Hema & Onco

Folate deficiency. The patient has a macrocytic anemia associated with malnutrition and presumed decreased consumption of folate-rich foods and chronic alcoholism. A major source of folate is grains and green leafy vegetables, but folate absorption is decreased in the presence of chronic alcoholism. This patient is at risk for folate deficiency based on his homelessness, cachetic appearance suggesting malnutrition, and chronic alcoholism. Folate is not efficiently stored, and folate deficiency can develop within weeks of inadequate intake. Measuring the folate level is often of limited utility because of the ease and safety of initiating folate replacement. This patient should receive supplemental folate in addition to mental health and social service support.

A 56-year-old man is brought to the emergency department after being found lying unresponsive in the local train station. Medical history is significant for chronic alcohol dependence. He is homeless. The patient is a frequent visitor to the emergency department for minor trauma and ailments; his last visit was 6 months ago. Until that time, the patient lived in various shelters and received at least one nutritious meal per day. His whereabouts and living circumstances since that time are unknown. His medical history is otherwise not significant, and at his last visit to the emergency department, he was taking no medications. On physical examination, vital signs are normal. The patient is disheveled, cachectic, and malodorous. He moans in response to painful stimuli and moves all extremities. He has poor dentition. Hepatomegaly is noted. Laboratory studies: Hemoglobin 7.4 g/dL (74 g/L), Leukocyte count 4200/µL (4.2 × 109/L) ,Mean corpuscular volume 110 fL, Platelet count 97,000/µL (97 × 109/L) ,Reticulocyte count 1% of erythrocytes , Blood alcohol level 500 mg/dL (108 mmol/L). Hypersegmented neutrophils are seen on the peripheral blood smear.Which of the following is the most likely cause of this patient's anemia?

Parvovirus B19 infection. presenting with pure red cell aplasia (PRCA). Patients with sickle cell anemia have chronic hemolysis and depend on increased erythrocyte production to maintain the hemoglobin level. Parvovirus B19 infection preferentially affects erythrocyte precursors in the bone marrow, causing transient PRCA. This patient's very low reticulocyte count is consistent with the decreased erythrocyte production seen in PRCA. Infection with parvovirus B19 in children can present as erythema infectiosum with fever and rash. Although adults can have flu-like illness and arthralgia, most are asymptomatic. However, in patients with hemolytic anemia, it can present with transient aplastic crisis. Supportive transfusions are usually required to treat symptoms from severe anemia.

A 22-year-old woman is evaluated in the emergency department for a 2-day history of progressive fatigue and shortness of breath. Medical history is significant for sickle cell disease diagnosed at age 6 years. Her sickle cell disease is under good control with rare crisis. Medications are hydroxyurea and folic acid. On physical examination, temperature and blood pressure are normal, pulse rate is 125/min, and respiration rate is 25/min. Oxygen saturation is 93% breathing ambient air. Lungs are clear without wheezing. Other examination findings are unremarkable. Laboratory studies: Hemoglobin 4 g/dL (40 g/L), Leukocyte count 13,000/µL (13 × 109/L), Platelet count 500,000/µL (500 × 109/L) , Reticulocyte count 0.1% of erythrocytes. Chest radiograph is normal Which of the following is the most likely diagnosis?

Rituximab. She has profound anemia and evidence of intravascular (decreased haptoglobin, hemoglobinuria, elevated lactate dehydrogenase) and extravascular (elevated indirect hyperbilirubinemia level) hemolysis. The positive direct antiglobulin test showing C3 on erythrocytes with agglutinated erythrocytes on the peripheral blood smear suggests cold agglutinin autoimmune hemolytic anemia. The improbably high mean corpuscular volume (MCV) calculated by the Coulter counter likely reflects measurement of agglutinated cells, although the reticulocytosis will also elevate the MCV. This disease can be primary, with no other underlying disorders, but may be associated with lymphoproliferative disorders, such as Waldenström macroglobulinemia, other B-cell non-Hodgkin lymphomas, and IgM monoclonal gammopathy of undetermined significance. Cold agglutinin disease may also be precipitated by infections, typically Mycoplasma pneumoniae or Epstein-Barr virus. In cold agglutinin disease, IgM antibodies are directed against erythrocyte antigens, resulting in complement fixation and intravascular hemolysis as well as clearance of complement-coated erythrocytes by Kupffer cells in the liver. Rituximab, a monoclonal antibody to the B-cell antigen CD20, has shown efficacy in case series of patients with cold agglutinin disease. Additionally, all patients with cold agglutinin disease should be kept warm, and all infusions should be administered at body temperature.

A 32-year-old woman is hospitalized with progressive exertional dyspnea. She has noted dark urine for the last week and yellowing of her skin for several days. Medical history is unremarkable, and she takes no medications. On physical examination, temperature is 36.7 °C (98.0 °F), blood pressure is 100/70 mm Hg, pulse rate is 100/min, and respiration rate is 18/min. Icteric sclera and skin are noted. Cardiac examination reveals a grade 2/6 systolic flow murmur. No lymphadenopathy or hepatosplenomegaly is present. The remainder of the examination is noncontributory. Laboratory studies: Haptoglobin Undetectable ,Hemoglobin 4.8 g/dL (48 g/L), Leukocyte count 8200/µL (8.2 × 109/L), Mean corpuscular volume 134 fL ,Platelet count 230,000 (230 × 109/L), Reticulocyte count 12% of erythrocytes ,Bilirubin Total 6.7 mg/dL (114.6 µmol/L) ,Direct 1.2 mg/dL (20.5 µmol/L), Lactate dehydrogenase 660 U/L ,Urinalysis Dipstick positive for 4+ blood; 0-1 leukocytes/hpf, and 0 erythrocytes/hpf. A peripheral blood smear shows erythrocyte agglutination. A direct antiglobulin (Coombs) test is positive for C3. Diagnostic testing for Mycoplasma and Epstein-Barr virus is negative.Which of the following is the most appropriate treatment?

α-thalassemia trait. This patient has a chronic microcytic anemia. Patients with α-thalassemia trait have inadequate production of two copies of the α gene on chromosome 16 (α−/α− or −−/αα). Such patients have a chronic microcytic anemia with hemoglobin levels of approximately 10 g/dL (100 g/L). Hemoglobin A levels, although reduced in quantity, are otherwise normal in these patients and will migrate in a normal pattern on electrophoresis. Furthermore, there is no increase in the minor hemoglobin components, hemoglobin A2 and hemoglobin F. It is possible to identify specific chromosomal abnormalities that establish the diagnosis of α-thalassemia, but physicians typically make a clinical diagnosis based on family history, complete blood count, peripheral blood smear, and hemoglobin electrophoresis and by ruling out other causes of microcytic anemia. Patients with thalassemia should receive supplemental folate but should not receive iron supplementation; they are not iron deficient and they have an increased ability to absorb iron, which can lead to iron overload. Genetic counseling may be indicated in reproductive planning.

A 22-year-old woman undergoes routine evaluation for chronic anemia, which was diagnosed 6 years ago. Medical history is otherwise unremarkable, but a maternal aunt also has anemia. Her only medication is a combination oral contraceptive pill. On physical examination, vital signs are normal. No hepatosplenomegaly is noted.Laboratory studies: Hemoglobin 10 g/dL (100 g/L) ,Mean corpuscular volume 67 fL ,Iron studies ,Ferritin 200 ng/mL (200 µg/L) , Iron 150 µg/dL (27 µmol/L) ,Total iron-binding capacity 340 µg/dL (61 µmol/L). Hemoglobin electrophoresis reveals a normal pattern of migration of hemoglobin A and normal levels of hemoglobin A2 and hemoglobin F. Which of the following is the most likely diagnosis?

Flow Cytometry. This patient has pancytopenia with significant intravascular hemolysis and hemoglobinuria, most likely caused by paroxysmal nocturnal hemoglobinuria (PNH). Patients with PNH commonly note fatigue and nonspecific abdominal pain, which worsens during times of increased hemolysis. These patients have a mutation in the gene that regulates production of glycophosphatidylinositol-anchoring proteins. Flow cytometry will demonstrate the absence of glycophosphatidylinositol-linked proteins, such as CD55 and CD59, on leukocytes; these proteins normally prevent complement activation on the erythrocyte surface. Bone marrow aplasia and corresponding pancytopenia in these patients are common, and they have an increased risk of evolving to a myelodysplastic syndrome or acute leukemia. Patients with PNH also have an increased risk for thrombotic complications, including thrombi in unusual sites, such as the portal venous system or sagittal veins in the central nervous system.

A 24-year-old man with progressive fatigue and intermittent dark urine over several months is evaluated in the emergency department for exertional dyspnea, abdominal pain, and red urine. On physical examination, he is pale. Temperature is 37.0 °C (98.6 °F), blood pressure is 110/70 mm Hg, pulse rate is 112/min, and respiration rate is 16/min. Oxygen saturation is 98% breathing ambient air. Scattered petechiae are visible on the skin. The abdomen is not distended and is diffusely tender to palpation without guarding. Bowel sounds are normal. The remainder of the examination is normal. Laboratory studies: Haptoglobin Undetectable , Hemoglobin 7.2 g/dL (72 g/L) ,Leukocyte count 1200/µL (1.2 × 109/L) with 70% neutrophils and 30% lymphocytes , Mean corpuscular volume 84 fL ,Platelet count 23,000/µL (23 × 109/L) ,Reticulocyte count 8% of erythrocytes, Lactate dehydrogenase 500 U/L ,Urinalysis 4+ blood; 0-1 erythrocytes/hpf; 0 leukocytes/hpf. The peripheral blood smear shows normal-appearing erythrocytes without spherocytes, schistocytes, agglutinated erythrocytes, or immature-appearing leukocytes. Which of the following is the most appropriate next test?

Antithrombin deficiency (ATD). This patient's clinical presentation is consistent with heparin resistance, which occurs when the activated partial thromboplastin time (aPTT) does not increase into the therapeutic range despite increasing doses of heparin or when unusually high doses of heparin are required to achieve a therapeutic aPTT. Heparin achieves its anticoagulant effect through antithrombin. The heparin-antithrombin complex then inactivates thrombin, activated factor X (fXa), and other activated clotting factors. If the amount of available antithrombin is decreased, a reduced response to heparin is seen. Heparin resistance can also occur with increased clearance of heparin or an increase in acute phase reactant proteins such as factor VIII, which can bind to and neutralize heparin. ATD is diagnosed by assaying antithrombin activity. Acquired causes must be ruled out.

A 24-year-old woman is admitted to the hospital with a right lower lobe pulmonary embolism. Her mother experienced a deep venous thrombosis 25 years ago. Weight-based intravenous heparin is initiated. On physical examination, temperature and blood pressure are normal, pulse rate is 120/min, and respiration rate is 19/min. Oxygen saturation is 91% breathing ambient air. The examination is otherwise unremarkable. Despite appropriately increasing doses of heparin, her activated partial thromboplastin time remains in the normal range. Which of the following is the most likely diagnosis?

Echocardiography. The patient's symptoms, cardiac examination, and electrocardiography suggest pulmonary hypertension (PH). PH is associated with significant morbidity and a 30% to 50% mortality rate. Prevalence is approximately 10% in nonpregnant patients but increases in women with sickle cell disease (SCD) who become pregnant. Risk factors for development of PH include severity of anemia, iron overload from transfusions, and history of thromboembolic disease. Although cardiac ultrasonography may underestimate the severity of PH, it remains a useful initial noninvasive screening test even if right heart catheterization is eventually required to more definitively evaluate the hemodynamics.

A 24-year-old woman is evaluated for an episode of syncope. She is in her sixth month of pregnancy. She reports exertional dyspnea and occasional chest pain. She has sickle cell disease characterized by acute pain events occurring four to five times per year, typically not requiring hospitalization. She had an episode of acute chest syndrome 1 year ago, at which time she received exchange transfusion. Medications are a prenatal multivitamin and folic acid supplement. On physical examination, temperature is 37 °C (98.7 °F), blood pressure is 90/60 mm Hg, pulse rate is 110/min, and respiration rate is 20/min. Oxygen saturation is 98% breathing ambient air. Cardiac examination reveals a parasternal heave. The pulmonic component of the S2 is accentuated, and a holosystolic murmur that increases with inspiration is heard at the apex. Other examination findings are normal. Electrocardiography reveals right axis deviation, a tall R wave in lead V1, and inverted T waves in V1 to V3. Laboratory studies: Hemoglobin 8.2 g/dL (82 g/L) ,Leukocyte count 13,600/µL (13.6 × 109/L) ,Platelet count 385,000/µL (385 × 109/L), Reticulocyte count 7% of erythrocytes. Which of the following is the most appropriate diagnostic test to perform next?

Delay Chemotherapy until counseled by fertility specialist. Young women with cancer who may wish to bear children after cancer treatment can be seen emergently and counseled about their options. An established fertility preservation option for a woman with a partner is in vitro fertilization with embryo freezing. Newer options include freezing of unfertilized eggs and ovarian cryopreservation with future reimplantation. Delaying initiation of chemotherapy for a brief time in a stable patient so she can be assessed and eggs or embryos harvested if appropriate is acceptable. Premenopausal women with breast cancer who do not wish to become pregnant should use a nonhormonal method of birth control.

A 38-year-old woman is evaluated. She has just been diagnosed with hormone receptor-negative, HER2-positive stage II infiltrating ductal breast cancer. She takes no medications. Neoadjuvant chemotherapy with docetaxel, trastuzumab, and pertuzumab is planned; a port has been placed, and treatment is to start next week. The patient has a 2-year-old daughter and has very recently decided that she wishes to conceive again. On physical examination, vital signs are normal. A 2.5-cm left breast mass is noted, with no regional lymphadenopathy. Which of the following is the most appropriate management?

Hemoglobin S β-thalassemia. Patients with Sβ-thalassemia generally have milder disease than those homozygous for hemoglobin S (HbS). However, patients with Sβ-thalassemia can have painful crises of varied frequency and intensity. Some of the variability in presentation depends on the relative expression of the β-globin gene (from β+ to β0), which in turn determines the relative amount of hemoglobin A (HbA). Most black persons with Sβ-thalassemia are β+ and have between 5% and 30% HbA; the more HbA present, the less severe the symptoms and fewer the complications. Occasionally, with a milder disease course, patients do not present until adolescence or early adulthood. Hemoglobin electrophoresis is essential in making a specific diagnosis of a sickling disorder. Patients with Sβ-thalassemia have a slightly reduced hemoglobin level and microcytic erythrocytes. Characteristically, their HbS levels are about 60%. In contrast, patients with sickle cell trait have HbS levels well below 50%, typically closer to 30%, and proportionally more HbA. More notably, patients with sickle cell trait do not experience painful crises and have normal hemoglobin levels.

