Imatinib (Gleevec®)

Describe the ethical considerations underlying the use of gene therapy, and in particular, the use of gene therapy to modify the germline.

In germ cell therapy, the patients egg or sperm cells are changed with the goal of passing on the changes to their offspring

Differentiate myelodysplatsic syndroms and myeloproliferative disorders?

In myelodysplastic syndroms, ineffective hematopoiesis results in peripheral blood cytopenias (normally due to chemo or stem cell defect) In myeloproliferative disorders, increased production of differentiated myeloid elements leads to elevated peripheral counts

Vinca alkaloids

Inhibit mitosis by blocking polymerization of microtubles (M-phase specific) 1. Vincristine- ALL, Hodgkin's/ non-Hodgkin's 2. Vinblastine 3. Vinorebline- NSCLC Adverse effects: vesicant (blistering), myelosupression (vinblastine > vincristine), dose-limiting neurotoxicity, SIADH

Describe the nature of leukocyte infiltrates in inflammatory reactions.

Initially the fluid phase, followed by the neutrophil phase (6-24 hrs), and the macrophage phase (24-48 hrs)

Platinum analogs

Inorganic metal complex, DNA cross-linking; cell cycle non-specific; used for solid tumors only → Cisplatin and Carboplatin for lung, Cisplatin for breast and ovarian, Oxaplatin for colorectal; N/V common to all 1. Cisplatin- renal impairment, ototoxic 2. Carboplatin- less renal toxicity 3. Oxaloplatin- colorectal cancer

Name the hemolytic anemias. Differentiate those destroyed intravascularly vs. in the spleen.

Intravascular hemolysis: 1. Ab mediated- autoimmune, transfusion runs, hemolytic disease of newborn 2. Mechanical damage- microthrombi (TTP, DIC), macro (heart valves) 3. Maleria Extravascular hemolysis (spleen) 1. Hereditary spherocytosis 2. G6PD deficiency 3. Thalassemia 4. Sickle cell 5. Paroxysmal nocturnal hemoglobinuria (PNH)

Compare and contrast features of intravascular and extravascular hemolysis.

Intravascular: destruction of RBCs within vessels. Manifests as hemoglobinuria, hemoglo binemia, hemosiderinuria (PNH, G6PD deficiency, immune hemolytic anemia, microangiopathic) Extravascular: RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes). Manifests as anemia with splenomegaly, jaundice due to uncounted bilirubin and increased risk of bilirubin gallstones (hereditary spherocytosis, sickle cell)

Common pathway

Involves factor I (fibrinogen), factors II (prothrombin), V, X 1. thrombin converts soluble fibrinogen to insoluble fibrin 2. Factor XIII cross links fibrin to increase stability of clot

Explain the biochemical mechanisms in cell injury and the possible consequences of ischemia to cells.

Ischemia (decreased blood flow to organ)→ Hypoxia (low oxygen delivery to tissue) → Oxygen is the final electron acceptor for ox. phos.→ Decreased oxygen impairs ox. phos. resulting in decreased ATP production. → Low ATP disrupts cellular functioning (Na/K pump results in water buildup in the cell; Ca builds up in the cell and activates enzymes; anaerobic glycolysis results in lactic acid formation, low pH, denaturing of proteins, and precipitation of DNA)

Describe the mechanisms underlying genomic imprinting disorders. Give examples of such disorders.

Associated with differences in methylation status of genes inherited from parents; methylation of cytosine residues in CpG dinucleotides is generally associated with transcriptional repression; genomes of mature differentiated cells are heavily methylated and differences in methylation patterns will be observed in different cell types, which reflect the specific genes that are expressed in those cell types; reset during gametogenesis, allowing a clean slate for the zygote with a small subset of genes that retains an "imprint" Prader-Willi syndrome, Angelman syndrome- both associated with internal deletion of common regions of chromosome 15; the consequence of the deletions depends on whether they occur in the maternally or paternally inherited chromosome

Describe arachadonic acid (AA) metabolism.

AA is a 20 C polyunsaturated fatty acid released by phospholipase A2 due to mechanical, chemical, or physical stimuli and then acted upon by clooxygenases (COX-1 for homeostasis, COX-2 for inflammation) to produce prostaglandins & thromboxanes or lipoxygenases to produce leukotrienes & lipoxins (suppress inflammation by inhibiting recruitment of LTs)

t(15;17)

AML-M3; Retinoic acid receptor

Match important leukocyte antigens to normal cells and neoplasms on which they are typically expressed.

AML: MPO ALL: TdT T-ALL: CD2-8 B-ALL: CD10, CD19, CD20 Lymphomas (except Hodgkins): CD20 Hodgkins lymphoma: CD15, CD30 Myeloid cells/monocytes: CD13, CD33

Which WBC disorder is associated with a high incidence of DIC?

AML; t(15;17)

Discuss the differences between congenital and acquired causes of defective platelet function.

*Congenital* 1. Adhesion defects: Bernard-Solulier syndrome (AR, GPIb deficiency) 2. Aggregation defects: Glanzmann's thrombasthenia (AR, GPIIb/IIIa defect); does not aggregate in response to epinephrine, collagen, or ADP but will to ristocetin 3. Platelet secretion defects: storage pool disorders (grey platelet syndrome, α), delta storage pool deficiency, Chediak-Higashi, Wiskott-Aldrich *Aquired* 1. Drug induced: NSAIDs (COX inhibitor, TXA2) 2. Uremia 3. Liver disease 4. Paraneoplastic platelet dysfunction

X-linked dominant pedigree analysis.

*Females more common than males* 1. All daughters of an affected male will inherit the trait 2. sons of an affected male will not inherit the trait 3. 50% of sons of an affected female will inherit the trait 4. 50% of daughters of an affected female will inherit the trait 5. the severity of the trait in females may be modulated by random X chromosome inactivation

X-linked recessive pedigree analysis.

*Males more common than females* 1. unaffected males do not transmit the disorder. 2. all the daughters of an affected male are heterozygous carries 3. Heterozygous women transmit the mutant allele to 50% of the sons and 50% of the daughters (carriers) 4. If an affected male marries a heterozygous woman, half their sons will be affected, giving the erroneous impression of male-to-male transmission

Differentiate dystrophic calcification and metastatic calcification.

*d*ystrophic: depositon in *d*ead tissue that tends to be localized (e.g. calcified aortic stenosis) metastatic: widespread calcification in normal tissues (predominantly interstitial tissues of kidney, lung, and gastric mucosa) where increased pH favors Ca deposition; secondary to hypercalcemia (hyperparathyroidism), or high calcium-phosphate levels (metastatic cancer, renal failure)

Name the tyrosine kinase inhibitors and the receptor they act on.

-nib 1. Imantinib/Dasantinib: BCR-ABL (Ph+, 9/22 tl), c-kit (GIST), PDGFR, stem cell factor 2. Erlotinib/Gefitinib/Lepatinib: EGFR (NSCLC, EGFR mutation in young asian non-smokers) 5. Sunitinib/Sorafenib: VEGF

Foreign-body granulomas.

