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Right answer is D) He would likely not benefit from 5-FU

Colon cancer patients who have high-levels of microsatellite instability (MSI-H) or defective DNA mismatch repair have a good prognosis and do not benefit from 5-FU chemotherapy.

One study showed that 70 of 457 (15%) were MSI and those patients had no DFS improvement with 5-FU chemotherapy compared to surgery alone. Conversely, who were microsatellite stable (proficient DNA mismatch repair) had benefit with adjuvant 5-FU (0.67; P = .02).

**Pearl: 15% of sporadic tumors are MSI

**Pearl: MSI-H tumors are often right-sided, have undifferentiated histology, present as stage II, and occur often in females.

The right answer is E) Give EP alone for 3 more cycles

For Stage IIB (S1) NSGCT, can give either BEP x 3 cycles or EP x 4 cycles.

As he has bleomycin lung toxicity, do not risk giving more bleomycin.  One would not want him to develop pulmonary fibrosis (which can be fatal).  EP x 4 is a perfectly acceptable regimen.  As he had 1 cycle of BEP already (and therefore EP x 1), give 3 more cycles of EP and stop therapy.

Bleomycin pulmonary toxicity can often start off as pneumonitis, but can progress to fibrosis.   The incidence of bleomycin-induced pulmonary fibrosis can be as high as 10%.  After stopping the drug, high-dose steroids can be used for therapy

**Pearl: If patient has Intermediate or Poor risk disease, can substitute Ifosfamide for Bleomycin (VIP regimen) if there is concern about bleomycin toxicity

Right answer is B) HUS from Gemcitabine

Gemcitabine is a Pyrimidine analog.  It is metabolized within cells to the active nucleoside forms: diphosphate and triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase.  Gemcitabine triphosphate competes to be incorporated into DNA. DNA synthesis is halted

Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure.

One can also see an elevated LDH, low haptoglobin and schistocytes on the peripheral blood smear.  A renal biopsy would show microvascular damage of arterioles and small arteries occluded by eosinophilic hyaline thrombi containing fibrin and platelet aggregate.

Several etiologies that can cause this condition include cancers, chemotherapy drugs and infections.

The mechanism of gemcitabine-induced HUS is unclear.  Some posit that this chemotherapy medication may lead to microvascular endothelial damage or immunocomplex mediation.

There is no consensus as to the best treatment for Gemcitabine related HUS.

However, one should immediately discontinuation of gemcitabine. Other potential therapies include steroids, FFP administration, plasmapheresis or hemodialysis.

**Pearl: Mitomycin C can also cause HUS

The right answer is E) Treat her as you would an epithelial ovarian cancer

Carcinosarcomas consists of malignant epithelial and mesenchymal components.  They account for <2% of malignant ovarian cancers.  Data has shown that Carcinosarcomas should be treated as you would an epithelial ovarian cancer and that Carboplatin/Paclitaxel is an active regimen.

Ovarian Carcinosarcoma: 

Stage I-IV: Treat like Epithelial ovarian cancer

However, some give Platinum + Ifosfamide 

D) Fractionated external beam radiation therapy and neoadjuvant or adjuvant lomustine, procarbazine, and vincristine (PCV) chemotherapy

Anaplastic oligodendrogliomas are chemotherapy-sensitive tumors.  A phase III study (EORTC 26951) evaluated addition of adjuvant PCV x 6 cycles with RT vs. RT alone (59.4 Gy).  A total of 368 patients enrolled.  OS favored the RT/PCV group (42.3 vs. 30.6 mo; HR=0.75). 

In 80 patients with 1p/19q codeletion, OS favored PCV arm (Not reached vs. 112 mo; HR=0.56). IDH mutational status was also of prognostic significance.

Having 1p/19q codeletion confers a better prognosis.

RTOG 9402 randomized 291 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma to PCV followed by immediate RT or RT alone. No difference in median Overall survival was seen between both arms (4.6 years vs. 4.7 years; P=0.10). However, an unplanned subgroup analysis of the 126 patients whose tumors were 1p19q co-deleted found a doubling in median Overall survival (14.7 vs. 7.3 years; HR=0.59; P=0.03) when PCV was added to RT as upfront treatment.