A 24-year-old woman is evaluated for severe pain in her arms and legs of 5 hours' duration. Medical history is notable for lifelong mild anemia and four episodes of similar pain without precipitating factors, each episode resolving in 3 to 4 days. She has a cousin with sickle cell disease. She takes no medications. On physical examination, vital signs are normal. She has normal range of motion in all joints with no skeletal deformities. Laboratory studies: Hemoglobin 11.2 g/dL (112 g/L) ,Mean corpuscular volume 76 fL Hemoglobin electrophoresis Hemoglobin A 33% ,Hemoglobin A2 4%, Hemoglobin S 63% ,Hemoglobin F 0% Which of the following is the most likely diagnosis?

Temporarily stop rivaroxaban in 1 year and test 2 weeks later. Long-term anticoagulation is indicated in the setting of idiopathic thrombosis. Because of the unprovoked nature of this patient's thrombotic event, his thrombotic risk remains high even after 3 months of anticoagulation. Therefore, it is safer to continue anticoagulation for 1 year before testing. Testing for inherited thrombophilia remains controversial. Guidelines and systematic reviews recommend against routine population screening or screening in most adults with idiopathic venous thromboembolism (VTE) and in asymptomatic family members of patients with VTE and known factor V Leiden or prothrombin G20210A gene mutation. Most experts agree that thrombophilia evaluation can be considered in select populations, such as patients with thromboses at unusual sites or recurrent idiopathic thrombosis, patients younger than 45 years with unprovoked thrombosis, patients with VTE and a clear family history of thrombosis in one or more first-degree relatives, and patients with warfarin-induced skin necrosis. After an informed discussion of the risks and benefits of testing, patients who desire evaluation should receive genetic counseling before testing. Testing typically focuses on factor V Leiden mutation; prothrombin G20210A mutation; protein C, protein S, and antithrombin deficiencies; and antiphospholipid antibody syndrome. However, the thrombophilia evaluation should not be performed during an acute episode of thrombosis. Additionally, although genetic tests such as factor V Leiden and prothrombin gene mutation can be performed at any time, the other assays can be variably affected by the presence of an acute thrombosis, heparin, and other anticoagulants. For example, during the acute phase of thrombosis, plasma levels of antithrombin and occasionally proteins C and S may transiently decrease, and fibrinogen and factor VIII levels may increase. Depending on the assay used, dabigatran therapy may result in increased measurements of antithrombin and protein S and C levels, whereas the factor Xa inhibitors (for example, rivaroxaban and apixaban) may result only in increased measurements of antithrombin. Warfarin therapy reduces vitamin K-dependent factors, including proteins C and S, which do not resolve for 4 to 6 weeks after discontinuation. Most experts agree that with the exception of testing for genetic mutations, testing should not be done in the acute setting or while receiving anticoagulant therapy and should be delayed at least 2 weeks after discontinuation of anticoagulant therapy to minimize diagnostic error.

A 26-year-old man undergoes follow-up evaluation after hospitalization for deep venous thrombosis last week. He reports no recent travel, surgery, or immobilization. He has a sister who was diagnosed with an unprovoked deep venous thrombosis 1 year ago at 35 years of age. Medical history is otherwise unremarkable. His only medication is rivaroxaban. On physical examination, vital signs are normal. The examination is otherwise unremarkable. The possibility of an inherited thrombophilia is discussed with the patient. After reviewing the risks and benefits of additional testing, he would like to be further evaluated for a possible thrombophilia. Which of the following is the ideal testing strategy?

Lipid profile and fasting blood glucose. Adult survivors of childhood leukemia (primarily acute lymphoblastic leukemia [ALL]) have health risks largely secondary to the cancer therapy they received. Requesting a treatment summary or referral to a survivor clinic at a comprehensive cancer center is the first step in providing care. Increased risks of cardiovascular disease, the metabolic syndrome, and secondary cancer are the most relevant concerns. Compared with control populations, survivors of ALL are more likely to have features of the metabolic syndrome, including high BMI, truncal obesity, dyslipidemia, insulin resistance, and hypertension. Screening for lipid profile, diabetes, and hypertension is recommended by multiple guidelines for adult survivors of childhood ALL.

A 27-year-old woman arrives to establish primary care. She feels well. Her last menstrual period was 2 weeks ago, and menses are regular. Medical history is significant for acute lymphoblastic leukemia diagnosed at 5 years of age. She received treatment for 2 years and has been leukemia free since the completion of therapy. She takes no medications. On physical examination, vital signs are normal; BMI is 27. Other examination findings are unremarkable. Complete blood counts performed within the past year were normal. The patient will arrange a treatment summary to be transferred to the office. Which of the following is the most appropriate test to obtain next in this patient?

Now. Annual mammography or breast MRI starting now is the most appropriate screening strategy in this patient. She has a history of radiation to the chest wall to treat Hodgkin lymphoma at age 19 years and is at high risk for breast cancer. Among this group, the cumulative breast cancer incidence by age 40 to 45 years ranges from 13% to 20% and is similar to that in BRCA gene mutation carriers. The risk varies with the dose of radiation used, and the strength of the screening recommendation is highest for women who received the highest dose of radiation (20 Gy or higher). For women with low- to moderate-dose chest radiation (less than 20 Gy), the decision to screen should be an individual one, taking into account additional risk factors and patients' values. The increased risk for breast cancer begins within 8 years after treatment. The International Late Effects of Childhood Cancer Guideline Harmonization Group recommends that for women who received chest wall radiation before the age of 30 years, screening should begin at age 25 years or 8 years after completion of radiation therapy, whichever is last. The Guideline Harmonization Group notes that the ideal screening modality is unknown because of a lack of sufficient evidence, but breast MRI, mammography, or a combination of mammography and breast MRI are all reasonable choices. National Comprehensive Cancer Network guidelines recommend annual mammography and MRI starting after age 25 for patients receiving radiation between ages 10 and 30, beginning 8 to 10 years after irradiation.

A 27-year-old woman seeks advice on breast cancer screening recommendations. Medical history is significant for stage IIB Hodgkin lymphoma diagnosed at age 19 years, treated with mantle and para-aortic radiation; there has been no evidence of recurrence. The patient is premenopausal and has no family history of breast or ovarian cancer. She takes no medications. On physical examination, vital signs are normal. BMI is 28. There is a healed right supraclavicular incision from a previous lymph node biopsy. Breast examination findings are normal. When should this patient begin breast cancer screening?

Measure β-human chorionic gonadotropin and α-fetoprotein levels. In the setting of unilateral testicular swelling or a palpable testicular mass in a young man, cancer is a diagnosis of exclusion. This patient has unilateral testicular swelling. Physical examination and ultrasonography both point to the presence of a testicular mass. Although extrinsic processes can cause testicular swelling, ultrasonography is very accurate in differentiation of intrinsic from extrinsic testicular pathology. In a patient found to have a testicular mass, the diagnosis of cancer must be confirmed histologically. Germ cell tumors are the most common type of testicular cancer. These tumors can be pure seminomas or nonseminomas. However, before histologic confirmation, α-fetoprotein and β-human chorionic gonadotropin levels should be measured to most accurately determine stage and prognosis. The serum α-fetoprotein level is never elevated in patients with pure seminomas, and β-human chorionic gonadotropin is elevated in only approximately 20% of patients with pure seminomas. Nonseminomatous germ cell tumors can contain elements of seminoma, but those elements are mixed with tumors with nonseminomatous histologies, which include yolk sac tumor, choriocarcinoma, and embryonal carcinoma. This distinction is important for determining the correct treatment. However, these measurements do not determine diagnosis and are not a substitute for histologic evaluation. Because levels will fall after orchiectomy, measurement before surgery is recommended. Failure of the levels to fall suggests inadequate therapy, and elevation of the levels after treatment suggests recurrent disease.

A 28-year-old man is evaluated for a 1-month history of right testicular swelling. His medical history is unremarkable, and he takes no medications. On physical examination, vital signs are normal. Palpation reveals an enlarged right testicle that is firm and mildly tender. Scrotal ultrasonography shows a 5-cm right testicular mass. Which of the following is the most appropriate management?

Drug Induced Hemolysis. She has an acute anemia in association with ceftriaxone treatment for Lyme-related meningoencephalitis. Acute anemia in hospitalized patients should raise the suspicion for blood loss (including from laboratory testing) or hemolysis. An elevated lactate dehydrogenase level along with the positive direct antiglobulin test (DAT) and spherocytes on the peripheral blood smear should further raise suspicion for hemolysis from an IgG autoantibody. Many drugs are associated with drug-induced hemolytic anemia, and antibiotics are the most frequently encountered cause of this condition, with ceftriaxone being one of the most common. It is believed that ceftriaxone may become affixed to the erythrocyte membrane, leading to an immune reaction resulting in erythrocyte hemolysis. Treatment of drug-induced hemolysis involves stopping the offending drug. Importantly, Lyme disease itself is not associated with hemolysis.

A 28-year-old woman is evaluated for severe anemia. She was admitted to the hospital 5 days ago for Lyme-related meningoencephalitis. Her only medication is intravenous ceftriaxone. On physical examination, temperature is 36.7 °C (98.0 °F), blood pressure is 110/70 mm Hg, pulse rate is 100/min, and respiration rate is 15/min. She is alert and oriented. She has icteric sclera. Cardiac examination is normal, and no lymphadenopathy or organomegaly is noted. Laboratory studies: Hemoglobin 6.5 g/dL (65 g/L), Leukocyte count 11,000/µL (11 × 109/L), Platelet count 145,000/µL (145 × 109/L) ,Reticulocyte count 10% of erythrocytes, Lactate dehydrogenase 400 U/L. The peripheral blood smear shows occasional spherocytes. A direct antiglobulin (Coombs) test is positive for IgG.Which of the following is the most likely diagnosis?

Germ cell chemotherapy regimen. The most appropriate treatment is a germ cell chemotherapy regimen of cisplatin and etoposide. Cancer of unknown primary (CUP) is a diagnosis of exclusion established in patients with a solid metastatic tumor after a detailed medical history and physical examination have been done and imaging studies or other diagnostic studies have not identified a primary tumor site. Diagnostic efforts should focus on identifying whether a patient is among the approximately 20% of patients with CUP who fall into identifiable subgroups with a more favorable prognosis and who can benefit from a specific treatment strategy. A biopsy obtained from the site that can be sampled in the safest, least invasive manner is done, and specimens are often evaluated by immunohistochemical stains consistent with the tumor's pattern of presentation to attempt to establish a diagnosis of a more treatable subtype of CUP. The patient is a young man with a poorly differentiated CUP site that is predominantly midline in presentation. In the absence of an identified primary tumor, these patients should be treated presumptively for metastatic germ cell tumor. The absence of abnormal findings on testicular examination or ultrasonography or the absence of germ-cell specific markers, such as α-fetoprotein and β-human chorionic gonadotropin, does not exclude this diagnosis or this course of action. Even if these evaluation results are negative, an unrecognized germ cell tumor may still exist, and these patients should be treated for this possibility with a platinum-based chemotherapy regimen.

A 29-year-old man is evaluated for a 2-month history of night sweats, fevers, a sense of abdominal fullness, and fatigue. He takes no medications. On physical examination, vital signs are normal. The abdomen is distended with diffuse tenderness without rebound or guarding. Bowel sounds are normal. Other examination findings are normal. Laboratory results, including complete blood count and serum bilirubin, creatinine, alkaline phosphatase, aminotransferase, α-fetoprotein, and β-human chorionic gonadotropin levels, are normal. A contrast-enhanced CT scan of the chest, abdomen, and pelvis shows bulky retroperitoneal lymphadenopathy (the largest mass is 10 cm in diameter) with somewhat smaller but still enlarged mediastinal lymphadenopathy. A biopsy specimen of the most accessible enlarged node shows poorly differentiated carcinoma. A testicular ultrasound is unremarkable. Which of the following is the most appropriate treatment?

Conization. which consists of excision of a cone-shaped portion of the cervix. Discussion of the impact of treatment options on fertility is important for reproductive-age patients with cancer and especially relevant for women with cervical cancer, almost half of whom are younger than 45 years of age. Patients with early-stage cervical cancer, which includes stage IA (microscopic disease without visible tumor), and stage IB1 (visible tumor less than 4 cm in size confined to the cervix) who desire future childbearing are candidates for fertility-sparing surgery. Conization is an option limited to stage IA disease without vascular invasion.

A 29-year-old woman diagnosed with stage IA cervical cancer is evaluated during a follow-up visit. The patient would like to preserve fertility. She has no other medical problems and takes no medications. On physical examination, vital signs are normal. The general physical examination is normal. Which of the following is the most appropriate management?

Observation. The most appropriate management for this patient is clinical observation. He has hereditary spherocytosis (HS) characterized by a mild lifelong anemia in association with symptomatic cholelithiasis at an early age. The presence of spherocytes is supported by an elevated mean corpuscular hemoglobin concentration frequently seen in this disorder. HS is caused by mutations in several scaffolding proteins that make these cells less distensible and more susceptible to osmotic stress and hemolysis. Patients with this disorder may have mild anemia, an elevated reticulocyte response, and few or no symptoms. The development of pigmented gallstones resulting from excess bilirubin production may result in symptomatic cholelithiasis. Symptoms of anemia may arise when the bone marrow is suppressed, most commonly by an acute infection. In this situation, the reticulocyte count falls, and the patient rapidly develops symptomatic anemia. Parvovirus is most classically linked with bone marrow suppression, but many other viral and infectious agents can have a similar effect. The bone marrow suppression following acute infections is self-limited, but some patients may become symptomatic to the point of requiring blood transfusion.

A 30-year-old man is evaluated for worsening exertional dyspnea. One week ago, he developed fever, sore throat, and cough. Those symptoms have resolved, but he has become more easily fatigued and short of breath. He had cholecystectomy 2 years ago because of symptomatic cholelithiasis; at that time, he was noted to be anemic and was diagnosed with hereditary spherocytosis. His only medication is a folate supplement. On physical examination, he is pale but in no distress. Temperature is 37.0 °C (98.7 °F), blood pressure is 100/60 mm Hg, pulse rate is 116/min, and respiratory rate is 16/min. Oxygen saturation is 98% breathing ambient air. The spleen is palpable 3 cm below the left costal margin. Other examination findings are normal. Laboratory studies: Hemoglobin 7 g/dL (70 g/L), Leukocyte count 5600/µL (5.6 × 109/L), with a normal differential ,Mean corpuscular hemoglobin concentration 40 g/dL (400 g/L), Platelet count 213,000/µL (213 × 109/L) ,Reticulocyte count 1% of erythrocytes ,Bilirubin Total 6.2 mg/dL (106 µmol/L), Indirect 5.6 mg/dL (95.8 µmol/L). Spherocytes are seen on the peripheral blood smear. A direct antiglobulin test is negative. Which of the following is the most appropriate management?