.

Describe some of the diagnostic cell morphologies found in leukemias/lymphomas and name the associated disease.

1. "Cerebriform" lymphocytes: Sázary Syndrome 2. "Cloverleaf" lymphocytes: Adult T-cell Leukemia/Lymphoma 3. "Smudge" lymphocytes: CLL 4. "Owls-eye": Hodgkin's Reed-Sternberg 5. "Stary-sky": Burkitt's 6. "Tennis-racket" (Burkbeck granules): Langerhan's cell histeocytosis 7. "Horseshoe-shaped": Anaplastic large cell lymphoma 8. Lacunar: Nodular Sclerosis Hodgkin Lymphoma 9. "Popcorn" (L&H): Lymphocyte predominant HL

Name the laboratory procedures needed to establish compatibility between donor and recipient

1. ABO/RH testing 2. Review of transfusion records 3. Testing the patients blood for Abs 4. Ab identification, if indicated 5. A crossmatch between donor blood and recipient

Discuss the disorders of acute inflammation.

1. ARDS 2. Acute transplant rejection 3. Asthma 4. Glomerulonephritis 5. Septic shock 6. Lung abscess

What cofactors are needed to convert prothrombin to thrombin?

1. Activated factor X with activated factor V 2. phospholipid surface (provided by platelet) 3. Ca

Name and describe the source of some important toxins and the associated cancers.

1. Aflatoxins: derived from the fungus Aspergillus (rice & grains), causes hepatocellular carcinoma 2. Cigarette smoke (polycyclic hydrocarbons): carcinoma of the oropharynx, esophagus, lung, kidney, bladder, and pancreas 3. Azo dyes: found in processed meat 4. Abestos: lung cancer and mesothelioma 5: Benzene: alkylating agent that causes leukemia as a side effect of chemo 6. Radon: lung cancer; associated with indoor air quality 7. Ionizing radiation: generates hydroxide free radicals known to cause acute leukemias (AML, CML) and papillary carcinoma of the thyroid

Name the common etiologies of esosiniohilic leukocytosis

1. Allergic disorders (asthma, hay fever) 2. Skin diseases 3. Parasitic infections 4. Drug xns 5. Hodgkin lymphoma 6. Myeloproliferative disorders

Describe the clinical consequences of edema.

1. Annoying to rapidly fatal 2. Can be indicator of disease (e.g. cardiac or renal failure) 3. Can impair wound healing 4. Can impair clearance of infection 5. Can interfere with normal ventilatory function, resulting in death 6. Can cause herniation of brain or compression of brainstem vascular supply, resulting in death

Describe the principle inflammatory actions of arachidonic acid metabolites (Eicosanoids).

1. Arteriole vasodilation: prostaglandins (D2, I2, E2) 2. Vasoconstriction: thomboxane A2; leukotrienes C4, D4, E4 3. Increased vascular permeability at postcapillary venule: lekotrienes C4, D4, E4 4. chemotaxis, leukocyte adhesion: leukotriene B4 5. Pain and fever: PGE2 6. SM contraction: PGC4, D4, E4

Name the indications for erythropoietin replacement therapy.

1. Autologous blood donation for elective non cardiac surgery 2. Anemia of prematurity 3. Zidovudine associated anemia in HIV 4. Anemia of chronic disease if EPO is low (i.e CKD)

Name the macrocytic anemias.

1. B12 deficiency 2. Folate deficiency 3. Drugs: SMP/TMX, Methotrexate, Zidovudin, Phenytoin 4. Alcoholism

Identify representative cancer associated tumor suppressor genes.

1. BCRA1/2: breast, ovarian, and pancreatic cancer 2. Rb: retinoblastoma, osteosarcoma 3. P53: most human cancers, Li-Fraumeni syndrome (multiple malignancies at an early age)

Name the common etiologies of neutrophilic leukocytosis.

1. Bacterial infection 2. Sterile Inflammation caused by tissue necrosis, MI, burns 3. Myeloproliferative disorders

Describe mechanisms for DNA repair and impact of defects in these processes (cancer, accelerated aging).

1. Base excision repair- base is excised by DNA glycosylase, nuclease removes surrounding damaged site, DNA polymerase and ligase repairs break 2. Nucleotide excision repair- multi protein complex recognizes abnormal structure (e.g. thymidine dimer), nuclease removed damaged site, DNA polymerase and ligase repairs break 3. Mismatch repair- mismatched region recognized by mutliprotein complex, nuclease removed by unmatched bases, DNA polymerase & ligase repairs break

Differentiate acute and chronic lymphadenitis

Acute: tender; microbial drainage from infection Chronic: nontender; chronic inflammation, carcinoma, lymphoma

Describe Leukocyte migration and adhesion.

1. Blood flow slows in postcapillary venules allowing lymphocytes to marginate 2. Selectin "speed bumps" are unregulated on endothelial cells (P-selectin by Weibel-Palade bodies mediated by histamine, E-selectin by TNF & IL-1)- Selectins bind Sialyl Lewis X-modified proteins on leukocytes resulting in rolling along vessel walls. 3. Cellular adhesion molecules (ICAM & VCAM) are upregulated on endothelium by TNF & IL-1; Integrins are unregulated on leukocytes by C5a and LTB4; interactions between CAMs and Integrins on results in firm adhesion to vessel wall; CD11/CD18 (LFA-1, Mac-1) to ICAM-1 or VLA-4 integrin binds VCAM-1

Describe molecular techniques used to detect genetic alterations.

1. Blots: checks for the presence of a specific sequence of nucleotides or protein in a sample; Southern (DNA), Northern (RNA), Western (protein) 2. DNA sequencing: PCR- amplify a specific DNA segment, Sanger 3. Fluorescent in situ hybridization (FISH): a cytogenetic technique to detect the presence and location of a specific sequence of DNA or RNA (e.g. translocations). 4. DNA microarray: a glass chip that contains an arrangement of thousands of sample genes. They are used to measure gene expression in any given cell by taking advantage of the fact that mRNA (and cDNA) binds to its parent DNA

Name the WBC diseases of the young.

1. Burkitt's 2. Anaplastic large cell 3. ALL

Discuss the two major classifications of triple expansion disorders and provide examples of each.

1. CAG repeats/polyQ disorders- repeated CAG sequence is located within the coding sequence for the protein, forming a codon for Glutamine (Q). Repeat expansion results in the formation of Poly-glutamine stretches that *disrupt protein function*; PCR can detect repeat number (e.g. Huntington Disease) normal range is 10-26, >40= full penetrance 2. Non-CAG repeats- generally in regions *outside the coding region* and affect *gene expression*. e.g. a CCG repeat in the FMR1 gene associated with fragile X syndrome located near the 5' end. Expansion of this repeat sequence generated a region with high proportion of CpG dinucleotides, which are targets for methylation. Hypermethylation of these repeats inhibits the the FMR1 promoter and the clinical phenotype is caused by lack of the product of the FMR1 gene (FMRP) another example is myotonic dystrophy with a CTG repeat in non-coding region DMTK gene that impacts splicing

Describe how to differentiate a leukemoid reaction from CML.