The phase III CODEL study was designed to assess the efficacy of Temozolomide for the treatment of newly diagnosed anaplastic oligodendrogliomas. The study was redesigned to compare RT + PCV to RT + Temozolomide in patients with anaplastic oligodendroglioma as well as low-grade oligodendroglioma. Results of this important study are pending.

Right answer is D) Concurrent chemoradiation with Cisplatin/Etoposide (radiation given in bid fractions), followed by PCI.

Cisplatin/Etoposide is preferred over Carboplatin/Etoposide for concurrent therapy in limited stage disease. For extensive stage (chemotherapy alone), either Carboplatin or Cisplatin is acceptable.

Twice a day (hyperfractionated) radiation confers benefit.  

     45 Gy in 3 weeks (1.5 Gy bid) > 45 Gy in 5 weeks (1.8 Gy daily)

    5-year OS 26% with bid XRT vs. 16% for daily RT  (P=0.04)

However, these doses were not biologically equivalent.

When BID fractionation is used, there should be at least a 6-hour interfraction interval to allow for repair of normal tissue. If one is using once-daily RT, higher doses of 60-70 Gy should be used.

RTOG 0538:

45 Gy in 30 treatments (bid in 3 weeks) vs.70 Gy in 35 treatments (7 weeks) vs 61.2 Gy given  in 34 treatments (daily x 3 weeks, then bid x 2 weeks; arm has been discontinued).

Right answer is C) Continue therapy

Responses to immune based therapy can be modest. One needs to be careful with stopping therapy too soon based on an interval CT image.  Sometimes, responses can occur even after radiologic evidence of initial disease progression. These responses can be delayed but durable.

Ipilimumab is a humanized monoclonal IgG1 antibody that targets the cytotoxic T-lymphocyte antigen-4 (CTLA-4).  CTLA-4 on T cells acts as a break for the normal immune system. By blocking CTLA-4, Ipilimumab unleashes the immune system leading to T-cell activation.

This drug attained FDA approval in 2011 as monotherapy (3 mg/kg) x 4 cycles for patients with unresectable or metastatic melanoma (both pre-treated or chemotherapy naive patients). 

Right answer is B) Imatinib

Dermatofibrosarcoma protuberans (DFSP) is a tumor of the dermis layer of the skin.

Up to 5% of these tumors can metastasize. It can appear as a bruise or pimple. Over 90% are slow growing tumors. A subset of DFSP can harbor a high-grade sarcomatous component.

The majority (>90%) will have t(17;22). The translocation fuses the collagen gene (COL1A1) with the platelet-derived growth factor (PDGF) gene; this results in a fusion protein that leads to a potent growth factor (PDGF).

The primary treatment is surgery to achieve negative margins.  Surgical approaches include:

CCPDMA: Complete circumferential and peripheral deep margin assessment

Mohs Micrographic surgery

Wide excision with at least 2-cm margins to investing fascia of muscle or pericranium with clear pathologic margins.

Phase II data of imatinib in patients with locally advanced or metastatic DFSP revealed an objective response rate of almost 50%.  The median time to progression was 1.7 years.

Imatinib is approved b the FDA for the treatment of unresectable, recurrent, and/or metastatic DFSP in adult patients.

Tumors lacking the t(17;22) translocation may not respond to imatinib.

The right answer is D) Radiation therapy

Oftentimes, follicular lymphomas do not present in a localized manner.  When they do, consider local therapy with radiation as some studies show a long term remission. Observation, single agent Rituximab, or Rituximab + chemotherapy are also options to consider.

On study retrospectively evaluated the effectiveness of radiation in 177 patients with stage I or II follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma.  Radiotherapy doses ranged from 35 to 50 Gy.  The median survival time was 13.8 years.  At 20 years, 37% patients were relapse-free.  Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. 

**Pearl: The NCCN guidelines mention that Stage I (<7 cm) or contiguous stage II (<7 cm) can be offered Involved Site Radiation therapy.