Simple transfusion to achieve a hemoglobin level of 10 g/dL (100 g/L). Transfusions may have significant adverse effects, including infection, alloimmunization, and cumulative risk of iron overload. Therefore, persons with sickle cell disease (SCD) should not receive transfusions unless they have significant symptoms or signs of end-organ failure from their anemia or are preparing for surgery. Patients with SCD are at increased risk for perioperative pulmonary, infectious, and thrombotic complications. In 1994, a landmark study was published showing that simple transfusion to a target hemoglobin level of 10 g/dL (100 g/L) was equivalent to exchange transfusion in low- to medium-risk surgeries (low-risk surgeries include adenoidectomy and inguinal-hernia repair; medium-risk surgeries include cholecystectomy and joint replacement) in reducing surgical complications in patients with SCD with less risk, reduced cost, and increased convenience. More recently, guidelines have been published on the care of patients with SCD that strongly recommend simple transfusion to a target hemoglobin level of 10 g/dL (100 g/L) in patients requiring general anesthesia. In addition to transfusion, the use of incentive spirometry has also been shown in a randomized trial to improve surgical outcomes in patients with SCD. Overtransfusion should be avoided in these patients because of complications arising from increased blood viscosity. Typically, hemoglobin levels are kept at or below 10 g/dL (100 g/L).

A 32-year-old man undergoes preoperative consultation for a hip replacement. He has an 18-month history of hip pain secondary to avascular necrosis of the left hip. He also has sickle cell disease, requiring three to four hospitalizations per year for vaso-occlusive crisis. Medications are ibuprofen, hydroxyurea, and folic acid. On physical examination, vital signs are normal. Cardiac examination reveals a grade 2/6 systolic flow murmur. He has left hip pain with abduction. Laboratory studies show a hemoglobin level of 5.8 g/dL (58 g/L; baseline, 5-6.5 g/dL [50-65 g/L]). Which of the following is the most appropriate preoperative transfusion management for this patient?

Leuprolide and an aromatase inhibitor. Two prospective randomized clinical trials have shown the superiority of ovarian suppression with leuprolide plus an aromatase inhibitor, such as exemestane, over ovarian suppression plus tamoxifen or tamoxifen alone in premenopausal women with higher-risk hormone receptor-positive early breast cancer.

A 32-year-old woman is evaluated during a follow-up visit for management of stage IIIA left breast cancer (3.5-cm, grade 3 invasive ductal carcinoma; estrogen receptor positive, progesterone receptor positive, and HER2 negative; four positive axillary lymph nodes). She has completed neoadjuvant chemotherapy, lumpectomy, and axillary dissection as well as primary breast radiation. She resumed menstruation after completing chemotherapy, and her estradiol levels are in the premenopausal range. She takes no medications. On physical examination, vital signs are normal. There are healed incisions on the left breast and axilla. There are no breast masses. Which of the following is the most appropriate treatment?

HIV Testing. Immune thrombocytopenic purpura (ITP) is caused by autoantibodies directed against glycoproteins on the platelet surface. ITP is diagnosed when thrombocytopenia is found with no alternate cause. ITP can be idiopathic, triggered by medications, or associated with other disorders, such as systemic lupus erythematosus (SLE), chronic lymphocytic leukemia, lymphoma, HIV, hepatitis C, or Helicobacter pylori infection. Unless additional cytopenias are discovered or other findings suggest an alternate diagnosis, a bone marrow biopsy in these patients is not necessary. ITP is not uncommon among patients with HIV infection, even early in the disease and in the absence of any other symptoms of immunosuppression or opportunistic infection. ITP is also associated with chronic hepatitis C that may also be asymptomatic. This patient's hepatitis C test was negative, so no further evaluation is needed; however, routine testing for HIV is recommended before starting any immunosuppressive treatment.

A 34-year-old woman is evaluated for a rash on her lower extremities that appeared 3 days ago. She also reports easy bruising for the past week and bleeding when she brushes her teeth. Her medical history is otherwise unremarkable, and she takes no medications. On physical examination, vital signs are normal. Petechiae are noted on the lower extremities, and ecchymoses are present on her right thigh and on her abdomen. No hepatomegaly, splenomegaly, or lymphadenopathy is noted. Laboratory studies: Hemoglobin 12.8 g/dL (128 g/L),Leukocyte count 6600/µL (6.6 × 109/L) with a normal differential ,Mean corpuscular volume 82 fL ,Platelet count 28,000/µL (28 × 109/L), Hepatitis C antibody Negative. Large and giant platelets are seen on the peripheral blood smear, but no schistocytes or platelet clumping is noted. Which of the following laboratory tests should be performed?

Imatinib. a tyrosine kinase inhibitor (TKI); he has chronic myeloid leukemia (CML) presenting in the chronic phase and requires therapy targeting the BCR-ABL fusion gene. Translocation of the long arm of chromosomes 9 and 22 leads to the fusion gene of BCR-ABL, which is characteristic of CML. CML is divided into the chronic phase, accelerated phase, or blast crisis depending on clinical and pathologic characteristics. Approximately 90% of patients with CML present in the chronic phase with less than 10% blasts in the blood and bone marrow. TKIs are effective in the treatment of the chronic phase of CML and are usually first-line treatment. The three TKIs approved for initial treatment of CML are imatinib, dasatinib, and nilotinib. Other newer generation TKIs are approved for patients who are intolerant of these first three TKIs or who have CML resistant to them. Although TKIs have some unique adverse effects and drug interactions, they are well tolerated compared with chemotherapy and transplantation.

A 35-year-old man is evaluated for a 6-month history of night sweats, malaise, and weight loss of 11.3 kg (25 lb). He reports no fevers or other localizing symptoms. His only medication is acetaminophen. On physical examination, vital signs are normal. Abdominal examination reveals splenomegaly. The remainder of the examination is noncontributory. Laboratory studies show a hemoglobin level of 12.5 g/dL (125 g/L); a leukocyte count of 55,000/µL (55 × 109/L), with 87% neutrophils, 2% myelocytes, 1% metamyelocytes, 0.5% basophils, 7% lymphocytes, and 2.5% monocytes; and a platelet count of 450,000/µL (450 × 109/L). Polymerase chain reaction for BCR-ABL fusion gene is positive. A bone marrow biopsy specimen shows hypercellular marrow with myeloid hyperplasia and 1% myeloid blasts. Which of the following is the most appropriate treatment?

Acute promyelocytic leukemia. This patient has pancytopenia, immature leukocytes with morphologic features consistent with promyelocytes, and laboratory features of disseminated intravascular coagulation (DIC), all of which are consistent with acute promyelocytic leukemia (APML). Acute leukemia can present with a leukocyte count within or below the normal range. It can include bleeding, as in this patient, from thrombocytopenia that may be accompanied by coagulopathy. APML is a subset of acute myeloid leukemia that often presents with bleeding and coagulopathy; this coagulopathy contributes to early mortality and morbidity. Features of DIC should prompt transfusion with fresh frozen plasma and cryoprecipitate (for hypofibrinogenemia) in addition to platelet transfusion for thrombocytopenia. A bone marrow aspirate and biopsy should be performed urgently to confirm the diagnosis because the coagulopathy of APML responds to therapy with all-trans retinoic acid, which targets the underlying defect in cellular differentiation.

A 35-year-old man is evaluated in the emergency department for fever and epistaxis. He has been experiencing malaise for several weeks and fever, chills, and anorexia for the past 3 days. Today he developed epistaxis. He takes no medications. On physical examination, temperature is 38.8 °C (100.4 °F), blood pressure is 105/70 mm Hg, pulse rate is 110/min, and respiration rate is 24/min. He is diaphoretic. Dried blood is noted in the nares, and gingival bleeding is present. No lymphadenopathy or hepatosplenomegaly is noted. He has petechiae bilaterally on the lower extremities. Laboratory studies: Activated partial thromboplastin time 60 s ,Hemoglobin 9.8 g/dL (98 g/L), Leukocyte count 3600/µL (3.6 × 109/L) with 20% neutrophils, 3% bands, 35% lymphocytes, 23% monocytes, and 18% "atypical" cells ,Platelet count 17,000/µL (17 × 109/L), Prothrombin time 24 s , Fibrinogen 93 mg/dL (0.93 g/L). The peripheral blood smear shows immature leukocytes with prominent granules in the cytoplasm.Which of the following is the most likely diagnosis?

JAK2 V617F gene mutation. This mutation is present in more than 95% of patients with polycythemia rubra vera and 50% of patients with essential thrombocytosis, even without the presence of erythrocytosis or thrombocytosis. Thromboses, including abdominal vein thromboses, are a major cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). Approximately 50% of cases of Budd-Chiari syndrome and 25% of cases of portal vein thrombosis are the result of an MPN, and JAK2 V617F gene mutations should be evaluated even in the absence of erythrocytosis or thrombocytosis. Portal hypertension and splenomegaly are often found, which may account for the relatively normal blood counts seen in some patients.

A 35-year-old woman arrives at the emergency department with epigastric abdominal pain of 3 months' duration, which has worsened during the past week. She also reports fatigue. Medical history is significant for a deep venous thrombosis that occurred 4 years ago, which was treated with 6 months of anticoagulation. She takes no medications. On physical examination, vital signs are normal, except for a pulse rate of 105/min. She has mildly diffuse abdominal tenderness. The physical examination is otherwise noncontributory. Laboratory studies: Haptoglobin 110 mg/dL (1100 mg/L) ,Hemoglobin 11 g/dL (110 g/L), Leukocyte count 3800/µL (3.8 × 109/L) ,Mean corpuscular volume 80 fL ,Platelet count 252,000/µL (252 × 109/L) ,Alkaline phosphatase 158 U/L ,Bilirubin Total 3.5 mg/dL (59.9 µmol/L) ,Direct 3.0 mg/dL (51.3 µmol/L) ,γ-Glutamyltransferase 120 U/L. Prothrombin and activated partial thromboplastin times are normal. Testing for hepatitis B and C are negative. A triphasic CT scan of the abdomen shows occlusion of the hepatic veins, ascites, splenomegaly, and abdominal varices; no cirrhosis is seen. Which of the following is the most appropriate diagnostic test to perform next?

Tamoxifen. In addition to primary breast radiation, this patient should receive adjuvant tamoxifen. She has a 2.5-cm, node-negative, hormone receptor-positive, HER2-negative breast cancer. Gene-expression assays, such as the 21-gene recurrence score, are helpful in determining the benefit of adding adjuvant chemotherapy to tamoxifen in patients with node-negative, hormone receptor-positive, HER2-negative breast cancer. The 21-gene recurrence score has been shown to be not only prognostic for the risk of distant recurrence but also predictive for the magnitude of benefit of adding chemotherapy to tamoxifen.

A 40-year-old woman is evaluated in the office following a recent diagnosis of stage IIA breast cancer. Pathologic findings showed a 2.5-cm, grade 2 invasive ductal carcinoma with no lymphatic or vascular invasion and negative margins. The cancer was estrogen receptor positive, progesterone receptor positive, and HER2 negative. Two sentinel nodes were negative. The 21-gene recurrence score is 8 (low risk of recurrence). She takes no medications. She is seeking advice about adjuvant systemic therapy. The patient is premenopausal and has no family history of breast or ovarian cancer. On physical examination, vital signs are normal. There is a healed right-upper outer breast incision and healed right axillary incision. The remainder of the examination is normal. Laboratory studies show normal findings on complete blood count, basic metabolic panel, and liver chemistry tests. In addition to primary breast radiation, which of the following is the most appropriate treatment?

Peripheral blood smear. The finding of schistocytes on the peripheral blood smear is all that is needed to initiate therapy for presumed thrombotic thrombocytopenic purpura (TTP). This patient's clinical features of fever, change in mental status, thrombocytopenia, and features of hemolytic anemia (low haptoglobin level, elevated lactate dehydrogenase level, elevated reticulocyte count) suggest TTP. The presence of schistocytes on the peripheral blood smear will confirm the diagnosis of a microangiopathic hemolytic anemia (MAHA) and a presumptive diagnosis of TTP and allows for early treatment. Prompt diagnosis is critical because TTP is fatal in 90% of patients without therapy. Patients require emergent treatment with plasma exchange.

A 42-year-old man is admitted to the hospital with an acute change in mental status and fever of 2 days' duration. Medical history is noncontributory, and he takes no medications. On physical examination, temperature is 38.2 °C (100.8 °F), blood pressure is 108/70 mm Hg, pulse rate is 104/min, and respiration rate is 18/min. Oxygen saturation is 96% breathing ambient air. He is agitated and disoriented to place and time. Petechiae are noted on his shins. The remainder of the examination is normal. Laboratory studies: Haptoglobin 20 mg/dL (200 mg/L) ,Hemoglobin 10.2 g/dL (102 g/L), Leukocyte count 9800/µL (9.8 × 109/L) ,Platelet count 44,000/µL (44 × 109/L), Reticulocyte count 6.8% of erythrocytes ,Creatinine 1.4 mg/dL (123.8 µmol/L), Lactate dehydrogenase 1600 U/L. The direct antiglobulin (Coombs) test is negative.Therapy should be immediately initiated pending results of which of the following studies?

History, physical examination, and gynecologic examination every 3 months. The most appropriate posttreatment surveillance for this patient with cervical cancer is a history, physical examination, and gynecologic examination every 3 months to monitor for local recurrence. Guidelines for posttreatment surveillance of patients with cervical cancer recommend a thorough history and examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for years 2 through 5. Higher-risk patients, such as those treated with chemotherapy or radiation, should be evaluated every 3 months for 2 years, then every 6 months for years 2 through 5; those with lower-risk disease treated with surgery alone should be evaluated every 6 months for 2 years, then annually through year 5. The main goals of surveillance are to detect central pelvic (not involving the pelvic sidewall) recurrences that might be amenable to curative therapy and to address treatment-related symptoms. Treatment-related symptoms include bladder and bowel dysfunction; dyspareunia; difficulty achieving sexual arousal and orgasm; hot flushes; lymphedema of the lower extremities; fatigue; and mood disturbances related to fear of recurrence, altered body image, and loss of fertility. Patients also should be educated at these visits about symptoms that might indicate recurrence, including vaginal bleeding or new abdominal or pelvic pain. Most recurrences are symptomatic and are detected within 2 years of primary treatment, with nearly all detected by 5 years. Additional laboratory or imaging studies should be directed by signs or symptoms suggesting possible recurrence rather than done as routine studies in asymptomatic patients. Although annual cervical or vaginal cytology, or both, is recommended, it is unlikely that an asymptomatic recurrence will be found by cytology alone. In addition, pelvic radiation may alter tissue histology and make cytology interpretation difficult.

A 42-year-old woman is evaluated during a follow-up visit for stage IIA cervical squamous cell cancer. She has completed therapy with pelvic external-beam radiation and concomitant weekly cisplatin chemotherapy, with cervical brachytherapy added during the fourth week of therapy. She has had an excellent response to treatment. She is otherwise well and takes no medications. On physical examination, vital signs are normal. Pelvic examination reveals no evidence of tumor, and the remainder of the examination is normal. Which of the following is the most appropriate posttreatment surveillance for this patient?

Oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. Olaparib is an oral PARP inhibitor that is FDA-approved monotherapy for patients with germline BRCA-mutated advanced ovarian cancer previously treated with three or more lines of chemotherapy. PARP inhibition leads to the formation of double-stranded DNA breaks that in BRCA-competent tumors are repaired by homologous recombination. Tumors with germline BRCA mutations are unable to repair these defects, leading to cell death (referred to as synthetic lethality). A study of 298 patients with germline BRCA1- or BRCA2-associated cancers showed responses in ovarian, breast, pancreatic, and prostate cancers, with a 31% response rate and median duration of response of 7 months in platinum-resistant ovarian cancers. The most common side effects of olaparib were fatigue, nausea, vomiting, and anemia. In addition to the 15% of ovarian cancers with germline BRCA1 and BRCA2 mutations, up to 50% of high-grade serous ovarian cancers may be deficient in homologous recombination repair due to somatically acquired BRCA1 and BRCA2 mutations, epigenetic inactivation of BRCA1, or other defects in the homologous recombination pathway. These ovarian cancers with a "BRCAness" phenotype are also responsive to PARP inhibitors. Olaparib has also been approved for maintenance therapy in patients with BRCA1 or BRCA2 mutations who are in a complete or partial remission after first-line platinum-based chemotherapy.

A 42-year-old woman is evaluated during a follow-up visit. She was diagnosed 4 years ago with stage IIIA high-grade serous ovarian cancer, with a deleterious BRCA1 germline mutation found on genetic testing. She was treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and chemotherapy with intravenous and intraperitoneal cisplatin and paclitaxel. Her cancer recurred 18 months after she completed chemotherapy, and she underwent two additional sequential chemotherapies, including carboplatin and paclitaxel, cisplatin and gemcitabine, and bevacizumab. The cancer is progressing on her current treatment. Her performance status is good (Eastern Cooperative Oncology Group = 1). The patient is still taking chemotherapy medications. On physical examination, vital signs are normal. Abdominal distention with lateral dullness is present. The remainder of the examination is normal. Laboratory studies reveal a serum CA-125 value of 145 U/mL (145 kU/L) (1 month ago, 82 U/mL [82 kU/L]). CT scans of the chest, abdomen, and pelvis show increased size and number of peritoneal masses and increasing ascites. There are no pleural effusions. In addition to stopping the current chemotherapy regimen, which of the following is the most appropriate treatment?

Exemestane. This postmenopausal woman has lobular carcinoma in situ and atypical hyperplasia. These atypical lesions are associated with a 30% to 35% lifetime risk of breast cancer, and patients with these findings on breast biopsy are candidates for chemoprophylaxis with antiestrogens. Antiestrogen options include tamoxifen in both premenopausal and postmenopausal women as well as raloxifene and aromatase inhibitors (such as exemestane or anastrozole) in postmenopausal women. Because this patient had a deep venous thrombosis while taking oral contraceptives in the past, both tamoxifen and raloxifene are contraindicated, and exemestane is the best option if she is willing to take chemoprophylaxis.

A 55-year-old woman is evaluated in the office for a recent diagnosis of lobular carcinoma in situ and atypical lobular hyperplasia. She wishes to discuss options to decrease her risk of breast cancer. The patient is postmenopausal. Her medical history is significant for a left calf deep venous thrombosis at 25 years of age concurrent with oral contraceptive use. She takes no medications. On physical examination, vital signs are normal. There is a healed left upper breast incision. The remainder of the examination is normal. Which of the following is the most appropriate preventive measure for this patient?

Biopsy of the right inguinal lymph node. This patient has a 7-year history of follicular lymphoma with a recent onset of systemic symptoms and a rapidly enlarging right inguinal lymph node. Biopsy of the right inguinal node would be appropriate to evaluate for histologic progression of disease. Transformation to diffuse large B-cell lymphoma occurs in approximately 30% of patients with follicular lymphoma. Transformation may be suggested by a change in the clinical pattern of disease, such as the development of new systemic symptoms or rapid progression of a localized area of disease. In addition, a rise in serum lactate dehydrogenase level or markedly higher areas of standardized uptake values on PET scanning should raise suspicion of transformation. In such cases, a new lymph node biopsy is required to establish the occurrence of transformation. In this patient, rapid progression in just one area of disease, the onset of systemic symptoms, and a high serum lactate dehydrogenase level raise suspicion for transformation. If transformation to another, more aggressive lymphoma is demonstrated, a more aggressive course of treatment would be appropriate. Thus, a new biopsy in this setting is important to optimize management.

A 43-year-old woman with a 7-year history of relapsing follicular lymphoma is evaluated for fevers, night sweats, and a rapidly enlarging right inguinal nodal mass. Her lymphoma has been treated on multiple occasions. Her current relapse began 1 year ago with diffuse lymphadenopathy; however, the onset of her symptoms and the right inguinal node enlargement is recent. She takes no medications. On physical examination, all vital signs are normal. There is diffuse cervical and axillary lymphadenopathy bilaterally. The left inguinal node is enlarged to 2 cm; the right inguinal node is enlarged to 5 cm. There is no splenomegaly. Laboratory results are significant only for a serum lactate dehydrogenase level of 6420 U/L. Which of the following is the most appropriate management?

Evaluation for helminth infection. This patient should be evaluated for hypereosinophilic syndrome (HES), beginning with an evaluation for helminth infection. He has sustained moderate eosinophilia and end-organ damage (restrictive cardiomyopathy), which are characteristic of HES. Organ involvement is more common when the peripheral eosinophil count is greater than 1500/µL (1.5 × 109/L) as in this patient. The numerous neoplastic and nonneoplastic causes of eosinophilia can be recalled using the mnemonic CHINA (Collagen vascular disease, Helminthic infection, Idiopathic, Neoplasia, Allergy/Atopy/Asthma). Helminth infection is a common cause of eosinophilia and should be evaluated and ruled out in all patients. Eosinophilia of any cause can be associated with end-organ damage, and evaluation for organ involvement is indicated. Organs commonly involved are the skin (eczema, erythroderma, urticaria, and angioedema), lungs (parenchymal infiltrates, pleural effusion, lymphadenopathy, and pulmonary emboli), gastrointestinal tract (eosinophilic gastritis, enteritis, colitis, chronic active hepatitis, focal hepatic lesions, eosinophilic cholangitis, Budd-Chiari syndrome), and heart (mitral or tricuspid regurgitation, cardiomegaly, restrictive cardiomyopathy).

A 45-year-old man is evaluated for shortness of breath with exertion and lower extremity edema of 6 months' duration. He reports no chest pain, fever, or cough. He takes no medications. On physical examination, vital signs are normal. Jugular venous distention is noted. Cardiopulmonary examination reveals crackles at the base of the lungs. He also has 1+ lower extremity edema. Laboratory studies are remarkable for eosinophilia, with an absolute eosinophil count of 2500/µL (2.5 × 109/L). A review of the medical record shows an eosinophil count of 2900/µL (2.9 × 109/L) 1 year ago. An electrocardiogram shows sinus rhythm with low-voltage QRS and nonspecific ST changes. An echocardiogram shows findings compatible with a restrictive cardiomyopathy. Which of the following is the most appropriate initial management?

Assess tumor tissue for human epidermal growth factor receptor 2 (HER2) amplification. He has metastatic adenocarcinoma of the distal esophagus. Approximately 25% of gastroesophageal cancers demonstrate HER2 amplification; such tumors achieve a superior response to chemotherapy when the anti-HER2 monoclonal antibody trastuzumab is added to standard chemotherapy. For this reason, determination of HER2 amplification status is necessary when initiating chemotherapy for patients with a gastroesophageal tumor.

A 48-year-old man is evaluated for increasing dysphagia during the past 2 months. He reports that he first noticed difficulty swallowing solid foods, such as steak, but that this symptom has advanced to occasional difficulty with liquids. He is, however, maintaining adequate hydration and nutrition. He is not currently taking medications. On physical examination, vital signs are normal. There is a 1.5-cm left supraclavicular node and a liver edge that is palpable below the right costal margin. A CT scan of the chest and abdomen shows a mass in the lower third of the esophagus just proximal to the gastroesophageal junction. The liver has multiple hypodense lesions consistent with metastases. Endoscopic evaluation reveals a near-obstructing lesion in the distal esophagus. Biopsy shows adenocarcinoma. Which of the following is the most appropriate diagnostic test to perform next?

Continue tamoxifen for 5 more years. Two large randomized controlled studies have confirmed the benefit of extending tamoxifen to 10 years in decreasing breast cancer recurrence and breast cancer mortality. Ten years of tamoxifen compared with 5 years reduces breast cancer mortality by one third in the first 10 years and by one half after 10 years. The major adverse event with 5 additional years of tamoxifen use was a small increase in the risk for endometrial cancers with no increase in endometrial cancer deaths. There were no increases in fatal pulmonary emboli, stroke, or ischemic heart disease.

A 48-year-old woman is evaluated during a follow-up visit for breast cancer. At age 43 years, she was diagnosed with low-risk, stage IIA invasive ductal cancer. The cancer was estrogen receptor positive, progesterone receptor positive, and HER2 negative. She has completed 5 years of tamoxifen and has tolerated it well. She continues to have menstrual periods. She takes no other medications. On physical examination, vital signs are normal. There are well-healed incisions of the right breast and axilla. There are no breast masses. Which of the following is the most appropriate management?

Intravenous (IV) and intraperitoneal (IP) cisplatin and paclitaxel chemotherapy. This treatment is associated with a 16-month improvement in median overall survival in women with stage III ovarian cancer and no residual mass greater than 1 cm after surgical debulking compared with intravenous chemotherapy alone. Patients receiving IP/IV chemotherapy have a higher incidence of toxicities, including leukopenia, thrombocytopenia, fever, infection, fatigue, pain, and gastrointestinal events. Less than half of patients starting IP/IV therapy can complete all six cycles of therapy. However, the National Cancer Institute encourages the use of IP/IV chemotherapy for optimally debulked stage III ovarian cancer. Obstacles to the widespread adoption of IP/IV chemotherapy include not only the higher toxicities but also placement of an IP catheter and training of nursing staff in IP chemotherapy administration. The original IP/IV regimen required hospitalization for the first 3 days of each cycle. Modified regimens that allow all treatment to be given on an outpatient basis are now accepted options.

A 55-year-old woman is evaluated to discuss additional cancer therapy. She was recently diagnosed with stage IIIB ovarian high-grade serous carcinoma. She underwent surgical staging, total abdominal hysterectomy, salpingo-oophorectomy, and debulking, with residual tumor size less than 1 cm. Genetic testing was negative for BRCA1 and BRCA2 mutations. She takes no medications. On physical examination, vital signs are normal. There is a healing midline abdominal incision. The remainder of the examination is normal. Her performance status is excellent (Eastern Cooperative Oncology Group performance status = 0. Which of the following is the most appropriate treatment?

Oral imatinib. The most appropriate management for this patient is oral imatinib for 3 years. Gastrointestinal stromal tumors (GISTs) most commonly occur in the stomach, although they can arise anywhere in the digestive tract. Although rare, they are the most common sarcoma of the digestive tract. Location outside of the stomach, larger size, and higher mitotic index are all factors that increase the risk of recurrence after resection and indicate use of adjuvant therapy. Almost all GISTs have an activating mutation in the c-KIT proto-oncogene, leading to constitutive activation of the KIT receptor tyrosine kinase. Therefore, she should be treated with the small-molecule receptor tyrosine kinase inhibitor imatinib, which blocks c-KIT tyrosine kinase phosphorylation. In such high-risk patients, recurrence-free survival and overall survival are superior in patients who receive 3 years of imatinib therapy compared with 1 year of therapy.

A 50-year-old woman is evaluated for nausea and abdominal discomfort that have been present and increasing for the past 3 to 4 months. She takes no medications. On physical examination, vital signs are normal. BMI is 24. The abdominal examination reveals no masses, tenderness, or organomegaly. An esophagogastroscopy identifies a discrete 8-cm mass in the pylorus. The biopsy specimen shows a gastrointestinal stromal tumor (GIST). Immunohistochemical stain for the KIT gene is strongly positive. Contrast-enhanced CT scans of the chest, abdomen, and pelvis confirm the mass and do not identify any other abnormal findings. The patient undergoes a distal gastrectomy. Pathologic findings confirm a GIST and further note a high mitotic rate (10 mitoses per 50 high-power fields). Margins of resection and all lymph nodes examined are free of tumor. Which of the following is the most appropriate management?

No further treatment. This patient has stage II colorectal cancer (invades full thickness of the bowel [T3]), and lymph nodes are not involved [N0]). Patients with stage II colon cancer do not have a clear survival advantage with administration of adjuvant chemotherapy; consequently, surgery alone is the acceptable standard practice for most patients. Exceptions are patients with stage II colon cancer with characteristics associated with a high risk for recurrence (T4 primary tumor [invasion into adjacent structures or through the peritoneum], lymphovascular invasion, inadequate lymph node sampling [fewer than 12 lymph nodes examined], poorly differentiated histology, elevated postoperative carcinoembryonic antigen (CEA), or clinical perforation or obstruction). In these patients, the prognosis is similar to that of patients with stage III disease, and adjuvant chemotherapy may be appropriate. Exposing this patient to the toxicity of chemotherapy is not warranted, as data do not support a survival benefit in such patients. For patients with stage II disease and a high risk for recurrence, treatment with 5-fluororuracil/leucovorin or capecitabine may be appropriate. Patients with stage II disease with a substantial number of high-risk features may at times be considered for oxaliplatin-containing chemotherapy, such as parenteral 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX).

A 53-year-old man is evaluated after a hemicolectomy for a well-differentiated adenocarcinoma of the descending colon. Final pathologic findings showed a well-differentiated adenocarcinoma penetrating into the serosa (T3). Margins of resection were free of tumor. No lymphovascular or perineural invasion was seen. Twenty-seven lymph nodes were identified, and all were free of cancer. He takes no medications. CT scans of the chest, abdomen, and pelvis showed no evidence of metastatic disease. On physical examination, vital signs are normal. All other examination findings are normal. The postoperative carcinoembryonic antigen (CEA) level is normal. Which of the following is the most appropriate management?

Four-factor prothrombin complex concentrate (4f-PCC). Patients who receive anticoagulation with a vitamin K antagonist have an increased risk for major gastrointestinal and central nervous system bleeding and an increased risk for periprocedural bleeding. Although vitamin K alone can be effective in reversing the effect of warfarin, its hemostatic effect can take several hours, and, in urgent situations, simultaneous replacement of the vitamin K-dependent coagulation factors is necessary. 4f-PCC contains factors II, VII, IX, and X as a lyophilized powder and can be administered quickly in a small reconstituted volume. It provides effective hemostasis 90% of the time and is the preferred option for most patients who require urgent warfarin reversal. Thromboembolism is a potential adverse effect. 4f-PCC should be avoided in patients with a history of heparin-induced thrombocytopenia because it contains residual heparin.