1. CML has basophilia 2. t (9;22) 3. LAP score is low in CML, high in leukemoid

Describe the causes of the three categories of shock.

1. Cardiogenic: failure of myocardial pump resulting from intrinsic myocardial damage, extrinsic pressure, or obstruction to outflow (MI, arrhythmia, tamponade, PE) 2. Hypovolemic: inadequate blood or plasma volume (hemorrhage, loss of fluid-vomiting diarrhea, burns, trauma) 3. Septic: peripheral vasodilation and pooling of blood; endothelial activation/injury; DIC; activation of cytosine cascade (microbial infections, endotoxic shock, gram-positive septicemia, fungal sepsis, TSS caused by super antigens)

Name the common etiologies of monocytosis.

1. Chronic infection 2. Collagen vascular disease (SLE) 3. Inflammatory bowel 4. Myeloproliferative disorders

Name the common etiologies of lymphocytosis

1. Chronic inflammation (TB, brucellosis) 2. Viral infections 3. Bordetella pertussis 4. lymphoid leukemias

List and describe the prominent features of the different myeloproliferative disorders.

1. Chronic myeloid leukemia (CML): ↑granulocytes (especially basophils), t(9:22), most likely to progress to AML/ALL, splenomegaly 2. Polycythemia vera (PV): ↑RBCs, JAK2 mutation, thrombosis, splenomegaly 3. Essential thrombocythemia (ET): ↑platelets, ↑megs in BM, thrombosis & hemorrhage, ABSENT splenomegaly, JAK2 4. Myelofibrosis: ↑Megs, teardrop red cells, leukoerythroblastosis, splenomegaly, can progress to AML, JAK2

Recognize the clinical manifestations of cystic fibrosis.

1. Chronic pulmonary disease- bronchiectasis, bronchial destruction, pneumonia, emphysema 2. Deficiency exocrine pancreatic function 3. Complications of inspissated (thickened) mucus- skin, small intestine, appendix, liver, and reproduction tract (no vas deferens, sterile) 4. Meconium- difficulty passing the meconium stools 5. Rectal prolapse 6. Nasal polyps

Recognize the various subtypes of Hodgkin lymphoma.

1. Classical subtypes (CD15+, CD30+, CD45-, CD20+/-): nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depletion; characterized by RS cells 2. Lymphocte predominance type (CD15-, CD30-, CD45+, CD20+); characterized by L&H (popcorn) cells

Name the common etiologies of lymphopenia

1. Congenital immunodeficiency (DiGeorge 2. HIV 3. Glucocorticoids or cytotoxic drugs 4. Autoimmune disorders (SLE) 5. Viral infection 6. malnutrition

Describe the disorders which are characterized by microangiopathic hemolysis.

1. DIC: pathologic activation of the coagulation cascade 2. HUS: endothelial damage by drugs or infection; classical seen in children with E. coli O157:H7 dysentery 3. TTP: ↓ADAMTS13, an enzyme that normally cleaves vWF for degradation; uncleared multimers lead to abnormal platelet adhesion resulting in microthrombi; normally due to an autoantibody in adult females

List the four basic properties that define a tumor as benign vs. malignant, and name the two that are most important in this distinction.

1. Differentiation & anaplasia 2. Rate of growth 3. *Local invasion* 4. **Distant metastases**

Explain/describe principles of combination chemotherapy.

1. Each drug should be active when used alone 2. The drugs should have different mechanisms of action 3. Cross-resistance between drugs should be minimal 4. The drugs should have different toxic effects

Describe the abnormalities that lead to thrombus formation.

1. Endothelial injury: MI, atherosclerosis, inflammatory vasculitis or traumatic vascular injury result in dysfunctional endothelial cells that produce more procoagulant than anticoagulant 2. Hypercoagulation: important risk for venous thrombosis; prolonged bed rest or immobilization, DIC, heparin-induced thrombocytopenia, antiphospholipid antibody syndrome, genetic (mutations in fact V or prothrombin gene), CM, oral contraceptives, sickle cell, smoking 3. Abnormal blood flow: turbulence contributes to arterial and cardiac thrombosis; stasis contributes to venous thrombosis; prevents dilution or inhibition of clotting factors leading to endothelial cell activation, thrombosis, leukocyte adhesion

Name and describe the growth factors involved in regulation and repair.

1. Epidermal growth factor (EGF)- mitogenic for keratinocytes & fibroblasts; stimulates keratinocyte migration; stimulates formation of granulation tissue 2. Transforming growth factor-α (TGF-α)- stimulates proliferation of hepatocytes and many other epithelial cells 3. Hepatocyte growth factor (HGF)- enhances proliferation of hepatocytes & other epithelial cells; increases cell motility 4. Vascular endothelial growth factor (VEGF)- angiogenesis; stimulates proliferation of endothelial cells; increased vascular permeability 5. Platelet-derived growth factor (PDGF)- chemotactic for neutrophils, macrophages, fibroblasts, and smooth muscle cells; activates and stimulates proliferation of fibroblasts, endothelial & other cells; stimulates ECM protein synthesis 6. Fibroblast growth factors (FGFs)- chemotactic & mitogenic for fibroblasts; stimulates angiogenesis and ECM protein synthesis 7. Transforming growth factor- β (TGF-β)- chemotactic for leukocytes & fibroblasts; stimulates ECM protein synthesis; suppresses acute inflammation 8. Keratinocyte growth factor (KGF/ FGF-7)- stimulates keratinocyte migration, proliferation, and differentiation

Discuss the functions of the different types of leukocytes.

1. Erythrocytes: carry oxygen/carbon dioxide 2. Neutrophils: phagocytosis, killing 3. Monocytes: phagocytosis, killing, APC 4. Lymphocytes: host defense 5. Platelets: hemostasis

Recognize the role of hematopoietic growth factors.

1. Erythropoietin: produced in kidney for RBC synthesis 2. GM-CSF (granulocyte-monocyte colony stimulating factor): released from endothelial cells, stromal cells, and lymphocytes in response to infection 3. G-CSF (granulocyte colony stimulating factor): stromal cells in marrow in response to infection 4. Stem cell factor (CSF): stimulates totipotent and multipoint stem cells to enter differentiation pathway 5. Interleukins: mediated communication between WBCs (infection); *IL-3* helps maturation and differentiation of hematopoietic elements

Name the conditions that prolong PT.

1. Factor VII deficiency 2. Common pathway defect (I, II, V & X) 3. Warfarin use or overdose 4. Heparin overdose or contamination

What are the possible causes of abnormal PT, PTT and TT?

1. Factor deficiency 2. Severe liver disease 3. DIC 4. potent inhibitor 5. fibrinogen abnormality

What are the possible causes of abnormal PT with a normal PTT?