Right answer is E) Switch to a different TKI

At the 18 month follow-up mark, to see a cytogenetic relapse is disconcerting.  According to the NCCN guidelines, a BRC-ABL1 >1-10% at >15 months of being on therapy connotes treatment failure.  In situations like this, need to check for compliance and drug-drug interactions.  Prior to switching therapy for a presumed TKI failure, check the mutational status of BCR-ABL.  For second-line treatment for patients with TKI-resistant disease, one should switch to another alternate TKI and evaluate for allogeneic HCT.

There is a subset of BCR-ABL mutant clones associated with impaired responses to second-generation TKIs

For patients with a F317L mutation, would offer Bosutinib or Nilotinib,

Depending on mutational status, some TKIs may work better:

E255K/V, F317L/V/IC, F359V/C/I, T315A, Y253H: Use Bosutinib

T315I: Use Ponatinib, Omacetaxine, Allogeneic transplant

V299L, T315A, F317L/V/I/C: Use Nilotinib

Y253H, E255K/V, F359V/C/I: Use Dasatinib

T315I: Ponatinib, Omacetaxine, Allogeneic HCT or clinical trial

Right answer is D) ER-, PR-, Her-

Hereditary breast ovarian cancer syndromes are autosomal dominant disorders. BRCA1 and BRCA2 are tumor suppressor genes whose role is to control cell growth and cell death. Mutations disenable this function leading to increased cancer risk. Differences exist between both BRCA1 and BRCA2 related tumors.

BRCA1 breast cancers are mostly triple negative. BRCA2 breast cancers are mostly ER+

BRCA1: On chromosome 17

              50-85% risk of female breast cancer.  40% risk of ovarian cancer

              40-60% lifetime risk of developing a second breast cancer 

BRCA2: On chromosome 13

              40-60% risk of female breast cancer.  6% risk of male breast cancer

              10-15% risk of ovarian cancer

              Increased risk of stomach, melanoma, prostate, pancreatic

The right answer is B) Her tumor meets all the criteria not to offer RAI

RAI is not offered to every patient s/p surgery for a differentiated thyroid cancer. The size cutoff to offer it is often 4 cm in size, which she clearly is not close to having. All of her clinical and pathologic features are favorable so would not offer RAI.  

RAI does have toxicity, so need to carefully evaluate if a patient truly will benefit from it as adjuvant therapy.

RAI is typically recommended if any of the following features are present:

Gross extrathyroidal extension, primary tumor >4 cm or postoperative unstimulated Tg>5-10 ng/mL

Right answer is C) HJV/HAMP

This patient likely has Juvenile hemochromatosis.  It normally occurs in patients < 30 years of age and is inherited in an autosomal recessive manner.  The Hepcidin level is normally severely low

The majority have biallelic mutations in HJV.  HJV encodes a protein product, hemojuvelin, that is expressed in liver, heart, and skeletal muscle, and is thought to be involved in modulating hepcidin.  The low levels of hepcidin seen in JH are consistent with the markedly increased intestinal iron absorption as well as the presence of iron-depleted macrophages, both of which are characteristic of this disorder.

Other pathogenic gene mutations implicated include HAMP or serum transferrin receptor 2.

Patients with juvenile hemochromatosis normally have severe clinical symptoms with early onset liver damage, hypogonadism, cardiomyopathy, and diabetes.  These symptoms have been exacerbated as he has not received any therapy

Of note, in hereditary hemochromatosis, clinical manifestations normally occur later in life.  This is an important clinical distinction between the 2 disease processes

The treatment of juvenile hemochromatosis is generally similar to existing treatment options for classic hemochromatosis (phlebotomy).

https://www.uptodate.com/contents/search (Accessed May 2019)

Right answer is D) Wash the pRBC

IgA is concentrated in mucosal secretions and is believed to be important in the immune functioning of the mucosal barrier.

A minority of IgA-deficient individuals are symptomatic. These patients may develop recurrent sinopulmonary infections, autoimmune disorders, gastrointestinal disorders, allergic diseases, and rare anaphylactic reactions to blood products.

Two severities of IgA deficiency are distinguished. A serum IgA level <7 mg/dL is considered severe deficiency.

IgA deficiency is the most common human immunodeficiency. The presence of anti-IgA in an IgA deficient recipient can lead to anaphylaxis (against IgA antigen in the donor red cell units). 