A 55-year-old man is evaluated in the emergency department for abrupt loss of consciousness after a fall. Medical history is notable for atrial fibrillation. He has otherwise been well without additional medical problems. Medications are warfarin and metoprolol. On physical examination, temperature is 37 °C (98.6 °F), blood pressure is 135/85 mm Hg, pulse rate is 83/min and irregular, and respiration rate is 16/min. The patient is obtunded without localizing neurologic findings. Cardiac examination reveals an irregularly irregular rhythm. The remainder of the examination is unremarkable. Head CT scan shows a large subdural hematoma. Laboratory studies show a hemoglobin level of 13 g/dL (130 g/L), platelet count of 183,000/µL (183 × 109/L), and INR of 3.0. Intravenous vitamin K is administered, and plans are made for emergent neurosurgery. Which of the following is the most appropriate treatment?

Surgery. Based on the information available, this person has a T2N0, stage I midrectal cancer. Patients with rectal tumors that are not full thickness and do not have lymph node involvement (stage I) on pretreatment imaging usually undergo surgery, with a total mesorectal excision being the preferred procedure. The mesorectum is a fatty sheath covering the rectum that contains the regional lymph nodes. A total mesorectal excision entails a sharp dissection of the pelvis outside of the mesorectum to allow removal of the mesorectum fully intact en bloc with the rectum. Because this patient's tumor is 8 cm from the anal verge, this is a midrectal tumor. Resection of such a tumor would be anticipated to be sphincter sparing and so would not be anticipated to require a permanent colostomy. However, considerable expertise is required to avoid complications with this procedure, which should be performed only by a subspecialized surgeon.

A 55-year-old woman is evaluated for rectal bleeding and pain with defecation that had increased during the past 3 months. She takes no medications. On physical examination, vital signs are normal. BMI is 19. The rectal examination reveals a brown stool sample that is guaiac positive. The remainder of the physical examination is unremarkable. Hemoglobin level is 12.5 g/dL (125 g/L). Leukocyte count, platelet count, and liver chemistry test results are normal. A colonoscopy to the ileocecal valve identifies a fungating mass 8 cm from the anal verge, and a biopsy specimen shows adenocarcinoma. An MRI of the pelvis shows a nonobstructing tumor invading into the muscularis but not through the full thickness of the rectal wall (T2). No abnormal lymph nodes are seen. Contrast-enhanced CT scans of the chest and abdomen are normal. Which of the following is the most appropriate treatment?

Pelvic radiation therapy with concurrent chemotherapy. Anal carcinoma is a rare but increasing cause of cancer and accounts for approximately 2% of gastrointestinal cancers. Most anal cancers are squamous cell carcinomas and are associated with human papillomavirus (HPV) infection, particularly HPV 16 and HPV 18. Risk factors for anal cancer include HPV infection; sexually transmitted infections; multiple sex partners; men having sex with men; receptive anal intercourse; history of vaginal, cervical, or vulvar cancer; immunosuppression due to hematologic malignancy; solid organ transplantation; or HIV infection. Most patients present with a perianal lesion or mass associated with rectal bleeding or anal discomfort. This patient has locally invasive, node-positive squamous cell cancer of the anus. Curative-intent treatment with the combination of pelvic radiation therapy and concurrent systemic chemotherapy is indicated. This would be appropriate for patients with stages I, II, and III anal cancer. Mitomycin plus fluorouracil has been the standard chemotherapy regimen in patients with anal cancer for the past 50 years, although capecitabine, an oral fluorouracil prodrug, is now often used instead of parenteral fluorouracil.

A 56-year-old man is evaluated for a 3-month history of anorectal pain with bleeding. Medical history is significant for a long-standing HIV infection for which he is taking appropriate antiretroviral therapy. Viral load is undetectable, with a CD4 T-cell count of 650/µL. On physical examination, vital signs are normal. The examination is notable for a hard, tender mass palpable in the anal canal. There is no inguinal lymphadenopathy. Pelvic MRI shows a 3-cm mass in the anal canal and one enlarged 11-mm local-regional lymph node. Contrast-enhanced CT of chest and abdomen are normal. Which of the following is the most appropriate treatment?

Anastrozole. is the most effective adjuvant therapy for ductal carcinoma in situ (DCIS) in postmenopausal women younger than 60 years. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 clinical trial, 5 years of anastrozole was found to be more effective than 5 years of tamoxifen at decreasing both ipsilateral and contralateral breast cancer in postmenopausal women with DCIS who were younger than 60 years when starting treatment. Almost 95% of the anastrozole group was free from local or contralateral recurrence compared to 88% of the tamoxifen group. Overall 10-year survival, approximately 90%, was comparable between the two groups. In women age 60 years or older, anastrozole and tamoxifen yielded equivalent results. All women in this trial were postmenopausal and underwent lumpectomy and breast radiation. Unlike in invasive breast cancer, there is no survival advantage to treatment with antiestrogens for patients with DCIS, and such treatment is discussed as an option for patients who wish to decrease their risk of local recurrence and contralateral breast cancers. Because this patient is younger than 60 years, anastrozole is the most effective adjuvant antiestrogen option to achieve this goal.

A 57-year-old postmenopausal woman is evaluated following the diagnosis of right breast ductal carcinoma in situ after lumpectomy. Pathologic findings showed a grade 3 ductal carcinoma in situ spanning 2.5 cm with negative margins that is estrogen receptor−positive; lymph nodes were not sampled. She has received primary breast radiation therapy. She takes no medications. On physical examination, vital signs are normal. There is a healed right breast incision. There are no breast masses or lymphadenopathy. Which of the following is the most appropriate management to decrease the risk of ipsilateral and contralateral breast cancer?

CT scan of the abdomen. Although symptomatic erythrocytosis is most commonly associated with myeloproliferative neoplasms, such as polycythemia vera, it is important to assess for all possible causes. This patient has symptomatic erythrocytosis in the setting of a markedly elevated erythropoietin level and in the absence of organomegaly. This combination of findings is most consistent with autonomous production of erythropoietin, most commonly by an underlying tumor. Tumors known to be associated with this paraneoplastic syndrome include kidney cancer and, less frequently, hepatocellular carcinoma, cerebellar hemangioblastoma, pheochromocytoma, and uterine myomata. Clues to tumor-related erythrocytosis may include microscopic hematuria (kidney cancer); abnormal liver chemistry test results, hepatitis B, hemochromatosis, or cirrhosis (hepatocellular); headache, abnormal neurological findings (hemangioblastoma); hypertension, abnormal electrolyte levels, or hyperglycemia (pheochromocytoma); and menorrhagia (uterine myomata). In the absence of suggestive symptoms or findings, a CT scan of the abdomen is indicated as the first study for further evaluation of this patient.

A 58-year-old woman is evaluated for a 6-month history of headache and facial redness. Her medical history is unremarkable, and she takes no medications. On physical examination, she is afebrile. Blood pressure is 160/95 mm Hg, pulse rate is 96/min, and respiration rate is 20/min. BMI is 28. Oxygen saturation is normal. Facial plethora and palmar erythema are present. There is no hepatomegaly or splenomegaly on palpation. Laboratory studies: Erythropoietin Markedly elevated ,Hemoglobin 18.1 g/dL (181 g/L), Leukocyte count 5400/µL (5.4 × 109/L) with a normal differential, Liver chemistry tests Normal ,Platelet count 250,000/µL (250 × 109/L) ,Urinalysis Normal. Which of the following is the most appropriate diagnostic test to perform next?

Anoscopy. In the United States, approximately 35,000 patients receive a diagnosis of cancer of unknown primary (CUP) annually. The clinical evaluation should not involve an exhaustive search for a primary site because detection of an asymptomatic and occult primary tumor does not improve outcome. In a patient with CUP, it is important to look for treatable subgroups. Patients with CUP who have lymphadenopathy in a single lymph node or single lymph node region belong to a potentially more treatable subgroup of patients with CUP. Most patients with carcinoma, especially squamous cell carcinoma, involving inguinal lymph nodes have a primary site in the genital or anorectal area. In women this necessitates a careful examination of the vulva, vagina, and cervix. Men require a careful examination of the penis. Men and women should have a careful examination of the perineal skin, a digital rectal examination, and an anoscopy. This patient's examination is complete except for digital rectal examination and anoscopy. The anal region drains directly to the inguinal lymph nodes. Cancers of the anus that metastasize to the inguinal nodes are local-regionally advanced but not distantly metastatic and are potentially curable with a combination of chemotherapy and radiation therapy.

A 58-year-old woman is evaluated for a palpable mass in her right groin. She takes no medications. On physical examination, vital signs are normal. A hard, fixed, 3-cm lymph node is palpated in the right inguinal region. Careful inspection of the perianal skin, vulva, vagina, and cervix shows no findings. The remainder of the physical examination is normal. A biopsy of the enlarged node demonstrates poorly differentiated carcinoma. A contrast-enhanced CT scan of the chest, abdomen, and pelvis shows the enlarged inguinal node and no other abnormal findings. Which of the following is the most appropriate diagnostic test to perform next?

Combined chemotherapy and radiation. Treatment for stage III non-small cell lung cancer, which is defined in most cases by the presence of mediastinal lymphadenopathy, can vary significantly based on the extent of the primary tumor and the extent of associated lymphadenopathy. Patients with extensive primary tumors, such as this patient whose tumor invades the mediastinum, are not candidates for surgery. Patients with bulky, multistation (widespread mediastinal or hilar lymph node involvement) lymphadenopathy in the mediastinum do not fare well after surgery. These patients should be treated with combined chemotherapy and radiation, which has been shown to improve outcomes compared with either chemotherapy alone or radiation alone.

A 59-year-old woman is evaluated for a 2-month history of shortness of breath and cough. She has a 55-pack-year smoking history. She takes no medications. On physical examination, vital signs are normal. BMI is 23. Oxygen saturation is normal. Pulmonary examination reveals decreased breath sounds and crackles in the right base posteriorly. Her performance status is good. CT scan of the chest shows a large, centrally located right lower lobe mass, evidence of mediastinal invasion, bulky mediastinal lymph nodes, and hilar lymphadenopathy. Bronchoscopy with biopsy of an endobronchial lesion confirms non-small cell lung cancer. Brain MRI, CT scans of the abdomen and pelvis, and bone scan show no metastatic disease. Which of the following is the most appropriate management?

Cetuximab plus radiation. Several options exist for treatment of locally advanced head and neck cancer. However, in many cases, surgery is not recommended as first-line treatment. In addition, significant morbidity is expected with open surgery to resect large, locally advanced cancers. For these reasons, nonsurgical treatment is often recommended in this setting. The standard treatment of such patients is a combination of radiation with systemic therapy, most commonly either cisplatin or cetuximab. Randomized trials have clearly demonstrated improved survival in patients treated with either cisplatin or cetuximab plus radiation compared with those treated with radiation alone. For example, 3-year survival in a pivotal randomized trial was 55% in patients receiving cetuximab and radiation compared with 45% in patients treated with radiation alone. No study to date has determined whether cetuximab or cisplatin is preferred in this setting. However, because of long-term experience with cisplatin and the significantly higher cost of cetuximab, cisplatin is preferred unless there is a contraindication to use of this agent. For this patient, who has chronic kidney disease with a baseline creatinine level of 1.8, cisplatin is clearly contraindicated and, therefore, cetuximab combined with radiotherapy is the most appropriate treatment.

A 59-year-old woman is hospitalized with a biopsy-confirmed poorly differentiated squamous cell carcinoma of the base of tongue. Her medical history is significant for a 30-pack-year smoking history and moderate to heavy alcohol use. She takes no medications. On physical examination, vital signs are normal. BMI is 24. Right-sided lymphadenopathy is present on palpation. There is a large mass on the right base of the tongue extending across the midline, nearly obstructing the airway. Laboratory studies are notable for a serum creatinine level of 1.8 mg/dL (159.12 µmol/L). CT scan of the neck shows a very large mass on the right base of the tongue that crosses the midline, extending into the extrinsic muscles of the tongue and adjacent to the carotid artery. Multiple enlarged right-sided cervical lymph nodes are noted, with the largest being 3.5 cm. Enlarged nodes are also noted on the left side. CT scan of the chest is negative. Which of the following is the most appropriate treatment?

Whole body MRI. Smoldering multiple myeloma (MM) is characterized by a serum M protein level of 3 g/dL or greater (or ≥500 mg/24 hr of urinary monoclonal free light chains) or bone marrow plasma clonal cells of 10% or greater and no evidence of myeloma-related signs or symptoms requiring therapy. All patients with MM should be assessed for skeletal lesions at diagnosis, periodically thereafter, and when any new symptoms occur. Skeletal survey with plain radiography is commonly used to assess for lytic lesions in patients with monoclonal gammopathy. However, MRI has recently been found to be more sensitive at identifying myeloma bone lesions and soft tissue lesions from plasmacytoma. The International Myeloma Working Group recommends that all patients with smoldering MM undergo whole body MRI (or spine and pelvic MRI if whole body MRI is not available). Whole body MRI is considered the gold standard for imaging of the axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. If a patient is discovered to have more than one lesion greater than 5 mm, the patient should be considered symptomatic and requires consideration for treatment. With equivocal small lesions, a second MRI should be performed after 3 to 6 months; if the MRI shows progression, the patient should be treated as having symptomatic myeloma. In this patient with smoldering MM, negative findings on plain radiographs do not reliably rule out a skeletal lesion, and MRI is needed for further evaluation.

A 60-year-old man is evaluated for an asymptomatic elevation of serum protein. Medical history is unremarkable, and he takes no medications. On physical examination, vital signs are normal. Neurologic examination reveals no deficits. Laboratory studies: Hemoglobin 14 g/dL (140 g/L) ,Leukocyte count 7000/µL (7 × 109/L) ,Platelet count 300,000/µL (300 × 109/L) ,Calcium 9.4 mg/dL (2.4 mmol/L), Creatinine 1.1 mg/dL (97.2 µmol/L). Serum protein electrophoresis and immunofixation show an IgA spike of 3.5 g/dL. Skeletal survey findings are negative. Which of the following is the most appropriate next test?

Active surveillance. The American College of Physicians recommends that clinicians inform men between 50 and 69 years of age about the limited potential benefits and substantial harms of screening for prostate cancer. The decision to screen should be based on the patient's general health and life expectancy and patient preferences. This patient has very-low-risk prostate cancer based on his biopsy findings and prostate-specific antigen (PSA) level at diagnosis. Management of such patients has evolved during the past several years. Although treatment is a reasonable consideration, recent literature supports the use of active surveillance, which is a program of scheduled assessments that include digital rectal examination, PSA measurement, and prostate biopsy. The purpose of active surveillance is to identify early evidence of cancer progression in an effort to limit treatment to those most likely to benefit. It is appropriate only for men with low-risk or very-low-risk prostate cancer who have a life expectancy of at least 10 years. Although no randomized data are available to support this strategy, available data indicate that the 15-year metastasis-free survival in appropriately selected patients is up to 97%. Active surveillance is currently considered appropriate standard care in this patient population.

A 60-year-old man is seen for a routine evaluation. His family history is notable for prostate cancer in his father. He takes no medications. On physical examination, vital signs are normal. The remainder of the examination is normal. After discussion of the benefits and harms of prostate cancer screening, the patient wishes to proceed with screening. Laboratory studies reveal a serum prostate-specific antigen level of 5.1 ng/mL (5.1 µg/L). Biopsy of the prostate reveals cancer in two cores of the right lobe (Gleason score, 6), with less than 10% cancer in each core. Which of the following is the most appropriate management?