1. Factor deficiency in extrinsic pathway 2. specific factor inhibitor

What are the possible causes of abnormal PTT with a normal PT?

1. Factor deficiency of intrinsic pathway 2. Antiphospholipid Ab 3. Specific factor inhibitor (FVIII)

Recognize the clinical manifestations of Hirschsprung's disease.

1. Failure to pass meconium as neonate 2. Constipation and abdominal distention 3. Frequent association with trisomy 21 4. 4:1 M/F ratio

Name the 5 shared clinical manifestations of TTP, HUS, and DIC.

1. Fever 2. Thrombocytopenia 3. Microangiopathic hemolytic anemia 4. Neural defects 5. Renal defects

List differential diagnosis for different patterns of reactive lymphadenopathy.

1. Follicular hyperplasia (B cell region): RA, toxo, early HIV 2. Paracortical hyperplasia (T cell region): viral infections (mono), drugs (Dilantin), vaccination 3. Sinus Histocytosis (medulla): cancer

List secondary causes of myelodysplasia.

1. Genototxic drug 2. Radiation therapy (t-MDS)

Name the WBC diseases affecting women.

1. HL- NS subtype

Understand the possible complications of anemia treatments, especially erythyropoietin use.

1. HTN 2. Pure red cell aplasia 3. ↑risk of stroke due to thrombosis- AVOID in cardiac surgery blood transfusion 4. Stimulation of cancer growth due to EPO receptors- AVOID in cancer patients

Name the WBC disorders associated with splenomegaly.

1. Hairy cell leukemia 2. CLL 3. Myeloproliferative disorders: Myelofibrosis, CML, PV

Describe the clinical significance of the major hemoglobinopathies and the laboratory tests used in their diagnosis.

1. Hb electrophoresis: used to detect abnormal hemoglobin as HbS 2. Coombs test: used to diagnose immunohemolytic anemias 3. Reticulocyte count: distinguishes anemias caused by RBC destruction (hemolysis) from anemias caused by depressed production (marrow failure 4. Iron studies: iron deficiency anemia vs anemia of chronic disease 5. serum red cell folate and vitamin B12 concentration: used to identify the cause of megaloblastic anemia 6. Plasma unconjugated bilirubin and haptoglobin concentrations: used to support the diagnosis of hemolytic anemia.

Describe the immunologic types of transfusion reactions and complications that occur.

1. Hemolytic reactions: acute (IgM); delayed (IgG) 2. Febrile: *Recipient* Anti-HLA → fixing of compliment → rise in body temp by 1°C 3. Allergic: anaphylaxis most commonly occurs in IgA deficient patients who receive a transfusion containing IgA 4. GVHD: Cells from donor attack recipient tissue 5. Transfusion associated lung injury (TRALI): Anti-HLA antibodies from *donor*

Name and describe some important diseases that exhibit an X-linked recessive pattern of inheritance.

1. Hemophilia 2. Becker/Duchenne muscular dystrophy- allelic heterogeneity- deletions in the dystrophin gene; DMD is early onset (around 3), most die before 20; BMD is milder; classical symptom is Gower's maneuver; severity depends on whether deletion maintains protein reading frame and location in protein sequence (the later, closer to N-term, the better) 3. Lesh Nyhan- displays allelic heterogeneity; more than 200 independent mutations in HPRT1 gene; severe mutations display gouty arthritis

Understand the pathophysiology of heparin-induced throbocytopenia syndrome.

1. Heparin causes mild platelet activation with release of PF4. 2. Heparin-PGF4 form immune complexes with IgG 3. immune complexes bind the Fc region of platelets and mark them for destruction in splenic macrophages → thrombocytopenia 4. fragments of destroyed platelets may activate remaining platelets → thrombosis

Name the normocytic anemias.

1. Hereditary spherocytosis 2. Sickle cell 3. Paroxysmal nocturnal hemoglobinuria (PNH) 4. G6PD deficiency 5. Immune hemolytic 6. Microangiopathic

Describe the actions of the principle mediators of inflammation.

1. Histamine from mast cells, basophils & platelets- vasodilation, increased vascular permeability, endothelial activation 2. Serotonin from platelets- vasoconstriction 3. Prostaglandins from mast cells & leukocytes- vasodilation, pain, fever 4. Leukotrienes from mast cels and leukocytes- increased vascular permeability, chemotaxis, leukocyte adhesion and activation 5. Platelet-activating factor from leukocytes and mast cells- vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst 6. Reactive oxygen species from leukocytes- killing of microbes, tissue damage 7. nitric oxide from endothelium & macrophages- vascular smooth muscle relaxing, killing of microbes 8. cytokines from macrophages, endothelial cells, mast cells- local endothelial activation (expression of adhesion molecules); systemic fever, metabolic abnormalities, hypotension 9. Chemokine from leukocytes and activated macrophages- chemotaxis and leukocyte adhesion 10. complement- leukocyte chemotaxis (C5a), direct target killing (MAC), vasodilation (C3a, C5a) 11. Bradykinin- increased vascular permeability, smooth muscle contraction, vasodilation, pain

Name the cancers that can cause eosinophilia

1. Hodgkins lymphoma 2. Langerhans cell histiocytosis 3. Peripheral T cell lymphomas

Name the common etiologies of neutropenia

1. Immunologically mediated injury- SLE, drugs 2. Splenomegaly- splenic sequestration and destruction 3. Increased peripheral utilization- infection (bacterial, fungal, rickettsial)

Describe the indications for transfusion.

1. Increase oxygen carrying capacity of blood 2. Increase blood volume 3. Enhance coagulation properties, including platelets 4. improve leukocyte function 5. Reverse blood loss 6. Intrauterine exchange transfusion (uncommon due to Rh IgG (Rhogam)

List the features common to all myeloproliferative disorders.

1. Increased proliferative drive in the bone marrow 2. Extramedullary hematopoiesis 3. Variable transformation to a spent phase characterized by bone marrow fibrosis and peripheral blood cytopenias 4. Variable transformation to AML

Describe the non-immunologic types of transfusion reactions and complications that occur.

1. Infection (viral hepatitis, CMV, WNV, AIDS) 2. Transfusion associated circulatory overload (TACO)- cardiac compromise and heart failure seen in young and elderly undergoing rapid or excessive transfusion 3. Iron overload: repeated transfusions (thalassemia, BM hypoplasia)

Name the pathways that activate caspase mediated apoptosis.

1. Intrinsic mitochondrial pathway: cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2 → cytC leaks from inner mitochondrial matrix into cytoplasm to activate caspases. 2. extrinsic receptor-ligand pathway: FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases → tumor necrosis factor (TNF) binds TNF receptor on the target cell, activating caspases 3. cytotoxic CD8 T cell-mediated pathway: performs secreted by CD8 T cell created pores in membrane of target cells → granzymes from CD8 T cell enters pores and activates caspases

Name and describe the principal signaling pathways used by cell surface receptors.