Most patients with sIgAD do not form anti-IgA antibodies. These antibodies are usually only found in patients with undetectable serum IgA.

These patients can develop urticaria, wheezing, shock and cardiac arrest.  _Stop_ the transfusion immediately.  Patients may need Epinephrine.  On critical point is that patients with IgA deficiency who receive plasma products that carry the IgA antibody, will have an _immediate_ reaction to the blood product.

Patients with severe IgA deficiency can experience infusion reactions to blood products containing small amounts of IgA, typically in plasma including the following products: Rbc, Platelets, FFP, Cryoprecipitate and IVIG.

By washing the donor red cell units (saline, centrifuge, removal of supernatant), the IgA antibodies will be removed.  However, it shortens the shelf life of red blood cells to <24 hours

Indications to wash Red blood cells:

• --Severe allergic reactions


• --Removal of maternal antibodies for fetal transfusion (Hemolytic disease of newborn, Neonatal alloimmune thrombocytopenia)

https://www.uptodate.com/contents/search (Accessed May 2019)

Right answer is D) Xarelto 15 mg po bid x 3 weeks then 20 mg po daily

Xarelto is a factor Xa inhibitor.  It is approved for the following indications:

• Reduce the risk of stroke and embolism in patients with nonvalvular atrial fibrillation


• Treatment of DVT and PE and for the reduction in the risk of recurrence of DVT and of PE


• DVT prophylaxis of DVT in patients undergoing knee/hip replacement surgery

Given this patients history of HIT, it would not be ideal to rechallenge him with heparin or low-molecular weight heparin.

Coumadin needs several days to become therapeutic and thus he needs a bridge with a heparin product.   

One advantage of Xarelto is that no bridging therapy is needed

Nursing mothers should discontinue the drug or discontinue nursing.  Patients with renal impairment will need to avoid or adjust dose based on CrCl and Indication.  Patients with severe hepatic impairment (Child-Pugh B and C hepatic impairment or with any degree of hepatic disease associated with coagulopathy), should avoid using this medication.

For patients being treated for DVT, PE, and reduction in the risk of recurrence of DVT and of PE, one should avoid Xarelto for patients with a CrCl <30 mL/min .

https://www.uptodate.com/contents/search (Accessed May 2019)

The right answer is C) Cystectomy alone

For muscle invasive urothelial cancer (T2, T3, T4), the standard of care is to provide neoadjuvant Cisplatin based chemotherapy (Cisplatin/Gemcitabine or MVAC) followed by a cystectomy.

Guidelines have suggested that if a patient with muscle invasive urothelial cancer is not deemed to be a candidate for Cisplatin (ie, renal dysfunction), then they should not receive neoadjuvant chemotherapy. Carboplatin for this malignancy is not felt to be adequate (either given in the neoadjuvant or adjuvant setting).

The data for adjuvant chemotherapy for bladder cancer is less robust. However, guidelines do suggest that for those patients who do not receive neoadjuvant chemotherapy, you can consider adjuvant chemotherapy based on pathologic risk (ie, if a patient has T3 to T4 disease or positive nodes).

Of note, if a patient has a tumor that is pT2 or less and has no nodal involvement or LVI, then adjuvant chemotherapy is not recommended. This is important as often a Medical Oncologist will see a patient only after the patient has undergone a cystectomy; there was no opportunity to given neoadjuvant chemotherapy. So even if a patient were eligible to receive adjuvant cisplatin-based chemotherapy, would not offer it for a patient with a T2 tumor.

This patient has a T2 urothelial cancer and is not a candidate for Cisplatin. Would proceed with surgery/cystectomy. If he were not deemed to be a cystectomy candidate, you can consider 5-FU/Mitomycin-CT with RT after a maximal debulking TURBT.

The guidelines for Cisplatin dosing based on renal dysfunction are not standard. However, some guidelines to consider following

GFR (ml/min) >60   100% of the dose

                       45-59  75% of the dose

                       <45 Consider Carboplatin [Depending on the tumor type]

Some still will give Cisplatin if the GFR is < 45 ml/min. Some will use split dose cisplatin 

Dialysis: Give 50% of the dose. Dialysis should be performed within 3 hours after giving the dose.