Abdominal fat pad biopsy. This patient has cardiomyopathy, nephrotic syndrome, autonomic dysfunction, and macroglossia, which are likely caused by amyloidosis. Amyloid deposition can occur in one or more organs and cause symptoms related to the sites of deposition. Sites commonly involved are the kidneys, the gastrointestinal tract, and the cardiac, neurologic, coagulation, and musculoskeletal systems. In this patient, nephrotic-range proteinuria, cardiomyopathy, orthostatic hypotension, and macroglossia all suggest amyloidosis. The finding of an IgG λ monoclonal gammopathy can also be associated with amyloidosis. Diagnosis requires biopsy of the affected organ and demonstration of characteristic apple-green birefringence with Congo red staining. Fat pad biopsy is sometimes performed when multiorgan involvement is suspected because it is less invasive; however, if findings are unrevealing, biopsy of the organ(s) involved, such as the kidney, may be required. Because different proteins can be involved in amyloid deposition, protein typing with tests such as mass spectrometry is done after amyloidosis is diagnosed. Proper identification of the amyloid type is critical and guides appropriate therapy.

A 61-year-old man is evaluated for worsening symptoms of edema and dizziness with standing over the past 6 months. His only medication is as-needed acetaminophen. On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 105/60 mm Hg sitting and 80/50 mm Hg standing, pulse rate is 105/min, and respiration rate is 18/min. Indentations are noted on the sides of the tongue, which appears enlarged. Jugular venous distention is noted. Cardiopulmonary examination reveals decreased breath sounds at the lung bases and an S3 gallop. Dependent edema is present. On laboratory evaluation, the serum creatinine level is 1.5 mg/dL (132.6 µmol/L); 24-hour urine collection shows 3.5 g of albumin. Serum protein electrophoresis shows an IgG λ spike of 1.2 g/dL (0.012 g/L). Echocardiography shows increased thickening of the left ventricular wall and significant diastolic dysfunction. Left ventricular ejection fraction is 51%. Which of the following is the most appropriate diagnostic test to perform next?

Palliative care consultation. The most appropriate management in addition to platinum-based chemotherapy is palliative care consultation. In patients with metastatic non-small cell lung cancer, early institution of palliative care has been shown to improve both quality of life and survival. Palliative care does not preclude aggressive cancer treatment with platinum-based combination chemotherapy and other interventions. Palliative care complements cancer treatment through its emphasis on controlling both cancer- and treatment-related symptoms that may interfere with effective treatment. It also makes it easier for patients and treating physicians to decide when treatment is no longer indicated, either because of insufficient efficacy or problematic toxicity. Current standard care is to offer palliative care services at the time of diagnosis with metastatic non-small cell lung cancer and, by extension, in patients diagnosed with any advanced incurable cancer.

A 61-year-old man is hospitalized after several days of productive cough, fatigue, and fever. He quit smoking 10 years ago. He takes no medications. On physical examination, temperature is 39.2 °C (102.6 °F), blood pressure is 110/75 mm Hg, pulse rate is 110/min, and respiration rate is 24/min. Oxygen saturation is 90% breathing 2 L/min of oxygen through nasal cannula. Pulmonary examination reveals crackles in the right lower lung field. He has good performance status. Chest radiograph shows right lower lobe pneumonia and a right hilar mass. CT scan of the chest and abdomen confirms an endobronchial lesion and right hilar mass, multiple lytic bone lesions, and a right adrenal mass. Bronchoscopy with biopsy confirms squamous cell carcinoma. Bone scan confirms multiple osseous metastatic lesions. Brain MRI shows no metastatic disease. In addition to platinum-based chemotherapy, which of the following is most likely to improve outcome in this patient?

Low-dose noncontrast CT scan of the chest. Following definitive treatment for head and neck cancer, patients require ongoing surveillance to look for evidence of recurrence as well as evidence of second primary head and neck cancer. Especially in patients with smoking-related cancers, the risk of a second primary cancer is substantial. Surveillance consists of history, physical examination, and laryngoscopy to examine the entire upper aerodigestive tract.

A 61-year-old woman is evaluated for follow-up of stage IVA hypopharyngeal squamous cell carcinoma, which was treated with combined cisplatin and radiation therapy 1 year ago. She has xerostomia and some dysphagia since completing therapy. She has a 30-pack-year smoking history and quit smoking 1 year ago. She takes no medications. On physical examination, vital signs are normal. BMI is 21. There is chronic induration of the right neck and limitation in neck range of motion, findings that have been noted on previous examinations. There is no palpable lymphadenopathy. Laboratory studies reveal a normal thyroid-stimulating hormone level. Recent laryngoscopy identified no evidence of recurrent cancer or new primary cancer. Which of the following is the most appropriate screening or surveillance test to perform next?

Zoledronic acid. All patients with multiple myeloma (MM) requiring therapy should be given intravenous bisphosphonates, such as zoledronic acid or pamidronate, in addition to antimyeloma therapy. Zoledronic acid and pamidronate have been shown to prevent new skeletal-related events in patients with MM, but only zoledronic acid has been shown to improve survival. Close monitoring of kidney function and calcium level should be performed in all patients taking zoledronic acid; monitoring for pain and swelling that may be early signs of osteonecrosis of the jaw is also essential. Calcium and vitamin D supplementation is usually given to patients taking intravenous bisphosphonates unless a contraindication exists. Patients with MM are given intravenous zoledronic acid every 3 to 4 weeks. Experts have not reached a consensus on duration of therapy, but indefinite bisphosphonate therapy is often used. It is reasonable to consider remission status, extent of skeletal disease, kidney function, and patient preference when determining the duration of bisphosphonate therapy. In patients who stop therapy, bisphosphonates should be restarted at disease relapse.

A 62-year-old man arrives for follow-up consultation for multiple myeloma diagnosed 3 weeks ago. A skeletal survey showed multiple lytic lesions in the spine and pelvis, but the patient's vertebral height was maintained. MRI showed abnormalities in the vertebral bodies but no evidence of spinal cord compression. Myeloma therapy was begun with bortezomib, lenalidomide, and dexamethasone. Medical history is otherwise unremarkable. He takes no other medications. On physical examination, vital signs are normal. The lower spine is nontender to palpation. The remainder of the physical examination is unremarkable. Laboratory studies show a serum calcium level of 9.1 mg/dL (2.3 mmol/L) and a serum creatinine level of 0.8 mg/dL (70.7 µmol/L); a complete blood count and serum electrolyte levels are normal. Which of the following is the most appropriate management of this patient's lytic bone lesions?

Continue anastrozole for 5 years. In the North America Breast Cancer Group MA.17R trial, 1918 postmenopausal women with hormone receptor-positive early breast cancer who had completed 5 years of an aromatase inhibitor were randomly assigned to 5 years of letrozole or placebo. Most of the women had also received 5 years of tamoxifen before starting aromatase inhibitor therapy. The 5-year disease-free survival rate was 95% with letrozole versus 91% with placebo. Overall survival was the same in both groups. Patients on letrozole had a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. This patient has tolerated anastrozole therapy well, has preserved bone density, and remains at higher risk (tumor size greater than 2 cm and pathologically involved lymph nodes). Extending aromatase inhibitor therapy to 10 years is reasonable for this patient.

A 65-year-old woman is evaluated during a follow-up visit for breast cancer management. She was diagnosed 6 years ago with stage IIB left breast cancer. Pathologic findings showed a 2.5-cm, grade 3 infiltrating ductal cancer that was estrogen receptor positive, progesterone receptor positive, and HER2 negative. Three axillary lymph nodes were positive. She received adjuvant chemotherapy followed by 5 years of anastrozole. She takes no other medications. She has had no side effects from the anastrozole, and her bone density has remained normal. On physical examination, vital signs are normal. There are well-healed incisions of the left breast and axilla. There are no breast masses. Which of the following is the most appropriate management?

Test for activating mutations. The most appropriate management is to test for epidermal growth factor receptor (EGFR), ALK, and ROS1 alterations. Mutations in EGFR, translocation of the ALK and EML-4 genes, or mutation of the ROS1 gene have been identified in a few non-squamous cell lung cancers, usually adenocarcinomas. Patients with EGFR mutations have been found to derive significant benefit from treatment with erlotinib, whereas those with ALK translocations and ROS1 mutations derive similar benefit from crizotinib; these agents are recommended as initial therapy in these patients when mutation status is known before treatment is initiated. In patients who must start treatment before mutation test results are available, these agents can be used later in treatment. Current standard care is to test for these molecular alterations in any patient diagnosed with nonsquamous metastatic non-small cell lung cancer. Although testing can also be considered in patients with squamous histologic findings, the likelihood of finding an alteration is very low.

A 62-year-old woman is evaluated for a 3-month history of worsening cough and a 2-week history of shortness of breath. She has lost 9.1 kg (20.0 lb). She quit smoking 25 years ago. She takes no medications. On physical examination, vital signs are normal. Oxygen saturation is 94% breathing ambient air. Pulmonary examination reveals decreased breath sounds in the left lower lung field. CT scan of the chest shows a large left pleural effusion, multiple right-sided lung nodules, and hypodense lesions in the upper portion of the liver. Bone scan reveals metastatic lesions involving the ribs and thoracic spine. Brain MRI shows no metastatic disease. Thoracentesis is performed and cytologic findings confirm adenocarcinoma. Which of the following is the most appropriate management?

Adjuvant Chemotherapy. Most (80%) lung cancers are non-small cell lung cancers (NSCLCs), with the most common type being adenocarcinoma of the lung. Current treatment options for NSCLCs include surgical resection, radiation therapy, chemotherapy, and targeted therapies. Several studies have found a small but significant survival benefit associated with adjuvant chemotherapy in patients with stage II and stage III NSCLC. Although both cisplatin- and carboplatin-based chemotherapy regimens have been studied, only cisplatin-based chemotherapy has been shown to improve survival. At least four different cisplatin-based combination regimens can be used for adjuvant chemotherapy treatment; however, patients must be selected carefully because toxicity can be substantial. Based on this survival benefit, cisplatin-based chemotherapy is recommended after surgery for stage II and stage III NSCLC in patients such as this one without contraindications to chemotherapy.

A 65-year-old man is evaluated for an episode of hemoptysis. His medical history is significant for a 30-pack-year smoking history; he quit smoking 1 year ago. He takes no medications. On physical examination, vital signs are normal. BMI is 28. Oxygen saturation is 96% breathing ambient air. CT scan of the chest identifies a 3.5-cm spiculated mass in the right lower lobe and an enlarged hilar lymph node. PET/CT scans and brain MRI scans show no evidence of metastatic disease. Surgery is performed and reveals a 3.2-cm, poorly differentiated adenocarcinoma with negative margins, two hilar lymph nodes positive for metastatic adenocarcinoma, and negative mediastinal lymph nodes. Which of the following is the most appropriate management?

PPI and Abx. The appropriate treatment for this patient with gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with Helicobacter pylori infection is proton pump inhibitor and dual antibiotic therapy, such as clarithromycin and amoxicillin, for 7 to 14 days. Chronic antigen stimulation can lead to clonal expansion of MALT and progress to malignant transformation manifesting as lymphoma. The lymphoma originates in B cells in the marginal zone of MALT and expresses the CD20 surface antigen. Eradication of H. pylori infection is associated with a high rate of response and long-term remission for these tumors and is the treatment of choice given its efficacy and ease of use. Regression of these lymphomas occurs slowly, and serial endoscopy will be needed to document this patient's response to therapy.

A 65-year-old man is evaluated for persistent dyspepsia despite treatment with antacid therapy. He also has recent weight loss of 3 kg (6.6 lb) and development of epigastric abdominal pain. He does not smoke or drink alcohol. He takes no medications other than antacids. On physical examination, vital signs are normal. There is epigastric tenderness but no abdominal masses, no hepatosplenomegaly, and no lymphadenopathy. The endoscopic biopsy specimen shows evidence of mucosa-associated lymphoid tissue (MALT) lymphoma involving the stomach. Immunohistochemical stains for Helicobacter pylori are positive. A CT scan shows thickening of the gastric wall but no abdominal or other lymphadenopathy. Which of the following is the most appropriate management?

FOLFOX regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. This patient has stage IIIC colon cancer. Stage III is defined by metastases to the local-regional lymph nodes, and stage IIIC is defined by metastases to four or more nodes. Stage III colon cancer is potentially curable, although the risk of treatment failure increases with the number of nodes, and four or more positive nodes is a worrisome prognostic indicator. Currently all patients with stage III cancer are recommended to receive adjuvant chemotherapy after definitive surgery, as large randomized trials have shown that this modestly improves the likelihood of cure. For over a decade, the combination of oxaliplatin plus a fluoropyrimidine, such as 5-FU or its oral prodrug, capecitabine, have been the accepted standard management for stage III colon cancer. The drug 5-FU is usually given with the reduced folate leucovorin, which is inactive alone but causes 5-FU to bind more tightly to its target enzyme.

A 65-year-old woman is evaluated 3 weeks postoperatively following right hemicolectomy for colon cancer. Pathology of the surgical specimen revealed a 3-cm adenocarcinoma invading into but not through the colonic wall. Four of 17 local-regional lymph nodes examined contained metastatic cancer. All margins of resection were free of tumor. Contrast-enhanced CT scans of the chest, abdomen, and pelvis were unremarkable. She takes no medications. On physical examination, vital signs are normal. Surgical incisions are fully healed. The remainder of the examination is normal. Carcinoembryonic antigen (CEA) is 1.7 µg/L (normal is less than 5.0 µg/L). Which of the following is the most appropriate treatment?

Combined Chemotherapy and Radiation. This patient has limited small cell lung cancer. Limited disease is defined as nonmetastatic disease that can be encompassed within a single radiation portal. Because this patient's cancer is confined to the left chest and is not metastatic, it meets this definition. Although surgery can be considered for patients with small isolated tumors, this cancer most commonly presents with large centrally located tumors that are not amenable to resection, as it did in this patient. For these patients, standard management is combined chemotherapy and radiation, which can result in cure for about 20% to 30% of patients. Chemotherapy consists of a cisplatin-based combination (usually cisplatin and etoposide) and is started at the same time as radiation. It is important to integrate radiation early in the course of chemotherapy, as delaying radiotherapy has been shown to result in inferior outcomes. Chemotherapy typically continues for a total of four to six cycles.

A 65-year-old woman is evaluated for new-onset hemoptysis. Her medical history is significant for a 40-pack-year smoking history. She takes no medications. On physical examination, vital signs are normal. BMI is 29. Oxygen saturation is normal breathing ambient air. Digital clubbing is present. CT scan of the chest, abdomen, and pelvis shows a large left hilar mass; there are no other pulmonary lesions, and there is no evidence of metastatic disease. Bronchoscopy with biopsy reveals small cell lung cancer. Brain MRI shows no metastatic disease. Which of the following is the most appropriate treatment?