1. Intrinsic tyrosine kinase- ligand (EGF, VEGF, FGF, HGF) binding to one chain of the receptor activates tyrosine kinase on the other chain, resulting in activation of multiple downstream signaling pathways (RAS-MAP kinase, PL-3 kinase, PLC-γ) and activation of various TFs. 2. G-protein-coupled seven transmembrane receptors (GPCRs)- ligand (inflammatory mediators, hormones, chemokine) induces GDP-bound inactive form to GTP-bound active form; activates cAMP; Ca2+ influx 3. Receptors without intrinsic enzymatic activity- ligand (cytokines like INF, growth hormone, CSFs, EPO) binding recruits kinases (JAKs) that phosphorylated and activate transcription factors (STAT)

Name the microcytic anemias.

1. Iron deficiency 2. Anemia of chronic disease 3. Thalassemia's 4. Lead poisoning

Name some signs/symptoms of iron deficiency anemia.

1. Koilonychias: spoon-like curving of the nails 2. Chelitis: soreness of mouth with cracks at corners of lips 3. Glossitis: soreness/swelling of the tongue 4. RLS 5. Plummer-vinson syndrome: esophageal web, dysphagia 6. Pica: hunger for strange substances such as dirt, Brussels sprouts 7. Pagophagia: eating ice

Name the key mediators that attract/activate neutrophils.

1. LTB4 2. C5a 3. IL-8 4. bacterial products

Explain the impact of genetic variation on the expression and inheritance of the human genome.

1. Loss-of-function: gene product or activity is reduced (e.g. cystic fibrosis) 2. Gain-of-function: gene product is increased or has increased activity or gene expression occurs at the wrong place/time (e.g. Charcot-marie-tooth disease and PMP22 gene; Achondroplasia due to FGFR3) 3. Protein alteration- normal protein function is altered (e.g. Kennedy disease) 4. Dominant effects of recessive mutation- alleles are recessive at the molecular level but show a dominant mode of inheritance (e.g. Retinoblastoma is inherited as recessive allele, a mutation in the second normal allele results in tumor formation)

Name and describe the mediators of chronic inflammation.

1. Macrophages: Classical activation (M1)- by endotoxins produce IL-1, TNF, IL-6 for antimicrobial action ; by NK cell INF-g produce IL-12 for antiviral actions; by TH1 INF-g produce IL-12 for mycobacteria and fungi . Alternative activation (M2)- By IL-4 and IL-13 secrete growth factors (IL-10, TGF-B) that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis to promote tissue repair 2. T lymphocytes: CD4 T cells secrete cytokines that "help inflammation"- TH1 secretes IFN-γ (activates macrophage, promotes B cell class switching from IgM to IgG); TH2 secretes IL-4 (B cell class switching to IgE), IL-5 (eosinophil chemotaxis and activation, class switching to IgA), and IL-13. CD8 T cells for cytotoxic killing 3. B lymphocytes:

Name the CD4+ T cell lymphomas

1. Mycosis fungoides 2. Adult T cell leukemia/lymphoma

Name and describe the neoplastic proliferation of white cells.

1. Myeloid neoplasms 2. Lymphoid neoplasms 3. Histiocytoses

Name the antithrombotic factors of the normal vascular endothelium. What is the result of a defect in these factors?

1. NO & PGI2: vasodilators; inhibit platelet aggregation 2. Antithrombin III 3. Protein C & S : inactivates factor VIII 4. Tissue factor pathway inhibitor (TFPI) 5. Tissue type plasminogen activator (t-PA): cleaves plasminogen to plasmin, which cleaves fibrin to degrade clots defect results in a hypercoaguable state and thrombosis

Recognize the types and patterns of hemorrhage and the causes and consequences of each.

1. Petechiae: found on skin, mucous membranes and serial surfaces due to increased intravascular pressure, low platelet counts, defective platelet function, or loss of vascular wall support 2. Purpura: same as petechiae but can also be secondary to trauma, vascular inflammation or increased vascular fragility 3. Ecchymoses (bruises): subcutaneous; caused by enzymatic degradation of hemoglobin in tissue macrophages

Describe the effects of mutations in specific cancer-associated genes on tumor progression.

1. Point mutation (G12V) in RAS, blocking inhibition of the GTPase, leading to constitutive activation 2. Mutation in RB predisposes patients to retinoblastoma due to loss of heterogeneity. RB normally inhibits E2F, preventing G1 to S. without RB, the cell cycle can proceed unchecked 3. gene amplification e.g. NMYC in neuroblastoma

Name the 5 categories of lymphoid neoplasms.

1. Precursor B-cell: acute lymphoblastic leukemia (ALL) 2. Peripheral B-cell: chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, plasma cell myeloma, diffuse B-cell lymphoma, Burkitt lymphoma 3. Precursor T-cell: acute lymphoblastic leukemia (ALL) 4. Peripheral T-cell and NK cell: Mycosis fungicides/Sezary syndrome, anaplastic large cell lymphoma 5. Hodgkin lymphoma (reed-Sternberg)

Name the WBC diseases of the old.

1. Primary Myelofibrosis 2. Essential Thrombocytopenia 3. CLL/SLL 4. Diffuse large B cell 5. MM 6. MGUS 7. Lymphocyte-depletion Hodgkin Lymphoma 8. Follicular cell, Mantle cell, Marginal (MALT) 9. CML

Explain/describe the role of chemotherapy in the management of cancer patients.

1. Primary induction: in advanced tumor progression with no alternative treatment; the goal is to relieve the tumor-related symptoms, improve overall QOL, and prolong tumor progression 2. Neoadjuvant chemotherapy: in localized cancer goal is to reduce size BEFORE surgery 3. Adjuvant chemotherapy: AFTER surgery therapy in advanced disease; goal is to reduce the incidence of both local and systemic recurrence

Describe the mechanisms of resistance against antineoplastic agents in various cancers.

1. Primary resistance: malignant melanoma, renal cell, brain 2. inherent drug resistance: genomic instability (e.g. p53 mutation) 3. Loss of p53 function: resistance to radiation & wide range of anticancer agents 4. Defect in mismatch repair enzymes: linked to familial sporadic colon cancer (resistant to fluropyrimidines, thiopurines, ciplastin/carboplatin) 5. Must-drug resistance: MDR1 gene (encodes P-glycoprotein) over expression= resistance to vinca, anthracycline, taxanes, etoposide, imatinab

Describe the fate of the thrombus.

1. Propagation: increase in size, increasing the odds of vascular occlusion 2. Embolization: dislodging and transportation though vasculature 3. Dissolution: ONLY in newly formed clots; activation of fibrinolytic factors 4. Organization: invasion of connective tissue elements, becomes firm and grayish white 5. Canalization: new lumina lined by endothelial cells form within thrombus (capillary channels)

Correctly match five tumor markers with the neoplasms with which they are most closely associated.