The right answer is E) Emicizumab

The FDA has approved emicizumab-kxwh for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with and without factor VIII inhibitors.

Emicizumab bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in patients with hemophilia A.

Patients enrolled in the HAVEN 1 study were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B.  Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.

A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events among participants who were randomly assigned to emicizumab prophylaxis versus 23.3 events among those assigned to no prophylaxis.  This represents a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001).

A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001).

Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.

As mentioned above, Emicizumab also has FDA approval in patients with Hemophilia A who do not have an inhibitor.

The HAVEN 3 study tested emicizumab as prophylaxis in 152 patients aged 12 years or older with severe hemophilia A (Factor VIII activity <1%) who did not have an inhibitor.  Most of these patients were only receiving episodic therapy fro bleeding.

Compared with controls receiving only episodic therapy with factor VIII, individuals assigned to emicizumab prophylaxis had a dramatically reduced annualized bleeding rate (38 events versus 1.5 and 1.3 events at the two dosing protocols [1.5 mg/kg once weekly or 3 mg/kg every other week, respectively)

All controls had at least one bleeding event during the study (24 weeks), whereas more than half of participants in both emicizumab groups had no bleeding events during the study.

In the group of 48 patients who had been receiving routine factor VIII prophylaxis, transition to emicizumab reduced the annualized bleeding rate by 68 percent.

https://www.uptodate.com/contents/search (Accessed May 2019)

The right answer is D) Durvalumab

Most patients with locally advanced, unresectable, NSCLC have disease progression despite definitive chemoradiotherapy.

The PACIFIC study was a phase 3 study that compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.

Patients were randomly assigned in a 2:1 ratio, to receive durvalumab (10 mg/kg) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. 

Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). 

The median progression-free survival from randomization was 16.8 months with durvalumab versus 5.6 months with placebo (HR=0.52; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. 

The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). 

The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). 

A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.

The right answer is D) Gemzar + Platinum

Collecting (Bellini) duct carcinoma is a rare subtype of renal cell cancer. It is quite aggressive and it presents symptomatically at an advanced stage, and has a poor prognosis. Collecting duct carcinoma shares biologic features with urothelial carcinoma.

One group performed a systematic review of the literature on management options for collecting duct cancer.

The best studied therapy was felt to be Gemcitabine/Cisplatin. The role of targeted therapy (tyrosine kinase inhibitors such as sunitinib or sorafenib) in the management of collecting duct carcinoma has not been established.

A prospective multicentre phase II study evaluated the efficacy of gemcitabine and either cisplatin or carboplatin on Stage IV collecting duct cancer.

Participants received 21-day cycles of gemcitabine 1250 mg/m2 on days 1 and 8, plus cisplatin or carboplatin 70 mg/m2 (based on renal function) on day 1 (n = 23 gemcitabine, n = 12 cisplatin, n = 6 carboplatin, and n = 5 cisplatin then carboplatin). Participants underwent a median of 6 cycles of treatment (range: 1–8 cycles).

Participating patients demonstrated a 26% partial or complete response rate with 1 complete response. Another 10 patients (44%) experienced disease stabilization, and 7 had progressive disease (30%).  Progression-free survival was 7.1 months and overall survival was 10.5 months. 

C) Mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma defined by cyclin D1 (CCND1) overexpression.  The characteristic translocation seen in this lymphoma is t(11;14).

The Mantle Cell Lymphoma International Prognostic Index (MIPI) has been designed to stratify MCL patients into risk groups (low, intermediate or high risk) based on clinical prognostic factors, such as age, performance, Wbc count and lactate dehydrogenase (LDH) level.

Ki-67 expression over 30% portends a more aggressive clinical course.   TP53 expression and blastoid subtype are also associated with aggressive behavior.

In addition to CCND1, SOX11 is a diagnostic antigen in MCL.   Cyclin D1- (CCND1 negative) mantle cell lymphomas are not well characterized.   SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1negative variant. Data sets have demonstrated that Cyclin D1negative MCL patients are clinically and biologically similar to the conventional cyclin D1(+) MCL.

The prognostic role of SOX11 has shown conflicting results.