Cladribine. This patient has hairy cell leukemia, a low-grade B-cell disorder characterized by cytopenia and splenomegaly without lymphadenopathy. Hairy cells (classic appearance of thread-like projections emanating from the cell surface) are typically seen in the peripheral blood smear, and findings on flow cytometry demonstrate positivity for surface markers CD20, CD11c, CD25, and CD103. Cladribine is an appropriate initial therapy for hairy cell leukemia. Cladribine, as well as another purine nucleoside analogue, pentostatin, is associated with complete response rates exceeding 80% to 90%. A single 5- or 7-day course of cladribine is often all that is required. Many patients have durable remissions, although a significant minority do relapse and require retreatment with the same or alternate agents.

A 67-year-old man is evaluated for fatigue and anemia of approximately 2 month's duration. He has no other symptoms and takes no medications. On physical examination, vital signs are normal. Petechiae are noted on the lower extremities, and there is conjunctival pallor. The spleen is palpable 4 cm below the costal margin. There is no lymphadenopathy and no hepatomegaly. Laboratory studies: Hemoglobin 10.4 g/dL (104 g/L) ,Leukocyte count 2200/µL (2.2 × 109/L) with 63% lymphocytes, 34% segmented neutrophils, 3% monocytes, Platelet count 73,000/µL (73 × 109/L). Flow cytometry of peripheral blood confirms kappa-restricted CD20+ B cells expressing CD11c, CD25, and CD103. Peripheral blood smear is shown. Which of the following is the most appropriate treatment?

Platelet Function Analyzer-100 (PFA-100). Selective serotonin reuptake inhibitors (SSRIs) such as citalopram decrease serotonin uptake from platelets and have a reported association with gastrointestinal bleeding, especially in older adults. Herbal supplements like ginkgo biloba have been reported to increase platelet dysfunction in patients taking antiplatelet agents and may interact with this patient's SSRI. The PFA-100 provides a rapid screening test of platelet function and has replaced the bleeding time test. Anticoagulated whole blood is passed through small membranes coated with collagen and epinephrine or collagen and adenosine diphosphate. Platelets adhere to the membrane and close a small aperture. A prolonged closure time implies abnormal platelet activity.

A 68-year-old man is evaluated for epistaxis, gum bleeding, and easy bruising of 3 months' duration. Medical history is notable for anxiety, depression, and hyperlipidemia. Medications are atorvastatin, citalopram, a multivitamin, and ginkgo biloba. On physical examination, vital signs are normal; BMI is 21. Scattered petechiae and several small ecchymoses are visible on the anterior thigh. The examination is otherwise normal. Laboratory studies: Activated partial thromboplastin time (aPTT) Normal ,Hemoglobin 14.8 g/dL (148 g/L), Leukocyte count 4200/µL (4.2 × 109/L), Platelet count 245,000/µL (245 × 109/L) ,Prothrombin time (PT) Normal,Thrombin time Normal. Which of the following is the most appropriate diagnostic test to perform next?

Transfusion of crossmatch-incompatible blood. The most appropriate management is to transfuse with crossmatch-incompatible blood. Although the goal of pretransfusion testing is to ensure the provision of ABO and Rh crossmatch-compatible blood, compatibility might not be achievable in autoimmune hemolytic anemia. Autoimmune hemolytic anemia is caused by the production of autoreactive antibodies against the patient's own erythrocytes. The direct antiglobulin test detects the presence of IgG or complement coating the patient's erythrocytes. In many patients who have IgG autoantibodies, the autoantibodies are of sufficient concentration in the serum or plasma to cause an incompatible crossmatch with donor erythrocytes because the autoantibody is directed against a core antigen on erythrocytes that is present not only on the patient's erythrocytes but also on all donor cells. Although the autoantibody will shorten the survival of transfused cells, they will still survive for days or even weeks and should provide effective therapy for problems related to acute anemia until immunosuppressive therapy becomes effective. A response to immunosuppressive therapy takes 1 to 2 weeks. The major risk in these patients is the failure to identify any additional alloantibody that may be present and could lead to more fulminant acute hemolytic transfusion reactions. In the absence of pregnancy or previous transfusion, the likelihood of non-ABO erythrocyte alloantibody development is extremely low. Therefore, a unit that is ABO and Rh matched is appropriate, even if crossmatch incompatible.

A 68-year-old man is evaluated in the emergency department for fatigue and exertional dyspnea. He has a 5-year history of chronic lymphocytic leukemia, which has not required therapy. He takes no medications. On physical examination, temperature is 37 °C (98.6 °F), blood pressure is 123/82 mm Hg, pulse rate is 108/min, and respiration rate is 18/min. Oxygen saturation is 95% breathing ambient air. Cervical, axillary, and inguinal lymphadenopathy and splenomegaly are present. Laboratory studies: Hemoglobin 5 g/dL (50 g/L), Leukocyte count 35,000/µL (35 × 109/L) with 85% lymphocytes, 15% neutrophils, Platelet count 180,000/µL (180 × 109/L) ,Reticulocyte count 10% of erythrocytes. A direct antiglobulin test result is positive for IgG and C3. The patient is group A-positive and crossmatch incompatible with 5 units of group A-positive blood. Glucocorticoid therapy is started. Which of the following is the most appropriate management?

Babesiosis. The patient most likely has transfusion-transmitted babesiosis. This tickborne disease, caused primarily by Babesia microti in the United States, can be transmitted through transfusion but is not routinely screened for in blood donors. Babesia is endemic in New England and regions of the upper Midwest. Although blood donors who report a history of babesiosis are excluded from donating, 80% of infected persons are asymptomatic and may be parasitemic for months. The incubation period for transfusion-related babesiosis ranges from 11 to 176 days. Risk factors for severe disease include older age, splenectomy, or compromised immune function. Symptoms include fatigue, malaise, fever, nausea, anorexia, myalgia, abdominal pain, and diarrhea. Hemolytic anemia, thrombocytopenia, and elevated serum aminotransferase and alkaline phosphatase levels are common. The first clue often comes on the blood smear examination from the unexpected detection of the protozoal ring forms within erythrocytes; babesiosis is then confirmed by polymerase chain reaction.

A 68-year-old woman is hospitalized with fatigue, anorexia, and myalgia worsening over the last week. She underwent laparotomy 4 weeks ago for trauma sustained in a motor vehicle accident, which necessitated a splenectomy. She received 3 units of blood as well as pneumococcal, haemophilus, and meningococcal vaccination; she was discharged on postoperative day 8. Hemoglobin level at discharge was 11 mg/dL (110 g/L). Her only medication is acetaminophen as needed for pain. On physical examination, temperature is 38.6 °C (101.5 °F), blood pressure is 138/63 mm Hg, pulse rate is 92/min, and respiration rate is 18/min. The examination is otherwise noncontributory. Laboratory studies: Hemoglobin 9.9 g/dL (99 g/L), Leukocyte count 10,100/µL (10.1 × 109/L) with 82% neutrophils, 2% bands, 11% lymphocytes, 3% monocytes, and 2% atypical lymphocytes, Platelet count 92,000/µL (92 × 109/L) ,Reticulocyte count 8% of erythrocytes, Alkaline phosphatase 833 U/L ,Alanine aminotransferase 140 U/L ,Aspartate aminotransferase 134 U/L. Blood cultures are obtained. Peripheral blood smear is shown.Which of the following transfusion-transmitted diseases is the most likely diagnosis?

Assess immunoglobulin level. This patient with chronic lymphocytic leukemia (CLL) has had three hospitalizations for pneumonia in the past year, and assessing his immunoglobulin levels would be appropriate. Patients with CLL frequently are hypogammaglobulinemic and are prone to sinus and pulmonary infection. Intravenous immunoglobulin G replacement therapy has been shown to reduce the risk of infections in patients with CLL with documented hypogammaglobulinemia. Surveillance for viral infections and early initiation of antimicrobial agents for presumed bacterial infections are also essential.

A 69-year-old man with previously untreated chronic lymphocytic leukemia returns to the office after his third hospitalization this year for pneumonia. He received the pneumococcal conjugate vaccine at age 65 years and the polysaccharide vaccine at age 66 years. He is taking no medications. On physical examination, vital signs are normal. He has diffuse lymphadenopathy with nodes up to 2.5 cm in size and a palpable spleen below his left costal margin. The chest is clear to auscultation. Laboratory studies: Leukocyte count 34,000/µL (34 × 109/L) with 91% lymphocytes, 5% neutrophils, 3% monocytes, and 1% bands , Platelet count 118,000/µL (118 × 109/L) ,Hemoglobin 12.2 g/dL (122 g/L). Which of the following is the most appropriate management?

Neoadjuvant chemotherapy plus radiation therapy. Although only 30% to 40% of patients with gastroesophageal cancer have potentially resectable disease at presentation, patients with local and locoregional disease are typically treated surgically. Unfortunately, recurrence rates are high, and cure rates with surgical resection alone remain low. Studies have shown that administration of neoadjuvant chemotherapy improves outcome to a modest but statistically significant degree. Neoadjuvant chemotherapy plus radiation therapy is given before a planned curative-intent surgery to patients who are believed to have fully resectable disease to eradicate any micrometastatic disease that might be present outside of the surgical field and thus increase the chance for cure. There is often confusion between neoadjuvant chemotherapy and conversion chemotherapy. The key distinction between neoadjuvant chemotherapy and conversion chemotherapy is that in conversion chemotherapy, the patient's tumor is not believed to be currently resectable but could possibly become resectable if adequate tumor regression can be accomplished with chemotherapy. Thus, both neoadjuvant and conversion chemotherapy are given with a plan for surgery to follow; however, neoadjuvant therapy is administered to patients with micrometastatic disease thought to be resectable, whereas conversion therapy is given to shrink visible tumors in patients with unresectable disease in whom disease might become resectable with adequate tumor regression.

A 69-year-old woman is evaluated for 6 months of progressive dysphagia. She has been previously healthy and takes no medications. On physical examination, vital signs and the remainder of the physical examination are normal. Results of upper endoscopy and biopsy indicate adenocarcinoma of the gastroesophageal junction. The staging evaluation reveals a T3 tumor on ultrasound and no evidence of distant metastatic disease. The patient's tumor is technically resectable. Which of the following is the most reasonable treatment strategy?

Radiation therapy. The most appropriate treatment in this patient with early-stage laryngeal cancer is radiation therapy. In early-stage laryngeal cancer, it is important to consider predicted efficacy and anticipated voice quality and other potential functional impairments when deciding on a treatment plan. For patients with early-stage disease, cure rates are high with surgery and with radiation. For patients treated with surgery, the use of adjuvant radiation or combined chemotherapy and radiation is recommended based on findings at surgery. However, open hemilaryngectomy results in suboptimal functional outcomes and is associated with complications, including bleeding, infection, laryngocutaneous fistula, and aspiration. Radiation is highly effective with low morbidity, and functional outcomes are generally superior in patients with laryngeal cancer who are treated with radiation compared with those treated with surgery. Radiation therapy often causes xerostomia, thickening of saliva, mucositis, dysphagia, odynophagia, and malnutrition.

A 70-year-old man is evaluated for a 2-month history of persistent hoarse voice. He has a 50-pack-year smoking history. His medical history is otherwise normal, and he takes no medications. On physical examination, vital signs and other findings are normal. Laryngoscopy shows a small mass on the right vocal cord without fixation or limitation in mobility. CT scan of the neck shows a small lesion on the right vocal cord with no evidence of left-sided involvement, cartilage involvement, or lymphadenopathy. Which of the following is the most appropriate treatment?

Prothrombin complex concentrates (PCCs). Four-factor PCC is a combination of inactivated factors II, VII, IX, and X. Treatment recommendations for over-anticoagulation with warfarin are based on the degree of over-anticoagulation as measured by the INR and clinical manifestations of bleeding. The first step in all cases of over-anticoagulation is withholding warfarin. For patients with an INR of 4.5 to 10 and with no evidence of bleeding, routine use of vitamin K is not recommended. For patients with an INR greater than 10 and with no evidence of bleeding, oral vitamin K is recommended. For patients with major bleeding, such as this patient with an intracerebral hemorrhage, rapid reversal of anticoagulation is recommended with four-factor PCC rather than fresh frozen plasma (FFP). These patients are also likely to benefit from the addition of vitamin K by slow intravenous injection rather than using coagulation factors alone. Clinical trials have shown four-factor PCC to be noninferior to FFP in reversing warfarin anticoagulation. However, four-factor PCC is preferred because of its rapid reversal of the INR, rapid infusion and administration, and no risk of volume overload as is sometimes seen with plasma infusions. Additionally, four-factor PCC does not require thawing or typing.

A 70-year-old man is evaluated in the emergency department for headache, confusion, and weakness. Medical history is significant for ischemic cardiomyopathy with heart failure and mural thrombus. Medications are lisinopril, carvedilol, spironolactone, furosemide, and warfarin. On physical examination, the patient is disoriented. Temperature and respiration rate are normal, blood pressure is 160/90 mm Hg, and pulse rate is 88/min. The examination is otherwise unremarkable. Laboratory studies show an INR of 7.5. CT scan of the head shows left intraparenchymal hemorrhage. In addition to vitamin K administration, which of the following is the most appropriate treatment?

Inclusionary predictive tumor marker. The finding of a BRAF V600E mutation is best described in this situation as an inclusionary predictive marker. Predictive markers help identify specific aspects of the tumor that can guide clinicians in determining which therapies are or are not appropriate for particular patients. For example, specific BRAF-targeted treatment, such as vemurafenib and dabrafenib, is indicated only in the subset of patients in whom the BRAF V600E mutation is found, and patients with this mutation are predicted to respond favorably to these agents. Conversely, the absence of the BRAF V600E mutation in patients with metastatic melanoma excludes consideration of such therapy and strongly predicts an absence of benefit from such a treatment.

A 71-year-old man has a follow-up evaluation. He was recently diagnosed with metastatic melanoma characterized by a BRAF V600E mutation for which he was treated with a BRAF inhibitor. After treatment, he was found to have major tumor regression at all disease sites. He takes no medications. On physical examination, vital signs and other findings are normal. Which of the following best describes the type of tumor marker present in this patient?

Resection of all lesions. The role of postoperative surveillance in patients with colorectal cancer is to identify surgically curable recurrence, such as oligometastatic liver disease or lung metastases. The liver is the primary metastatic site for patients with colorectal cancer. About one third of patients with metastatic disease will have it confined to the liver and will be amenable to surgical resection and cure, with or without adjuvant chemotherapy. The criteria for surgical resection of hepatic metastases have expanded from the "three lesions or less" rule. Most patients with good performance status can be considered for surgical resection unless they have one of three conditions: tumor involvement of the common artery or portal vein or common bile duct; more than 70% liver involvement, more than six involved segments, or involvement of all three hepatic veins; and a predicted inadequate hepatic reserve after resection. This patient has recurrent colorectal cancer in a single organ in an oligometastatic pattern. As such, he is a candidate for surgery with curative intent.