1. Prostate specific antigen (PSA)- adenocarcinoma of prostate 2. Carcinoembryonic antigen (CEA)- adenocarcinoma of colon, pancreas, stomach 3. Alpha-fetoprotein (AFP)- hepatocellular carcinoma and yolk sac tumor 4. Human chjrinonc gonadotropin (HCG)- choriocarcinoma 5. CA-125- adenocarcinoma of ovary

Describe and differentiate the types of embolism.

1. Pulmonary: 95% from DVT; obstruction of the PA can lead to hemorrhagic pulmonary infarction; saddle emboli= sudden death; 2. Systemic: 80% from mural thrombi (mitral stenosis, MI); paradoxical= venous emboli that cross from the right to left heart and into the circulation 3. Fat embolism: long bone fracture, crushing trauma; marrow found 4. Gas embolism: "the bends" 5. Amniotic fluid embolism: trauma, placenta abruptio; fo to lungs or brain; DIC

Discuss the disorders of chronic inflammation.

1. RA 2. Asthma 3. Atherosclerosis 4. Chronic transplant rejection 5. Pulmonary fibrosis 6. Silicosis 7. Sarcoidosis

Name the blood components available and the indications or contraindications of each.

1. RBCs 2. Leukocyte poor RBCs: prevent febrile reactions to WBC (HLA) antibodies due to previous sensitization 3. Washed red blood cells: plasma removed to prevent anaphylactic reaction especially in patients with IgA deficiency or previous reaction 4. Platelet concentrate: short shelf life 5. Leukocyte concentrate: for serious infections (e.g. sepsis) in patients with REVERSIBLE leukopenia, NOT for use in patients with long term bone marrow suppression 6. Fresh frozen plasma: replaces clotting factors for coagulation defect *NOT used for VOLUME expansion* 7. Cryoprecipitate: Mostly used for fibrinogen replacement (DIC, massive hemorrhage), secondary treatment for von WIllebrand disease if there is no response to DDAVP

Describe the assumptions of the HWP and how exceptions affect allele frequencies.

1. Random mating 2. Population of infinite size 3. No mutation 4. No selection 5. No migration 6. Generations do not overlap

Extrinsic pathway

1. TF binds activated factor VII (VIIa) 2. TF-VIIa complex activates factor X 3. Activated factor X with activated factor V, anionic PLs (from platelets), and calcium as cofactors; convert prothrombin to thrombin

Name and describe the mediators of acute inflammation.

1. TLRs- recognize PAMPS; activation results in NF-KB → genes for production of immune mediators 2. AA metabolites- PGs & LTs 3. Mast cells- release of histamine mediates vasodilation & increased vascular permeability; production of LTs 4. Complement- C3a & C5a trigger mast cell degranulation, resulting in histamine mediated vasodilation and increased vascular permeability, C5a is chemotactic for neutrophils, C5b opsonizes for phagocytosis, MAC lysis 5. Hageman factor (XII)- pro-inflammatory produced by liver; activates coagulation & fibrinolytic systems, complement & Kinin system which mediates vasodilation and increased vascular perm as well as pain 6. Neutrophils- consume pathogens or necrotic tissue; HOCl generated by oxidative burst in phagolysosome destroys phagocytosed microbes

Name the hormones used to treat cancer and their mechanism of action.

1. Tamoxifen: Competative inhibitor of estradiol binding to ER used to treat ER+ breast cancer 2. Aromatase inhibitors (anastrozole, ietrozole): block conversion of androgen to estrogens in treatment of postmenopausal women with breast cancer 3. Flutamide: Inhibits ligand binding and consequent AR translocation form the cytoplasm to the nucleus 4. Glucocordicoids: induces anti-proliferative and apoptotic response in sensitive cells (lymphocyes); used to treat ALL 5. Goserelin/Leuprolide: GnRH agonist used to treat prostate and breast cancer

Describe the impact of human genetic diversity on the maintenance of disease-associated alleles in human populations.

1. The occurrence and risk of genetic disease is a reflection of an individual's family and population history 2. Genetic diversity is contributed by the distribution of disease-associated (and silent) mutations within a population. 3. The field of population genetics addresses the need to determine approximate allele distributions within a population 4. These types of analysis are relevant in clinical diagnosis, risk assessment (genetic counseling), and evolutionary biology.

Primary hemostasis

1. Transient vasoconstriction: reflex neural stimulation and endothelin release form endothelial cells 2. Platelet adhesion:endothelial injury exposes underlying basement membrane ECM; platelets adhere to ECM and become activated by binding vWF through GPIb platelet receptors 3. Platelet degranulation: upon activation, platelets secrete granule products that include calcium (activates coagulation proteins), ADP (promotes exposure of GPIIb/IIIa), and TXA2 (increase platelet activation and vasoconstriction) 4. Platelet aggregation: platelets aggregate via GPIIb/IIIa using fibrinogen as a cross-linking molecule= weak platelet plug

Name the monoclonal antibodies used in the treatment of cancer and the site of action.

1. Trastuzumab: binds HER2/nue (ErbB2) TK 2. Cetuximab: binds to EGFR TK 3. Rituximab: chimeric Ab that targets CD20 on B cells 4. Bevacizumab: targets VEGF

Discuss the differences in inheritance patterns of down syndrome.

1. Trisomy Down syndrome due to random nondisjunction in meiosis: 47, XY, +21, < 1% of the population 2. Translocation down syndrome: 46, XX, t(14q:21q), 33% chance if mother is a carrier

Name and describe the diseases caused by sex chromosome numerical abnormalities.

1. Turner syndrome (45, X)- webbed neck, coarctation of aorta (edema of hands and feet), shield-like-chest, short height 2. Klinefelter syndrome (47, XXY)- small testes, gynecomastia, tall height, infertility

What are the possible causes of abnormal PT/PTT with a normal TT?

1. Vitamin K deficiency 2. Liver diseases 3. Inhibitor effect 4. Factor deficiency in common pathway (II, V, X)

Name the mechanisms regulating cell populations.

1. changes in rates of cell proliferation of differentiation 2. increased or decreased rates of stem cell input 3. cell death by apoptosis

Differentiate the mechanisms of necrosis and give examples of each.

1. coagulative necrosis: necrotic tissue that remains *firm*; cell shape and organ structure are preserved by *coagulation proteins* but the nucleus disappears (e.g. ischemic infarction); often wed-shaped and pale; red infarction in pulmonary or testicular infarction 2. liquefactive necrosis: necrotic tissue that becomes *liquified*; enzymatic lysis of cells and proteins results (e.g. *brain infarction*, bacterial abscess) 3. gangrenous necrosis: coagulative necrosis that resembles mummified tissue (dry gangrene); can result in liquefactive necrosis (wet gangrene) if infection continues (e.g. ischemia of lower limb & GI tract) 4. caseous necrosis: soft and friable necrotic tissue with "cottage cheese-like" appearance; combination of coagulative and liquefactive (e.g. granulomatous inflammation due to TB or fungal infection) 5. fat necrosis- necrotic adipose tissue with chalky white appearance due to deposition of calcium (e.g. trauma to breast, acute pancreatitis, alcoholics, seatbelt injuries); saponification- FAs released by trauma combine with Ca 6. fibrinoid necrosis- necrotic damage to blood vessel wall; leaking of proteins into vessel wall results in bright pink staining (e.g. malignant hypertension, pre-eclampsia, vasculitis)

Recognize features of anaplasia.