A 71-year-old man is evaluated during a follow-up appointment for stage II rectal cancer that was resected 3 years ago. He takes no medications. On physical examination, vital signs are normal. BMI is 23. The liver edge is palpable 3 cm below the xiphisternum. A surveillance CT scan shows three new hypodense lesions in the left lobe of the liver consistent with metastatic disease. The largest lesion is 4 cm. No other abnormal findings are found on a contrast-enhanced CT scan of the chest, abdomen, and pelvis. Which of the following is the most appropriate management?

Testosterone. This patient's polycythemia is likely caused by testosterone injections. Polycythemia is a common adverse effect of testosterone (and anabolic steroid) supplementation, and evaluating the hematocrit level at initiation, 3 to 6 months after testosterone initiation, and annually thereafter is recommended by Endocrine Society guidelines. Guidelines also recommend interrupting the testosterone supplementation if the hematocrit value is greater than 54%. Secondary polycythemia can cause symptoms, such as headaches and elevated blood pressure, and increase the risk of thromboembolism. The risk of venous thromboembolic disease is directly related to hematocrit level. In this patient, stopping the testosterone supplementation until his polycythemia improves and restarting at a lower dose is recommended. In patients with severe symptoms, phlebotomy can also be considered. Testosterone supplementation can also exacerbate undiagnosed sleep apnea, and evaluation for an underlying sleep disorder should be performed in these patients with polycythemia.

A 71-year-old man is evaluated for headaches of 2 months' duration. He reports no shortness of breath and has a good energy level. Medical history is significant for hypertension, hypothyroidism, and hypogonadism; he has never smoked. Medications are lisinopril, levothyroxine, and testosterone injections. On physical examination, vital signs are normal except for a blood pressure of 160/92 mm Hg; BMI is 19. He has facial plethora. Cardiopulmonary examination is normal. No hepatosplenomegaly is noted. Laboratory studies: Erythropoietin 40 mU/mL (40 U/L), Hematocrit 56% ,Hemoglobin 18.9 g/dL (189 g/L) ,Leukocyte count 7000/µL (7 × 109/L) with normal differential, Platelet count 300,000/µL (300 × 109/L). Which of the following is the most likely cause of this patient's findings?

Infection. The most common indications for autologous hematopoietic stem cell transplantation (HSCT) are multiple myeloma and relapsed non-Hodgkin lymphoma. With appropriate supportive care, many older patients are eligible for autologous HSCT. Fatigue, altered taste, diminished appetite, and persistent mild diarrhea are common adverse effects of high-dose chemotherapy, an integral part of HSCT. The most common concern in patients who have undergone HSCT is the increased risk of infection, which persists for 6 to 12 months after HSCT. This risk is attributed to compromised function of neutrophils and lymphocytes and is sometimes associated with mild neutropenia and lymphopenia. For this reason, patients should be counseled to report warning symptoms, such as fever and respiratory or other localizing symptoms of infection, early in the course.

A 73-year-old man undergoes follow-up evaluation after autologous hematopoietic stem cell transplantation (HSCT) 3 weeks ago for multiple myeloma. He had induction chemotherapy 1 year ago. He is doing well, without fever, chills, cough, or localizing symptoms of infection. Medications are acyclovir and omeprazole. On physical examination, vital signs are normal; BMI is 20. He weighs 2.5 kg (6 lb) less than he did 2 months ago before HSCT. Alopecia is noted. In the next 30 days, this patient is at increased risk for which of the following treatment-related complications?

Lenalidomide. This patient with transfusion-dependent myelodysplastic syndrome (MDS).Treatment of MDS has two goals. The first goal is to relieve transfusion dependence; the second is to prevent transformation to acute myeloid leukemia (AML). He has low-risk MDS with chromosome 5q deletion (−5q), and lenalidomide will help with his transfusion-dependent anemia. Patients with infrequent transfusion requirements can be supported with periodic transfusions alone, but in patients requiring frequent transfusions, supplemental treatments to help decrease transfusion requirements should be used to improve quality of life and decrease transfusion-associated iron overload and alloimmunization. In more than 50% of patients with −5q MDS, treatment with low-dose lenalidomide has been shown to achieve transfusion independence and is recommended as first-line therapy. Other second-line treatments for low-risk MDS with −5q include recombinant erythropoietin and the hypomethylating agents azacitidine and decitabine. Hypomethylating agents can reduce transfusion requirements and delay transformation to AML. However, both also worsen blood counts initially and may take up to 6 months to show an effect. Finally, this patient is not at high risk for AML transformation.

A 74-year-old man is evaluated in follow-up for myelodysplastic syndrome diagnosed 3 months ago. Cytogenetic studies and fluorescence in-situ hybridization showed deletion of 5q. It was determined he has low-risk MDS by the Revised International Prognostic Scoring System. He requires erythrocyte transfusions every 2 weeks to prevent symptomatic anemia. He takes no medications. On physical examination, pulse rate is 120/min, and respiration rate is 24/min; other vital signs are normal. Skin pallor is noted. Cardiac examination reveals tachycardia. Laboratory studies show a hemoglobin level of 6.5 g/dL (65 g/L), leukocyte count of 2500/µL (2.5 × 109/L), and platelet count of 220,000/µL (220 × 109/L). Which of the following is the most appropriate treatment?

Administering vitamin K. This patient has developed vitamin K deficiency from poor oral intake and a prolonged course of antibiotics combined with diarrhea from concurrent Clostridium difficile infection. Although vitamin K is found in many foods, most vitamin K needed for coagulation is derived from saprophytic bacteria in the colon, and antibiotics destroy these bacteria. Diarrhea (from any cause) results in decreased absorption of vitamin K. Vitamin K is needed to activate certain factors (II, VII, IX, and X), and the prothrombin time (PT), which is most sensitive to a decrease in factor VII levels, will be elevated out of proportion to the activated partial thromboplastin time (aPTT), which will be normal or only mildly elevated. Vitamin K deficiency can be managed with oral or parenteral vitamin K, and the coagulopathy will begin to correct within 1 day.

A 74-year-old man is noted to have prolonged bleeding from venipuncture sites and new ecchymoses. He was admitted to the hospital 2 weeks ago for antibiotic treatment of a lung abscess. He developed Clostridium difficile-related diarrhea 1 week ago. His oral intake has been poor. Medical history is notable for hyperlipidemia. Medications are ampicillin-sulbactam, oral vancomycin, atorvastatin, and low-dose subcutaneous low-molecular-weight heparin. On physical examination, temperature is 38.2 °C (100.8 °F), blood pressure is 115/68 mm Hg, pulse rate is 96/min, and respiration rate is 24/min. He is thin and chronically ill appearing. On pulmonary examination, crackles are heard at the right lung base. The remainder of the examination is normal. Laboratory studies: Activated partial thromboplastin time 30 s ,Hemoglobin 11.8 g/dL (118 g/L) ,Prothrombin time 22 s ,Alanine aminotransferase 54 U/L ,Aspartate aminotransferase 56 U/L , Factor V 100%, Factor VIII 100% ,Factor X 24%. Which of the following is the most appropriate management?

Observation. The most appropriate management in this patient with early-stage prostate cancer and significant medical comorbidities is observation. His medical history is consistent with a predicted life expectancy of less than 5 years, his voiding symptoms are better after treatment with an α-blocker, and he has no other symptoms attributable to his cancer. Based on the typically indolent course of a low-grade localized prostate cancer, this patient will most likely die as a result of one of his other medical conditions rather than his prostate cancer. He is also at significant risk for complications associated with treatment. These issues should all be discussed with the patient so he can understand the competing issues involved and thereby permit him to be an active participant in decision making.

A 75-year-old man is evaluated for a 3-month history of worsening urinary hesitancy, decreased stream, and a sense of incompletely emptying his bladder. His medical history is significant for COPD, hypertension, and stroke. He has dyspnea with minimal exertion. His medications are ipratropium bromide, salmeterol, fluticasone, amlodipine, atorvastatin, and aspirin. On physical examination, there is evidence of mild muscle wasting. His respiration rate is 18/min; other vital signs are normal. Oxygen saturation is 92% breathing ambient air. Pulmonary examination reveals decreased breath sounds throughout both lung fields. Digital rectal examination reveals an enlarged prostate without any palpable nodules. Laboratory studies reveal a serum prostate-specific antigen level of 6 ng/mL (6 µg/L). Biopsy of the prostate confirms prostate cancer with a Gleason score of 6. The patient begins therapy with tamsulosin, and his voiding symptoms improve. Which of the following is the most appropriate management of his prostate cancer?

Observation. For this 75-year-old man with advanced-stage follicular lymphoma who is asymptomatic and does not have bulky disease, observation is an appropriate management strategy. There is no proof that earlier therapy for stage III to IV (nodes on both sides of the diaphragm [III]; noncontiguous extranodal involvement [IV]) follicular lymphoma provides benefit over deferring therapy until needed, provided the patient is comfortable with a strategy of surveillance. Patients with nonbulky follicular lymphoma who are not symptomatic may survive many years without the need for therapy.

A 75-year-old man is evaluated for generalized lymphadenopathy. He is otherwise asymptomatic and takes no medications. On physical examination, all vital signs are normal. There is generalized lymphadenopathy with nodes 1 cm to 2.5 cm in size in his cervical, supraclavicular, axillary, and inguinal areas bilaterally. There is no hepatosplenomegaly. The remainder of the physical examination is normal. CT scan of the chest, abdomen, and pelvis shows mediastinal and retroperitoneal nodes that are 1.5 cm to 2.0 cm in size. Laboratory results, including complete blood count, biochemistry profile, and lactate dehydrogenase level, are normal. Serum urate level is 9.5 mg/dL (0.56 mmol/L). Left inguinal node biopsy shows follicular lymphoma. Which of the following is the most appropriate management?

Direct antiglobulin (Coombs) test. Obtaining a direct antiglobulin (Coombs) test would be the appropriate initial diagnostic step to help guide management in this patient with chronic lymphocytic leukemia (CLL) with anemia. Concomitant autoimmune disease, including immune thrombocytopenia and hemolytic anemia, is common among patients with CLL. Anemia in patients with CLL can have many mechanisms, including myelophthisis (replacement of normal marrow elements by fibrosis or tumor) from the CLL itself, hypersplenism, chemotherapy, pure red cell aplasia, and autoimmune hemolytic anemia. The patient's reticulocytosis is strongly suggestive of a hemolytic anemia. Identifying the mechanism of anemia can help guide therapy. If the patient has a positive direct antiglobulin test result suggestive of a secondary immunohemolytic anemia, glucocorticoids would be the appropriate first treatment for this patient.

A 78-year-old woman is evaluated for increasing fatigue during the past 2 weeks. She has a 7-year history of chronic lymphocytic leukemia previously treated with bendamustine and rituximab with excellent results. One month ago, after presenting with persistent night sweats, she was diagnosed with relapsed chronic lymphocytic leukemia based on lymphocytosis on a complete blood count and results of peripheral blood flow cytometry. Her hemoglobin level at that time was 12.1 g/dL (121 g/L). She was started on oral ibrutinib. On physical examination, vital signs are normal. Scleral icterus is noted. The spleen is palpable 3 cm below the costal margin. There is no peripheral lymphadenopathy. Laboratory studies: Hemoglobin 7.4 g/dL (74 g/L) , Leukocyte count 22,000/µL (22 × 109/L) with 79% lymphocytes, Platelet count 122,000/µL (122 × 109/L) ,Reticulocyte count 11% of erythrocytes. Which of the following is the most appropriate management?

Hemolytic uremic syndrome. HUS is a diarrhea-associated syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury caused by Shiga toxin-producing Escherichia coli, typically with serotypes O157:H7, O104:H4, and, less commonly, Shigella dysenteriae. Shiga toxin binds to endothelial cells, triggering thrombosis and resulting in a thrombotic microangiopathy. It also binds to renal mesangial cells, podocytes, and renal tubular cells, causing direct damage. These actions lead to acute kidney injury. Although it is more commonly seen in children, it can also present in adults. Supportive care is a cornerstone of treatment, and fluid management with volume expansion is critical despite any existing oliguria.

An 18-year-old man is evaluated in the emergency department for abdominal cramping and bloody diarrhea of 6 days' duration. Medical history is unremarkable, and he takes no medications. On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 98/60 mm Hg, pulse rate is 100/min, and respiration rate is 16/min. Oxygen saturation is normal breathing ambient air. His abdomen is tender, without guarding or organomegaly. The examination is otherwise unremarkable. Laboratory studies: Haptoglobin Undetectable ,Hemoglobin 6.1 g/dL (61 g/L) ,Leukocyte count 6800/µL (6.8 × 109/L) ,Platelet count 37,000/µL (37 × 109/L), Reticulocyte count 9.8% of erythrocytes ,Creatinine 3.6 mg/dL (318 µmol/L) ,Urinalysis 3+ blood; 3+ protein; 0-2 erythrocytes/hpf; 0-2 leukocytes/hpf; several granular casts. The peripheral blood smear shows schistocytes and scant platelets without clumps. The direct antiglobulin (Coombs) test is negative. What is the most likely diagnosis?

Flow Cytometry in peripheral blood smear. This patient's elevated lymphocyte count and the identification of smudge cells on the peripheral blood smear, together with the presence of lymphadenopathy on physical examination, point to a possible diagnosis of chronic lymphocytic leukemia (CLL). B-cell CLL is the most common form of adult leukemia, accounting for 10% of hematologic malignancies. Patients are usually asymptomatic at presentation, with CLL identified by a lymphocytosis on a routine complete blood count. Flow cytometry is the most appropriate test to make an initial diagnosis of CLL. It can be easily performed on peripheral blood and will show B-cell antigens (CD19, CD20, and CD23), coexpression of CD5 (usually a T-cell marker), and low levels of a monoclonal surface immunoglobulin. In most cases, CLL can be suspected based on the complete blood count and review of a peripheral blood smear. However, other conditions may present with lymphocytosis, which flow cytometry can help distinguish from typical CLL. Other conditions include reactive lymphocytosis, T-cell leukemias, and other B-cell lymphoproliferative disorders involving the blood, such as mantle cell and marginal zone lymphomas and hairy cell leukemia.

An 82-year-old woman is evaluated for persistent swellings in her neck, armpit, and groin. She describes no additional symptoms. She has long-standing systolic hypertension for which she takes chlorthalidone. On physical examination, blood pressure is 154/82 mm Hg. The other vital signs are normal. There are bilateral enlargements of cervical, supraclavicular, axillary, and inguinal lymph nodes. The remainder of the examination is unremarkable. Laboratory studies: Hemoglobin 12.5 g/dL (125 g/L), Leukocyte count 14,000/µL (14 × 109/L) with 66% lymphocytes, 23% segmented neutrophils, 6% monocytes, 1% eosinophils, and 4% bands, Platelet count 174,000/µL (174 × 109/L). Smudge cells are noted on a peripheral blood smear.Which of the following is the most appropriate diagnostic test to perform next?