1. disorganized growth (loss of polarity) 2. nuclear pleomorphism and hyperchromasia (dark) 3. high nuclear: cytoplasmic ratio 4. high mitotic activity with atypical mitosis 5. invasion (through the BM or into local tissue)

Describe the mechanism of induced pluripotent stem cells.

1. genes that confer stem cell properties are introduced into a patient's differentiated cells 2. giving rise to stem cells 3. which can be induced to differentiate into various lineages

Describe cancer kinetics and dynamics and the effects of anticancer drugs.

1. growth of tumor is not constant (exponential growth is matched by exponential retardation due to blood supply limitations, etc.) 2. the growth rate peaks when tumor is 1/3 its max size 3. for patients with advanced cancer, the tumor mass is larger thus its growth rate is slower and the fraction of cell kill is small 4. cell cycle kinetics explain the limited effectiveness of anticancer drugs in part

Outline the sequence of healing.

1. hematopoietic plug and inflammation 2. proliferation of epithelial cells to form new blood vessels (angiogenesis) 3. formation of granulation tissue (proliferating fibroblasts, LCT, new blood vessels & inflammatory cells), 4. remodeling to produce fibrous scar (collagen III to collagen I)

Discuss complications in repair mechanisms.

1. hypertrophic scar formation- excess production of scar tissue proportional to the wound 2. keloid- excess production of scar tissue that is out of proportion to the wound (more prominent in AAs; upper extremities, faces, earlobes) 3. Dehiscence- rupture of a wound (abdominal surgery) 4. contracture- deformity of infection (esp. burn wounds)

What prolongs thrombin time (TT)?

1. hypofibrinoginemia 2. dysfibrinoginemia 3. heparin use or contamination 4. DIC

List some potential local effects of tumors.

1. impingement or destruction of surrounding structures due to expansile growth 2. obstruction of tubular structures 3. ulceration 4. secondary infection 5. bleeding 6. torsion, rupture, infarction

Discuss the pathophysiologic categories of edema.

1. increased hydrostatic pressure: A. Impaired venous return- CHF, ascites (liver cirrhosis) venous obstruction or compression (thrombosis, lower extremity inactivity) B. Arteriolar dilation- heat 2. Reduced osmotic pressure: hypoproteinemia- protein losing nephrotic syndromes, liver cirrhosis (ascites), malnutrition 3. Lymphatic obstruction- filariasis, breast cancer (peau d'orange) 4. Sodium retention- Excessive salt intake with renal insufficiency 5. Inflammation (increased vascular permeability) 6. Edema of the brain: focal (infarct, abscess, neoplasm) or generalized (encephalitis); trauma can cause both

Identify the pathologic features of SIDS.

1. intrathoracic petechiae- pleural surfaces of lungs, thymus, gasping in final seconds of life burst capillaries (centrally mediated airway failure such as apnea) 2. pulmonary congestion and edema 3. minor airway inflammation 4. absence of significant stress findings 5. absence of an acceptable alternative cause of death

List three pathways by which malignant tumors often metastasize.

1. lymphatic spread 2. hematogenous spread- most sarcomas 3. direct seeding of body cavities/surfaces

Y-linked pedigree analysis.

1. male-to-male inheritance only 2. if a male has a trail, it should be observed in his father and his sons 3. no affected females

Describe chromosome structure.

1. metacentric 2. sub-metacentric 3. acrocentric: 13, 14, 15, 21, 22; short p arms contain tandemly repeated rDNA genes

Autosomal recessive pedigree.

1. most affected individuals are children of phenotypically normal parents. 2. Often more than one child of sibship is affected (1/4 on average) 3. males and females equally likely 4. affected persons who marry normal persons tend to have phenotypically normal children 5. when a trait is exceedingly rate, the responsible allele is most likely a recessive trait if their is an undue proportion of marriages of close relatives among the parents of the affected offspring 6. unaffected siblings have a 66% chance of being carriers

Recognize the clinical manifestations of Wilm's tumors.

1. peak age= 2-4 years, rare in infancy or over 10 2. large abdominal mass (usually asymptomatic), may present with pulmonary metastases; often noticed when bathing the baby 3. increased risk with Beckwith-Wiedeman syndrome- macroglossia, kidney, and other visceromegaly, and hyperinsulemic hypoglycemia; WAGR syndrome- genitourinary malformations, aniridin, mental retard + WT; Denys-Drash syndrome- genital problems + WT 4. 11p deletion (WT1) gene

Explain the origin of genetic variation in individuals and populations.

1. point mutations (single nucleotide polymorphisms): missense, nonsense, silent, promoter/control region 2. insertions/deletions 3. translocations population isolation can lead to the accumulation of disease-associated alleles due to non-random mating and genetic drift

Who should you prophylaxis with folate?

1. pregnant 2. alcoholics 3. liver failure (↓stores) 4. hemolytic anemia 5. renal dialysis

Describe conventional and contemporary approaches to treatment of genetic diseases and genetic variation.

1. protein replacement (e.g insulin in diabetes, ADA in ADA deficiency) 2. dietary restriction (e.g low phenylalanine in PKU, low fat diet in hypercholesterolemia) 3. dietary supplementation (e.g. high carb diet in glycogen storage diseases, cholesterol in Smith-Lemil-Opitz syndrome) 4. removal of toxic product (e.g. bleed regularly in hemochromatosis) 5. stem cell therapy (e.g. BMT) patients should be screened for genetic variations in drug metabolizing enzymes/transporters for most effective treatment (e.g. CYP2D6 polymorphisms and morphine)

Describe the cardinal signs of acute inflammation.

1. redness (erythema) & warmth: histamine, prostaglandins, and bradykinin relax arterial SM resulting in vasodilation and increased blood flow 2. swelling: leakage of fluid from *postcapillary venues* into the interstitial space (exudate) due to histamine mediated endothelial cell contraction and tissue damage 3. pain: bradykinin and PGE2 sensitize nerve endings 4. fever: pyrogens (LPS) cause macrophages to release IL-1 & TNF which increase cyclooxyrgenase (COX) activity in perivascular cells of the hypothalamus; increased PGE2 raises temperature set point 5. loss of function

Name two tumors that commonly invade large veins and spread by direct extension without separation from the primary mass.

1. renal cell carcinoma 2. hepatocellulr carcinoma

Describe the molecular and cellular basis of cancer (i.e., The Hallmarks of Cancer).

1. self sufficiency in growth signals 2. insensitivity to anti-growth signals 3. evading apoptosis 4. sustained angiogenesis 5. limitless replicative potential 6. tissue invasion and metastasis

Autosomal dominant pedigree.

1. the affected offspring has one affected parent, unless the gene for the abnormal effect was the result of a new mutation. 2. unaffected persons do no transmit the trait to their children 3. males and females are equally likely 4. the trait is expected in every generation 5. the presence of two mutant alleles general presents with a more severe phenotype. Detrimental dominant traits rarely observed in homozygote

A 10 yo girl presents to your oncology clinic for follow up of her acute lymphoblastic leukemia, for which she is currently receiving chemotherapy. She was recently discharged from the hospital 2 days prior to her appointment at your clinic. Her mother tells you that the patient developed an episode of acute gout while in the hospital, after which she was placed on allopurinol in order to prevent future gouty attacks. You immediately decide to alter the doses of the patients chemotherapeutic regimen, as allopurinol directly inhibits the metabolism of one of the drugs in the patients chemotherapy regimen and can result in increased serum levels of this drug.

6-mercaptopurine (6-MP)

6-Thiopurines

6-thioguanine (6-TG), 6-Mercaptopurine (6-MP) MOA: purine antagonists; Inhibits purine synthesis; incorporates triphosphate into RNA & DNA, induction of apoptosis A/E: metabolized by thiopurine methyltransferases (TPMP); patients lacking the enzyme develop severe toxicities

Identify the pathologic features of Hirschsprung's disease.

A developmental problem caused by arrest of migration of neural crest cells before reaching anus; congenital absence of enteric ganglion cells; functional obstruction with dilatation proximal to affected segment rectal biopsy looking for ganglion hypertrophy, hypertrophied nerve trunks w/ acetylcholine esterase stain

Define myelodysplastic syndromes and name common clinical and hematologic features associated with them.

A group of clonal stem cell disorders characterized by maturation defects that are associated with a variable risk of transformation to AML; the abnormal cells stay in the bone marrow and the patients have peripheral blood cytopenias and chromosomal abnormalities (monosomes 5 & 7; deletions of 5q, 7q, and 20q; trisomy 8)

Describe lymphoid neoplasms

A group of tumors of B-cell, T-cell, and NK-cell origin; They are further divided into precursor and mature (or peripheral) categories; May present as lymphadenopathy/mass only (lymphoma) or/also marrow involvement (leukemia)

What is the pseudoautosomal region (PAR) and what are the implications of this?

A homologous region found on the X and Y chromosomes that escapes X inactivation. Any numerical anomaly (monogamy, trisomy etc.) will alter dosage of these genes e.g. SHOX genes. Thus Turner female have only one SHOX and are generally phenotypically short while Klinefelter males have 3 copies and are characteristically tall. Additionally, SRY is near PAR thus recombination may translocate this gene to the X chromosome resulting in reversal of sex phenotypes.

Understand the pathophysiology of antiphospholipid antibody syndrome.

A hypercoaguable state due to antiphospholipd antibodies (especially lupus anticoagulant). Results in arterial and venous thrombosis including deep venous, hepatic vein, placental (recurrent pregnancy loss), and cerebral (stroke) thrombosis. Requires lifelong anticoagulation

Define granuloma and discuss the constituents.

A microscopic aggregation of epithelioid macrophages surrounded by a collar of mononuclear leukocytes (lymphocytes, few plasma cells) that may become encased in fibroblasts and connective tissue Giant cells= fused epithelia macrophages; Langerhans in the periphery or haphazard foreign body

Understand the pathophysiology of DIC.

A. Pathological activation of the coagulation cascade leads to microthrombi with ischemia and infarction. Consumption of platelets (↓platelet count) and factors (↓fibrinogen) results in bleeding, especially from IV sites and mucosal surfaces. B. ↑PT/PTT due to ↓platelets & fibrinogen, ↑D-dimer due to fibrinolysis, microangiopathic hemolytic anemia C. Secondary to disease processes such as obstetric complications, sepsis, adenocarcinoma, acute promyelocytic leukemia, rattlesnake bite

Define neoplasm.

An abnormal mass of tissue, in which the growth persists after apparent cessation of the stimuli that evoked the change; may be benign or malignant cancer= any malignant neoplasm

Differentiate embolism from infarction.

An infarction is an area of ischemic necrosis caused by occlusion of vascular supply to tissues. 99% of infarcts are from thrombotic or embolic events

t(2;5)

Anaplastic large T cell lymphoma

Utilize CBC parameters to categorize disorders of RBCs.

Anemia= Hb< 13.5 g/dL in males & Hb< 12.5 g/dL in females Based on mean corpuscular volume (MCV), anemia can be classified as: microcytic (< 80 µm³) normocytic (80-100 µm³) macrocytic (> 100 µm³)

Describe necrosis vs. apoptosis.

Apoptosis is stimulated by programmed tissue remodeling, maintenance of cell pool size, or genomic damage; individual cells decrease in cell volume and condenses their chromosomes in preparation to be consumed by neighboring cells. Necrosis is caused by metabolic stress, lack of nutrients, changes in pH & temp, hypoxia, anoxia; groups of cells swell and lyse without cell signal, causing a marked inflammatory response.

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)

B cell lymphoma (CD20+) with monoclonal IgM production which causes a hyperviscosity syndrome (visual impairment, cryoglobulinemia, neurological problems, bleeding) BM: lymphocytes and plasma cells

t(12;21)

B-ALL (good prognosis)

Compare and contrast the absorption of B12, folate, and iron.

B12: heat stabile absorbed in ileum; high stores in liver (symptoms take a while to develop) Folate: heat labile; absorbed in proximal Jejunum; low liver stores (symptoms in days) iron: absorbed in duodenum and proximal jejunum; too much can kill you (Fenton rxn) thus uptake is regulated; Fe2+ is active, Fe3+ is stored and transported

Discuss hormone production by endocrine and non-endocrine neoplasms.

Benign OR malignant endocrine tumors can secrete their normal products. Some non-endocrine *malignant* tumors can ectopically secrete hormones (e.g. paraneoplastic syndrome)

Taxanes

Bind to MT with high affinity, enhancement of tubulin polymerization, inhibition of cell division (M-phase specific) 1. Paclitaxel (Taxol)- neuropathy 2. Docetaxel 3. Carbazitaxel- not a P-gp substrate 4. Abraxane (less side effects)

Paroxysmal cold hemoglobinuria (PCH)

Biphasic IgG (Donath-Landsteiner) against P-blood group antigen; binds compliment at low temp resulting in complement activation and intravascular hemolysis at body temp associated with measles, mumps, viral, flu-like, self-limiting

Describe the typical peripheral blood and bone marrow morphologic findings of acute myelogenous leukemia (AML).

Bone marrow: blasts > 20% PBS: prominent nucleoli, fine azurophilic granules in cytoplasm, Auer rods

t(8;14)

Burkitt's Lymphoma; c-myc to IgHC