1.
A 56-year-old male comes to see you to discuss adjuvant chemotherapy for his recently diagnosed T3 N0 Colon cancer that has been surgically removed. On his pathology report, he is found to have a Grade II tumor, no evidence of LVI or PNI, and negative lymph nodes (over 12 were removed). He is also found to be MSI-H. What does the latter feature portend in regards to adjuvant therapy?
A . He would be highly responsive to Bevacizumab
B . He would be highly responsive to 5-FU
C . He would highly benefit from FOLFOX
D . He would likely not benefit from 5-FU
E . He would likely not benefit from Bevacizumab
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) He would likely not benefit from 5-FU
The benefit of chemotherapy for patients with Stage II Colon cancer is somewhat muted. The NCCN panel believes that it is reasonable to accept the relative benefit of adjuvant therapy in Stage III disease as indirect evidence of benefit for Stage II disease, especially for those with high-risk features.
The QUASAR trial indicated a small benefit in OS for patients with Stage II disease treated with 5-FU/LV compared to patients not receiving adjuvant therapy (RR of recurrence at 2 years, 0.71; P=.01). In this trial though, 64% of patients had fever than 12 lymph nodes samples and may have been patients with higher risk disease who were more likely to benefit from adjuvant therapy.
Colon cancer patients with Stage II disease 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.
A group of investigators examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.
MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).
Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (HR=0.67; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; P = .04).
**Pearl: 15% of sporadic tumors are MSI
**Pearl: MSI-H tumors are often right-sided, have undifferentiated histology, present as stage II, and more often in females
**Pearl: Poorly differentiated histology is not considered a high-risk feature for patients with Stage II disease whose tumors are MSI-High
Reference: Sargent DJ et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28(20): 3219-26
2.
A 19-year-old male was recently diagnosed with Good risk, Stage IIB (S1) NSGCT. His AFP 4 weeks after right orchiectomy was 145 ng/ml. He started his first cycle of BEP. Bleomycin is being given 30 units weekly. Three days after finishing his 1st cycle of therapy (Day 1, 8, 15 of bleomycin, and days 1-5 of etoposide and cisplatin), he has dyspnea and a dry cough.
Chest imaging confirms pneumonitis from his bleomycin. He partially recovers from this episode and comes to see you for his 2nd cycle of therapy; the plan was to administer BEP x 3 cycles. What do you recommend?
A . Give bleomycin at full dose
B . Give bleomycin at a 25% dose reduction
C . Give bleomycin at a 50% dose reduction
D . Do not give bleomycin. Substitute ifosfamide instead
E . Give EP alone for 3 more cycles
Your Answer : Option
Not Answered
Correct Answer : Option
E
Explanation: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, one can substitute Ifosfamide for Bleomycin (VIP regimen) if there is concern about bleomycin toxicity
Reference: Maher J, Daly PA. Severe bleomycin lung toxicity: reversal with high dose corticosteroids. Thorax 1993; 48(1): 92-94
3.
A 72-year-old male has started Gemcitabine + Nab-Paclitaxel for Stage IV Pancreatic cancer with several liver metastases. He started therapy over 3 months ago and restaging scans show a partial response with 60% reduction of his liver lesions. He has tolerated therapy very well thus far. Of note, Next generation sequencing revealed no targetable lesions including no mutation in BRCA1 or BRCA2.
You get a call from the ER physician that the patient presented with acute onset of fatigue and acute renal failure. Labs reveal a Hb of 7.4 g/dl and the platelet count is 72,000 per mL. Cr is 3.2 mg/dl. PT and PTT are WNL. A smear is reviewed and shows lots of schistocytes. What is the most likely etiology for this patient’s acute clinical worsening?
A . DIC from Pancreatic cancer
B . HUS from Gemcitabine
C . Trousseau's Syndrome
D . ATN from Nab-Paclitaxel
E . Stauffer's Syndrome
Your Answer : Option
Not Answered
Correct Answer : Option
B
Explanation: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 and then 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.
In this condition, one will oftentimes 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 discontinue gemcitabine if HUS is seen. Other potential therapies include steroids, FFP administration, plasmapheresis or hemodialysis; it is unclear how well these therapies work.
**Pearl: Mitomycin C can also cause HUS
Reference: Muller S. Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution. Ann Hematol 2005;84(2): 110-4.
4.
A 62-year-old female is s/p TAH/BSO and comprehensive surgical staging for a recently diagnosed left ovarian cancer. Final pathology reveals a Malignant Mixed Mullerian tumor. The final pathology report puts her as having Stage II disease. Her CA-125 is 12 U/ml. She is in very good health with no comorbid medical conditions. What do you recommend as adjuvant therapy?
A . Reassure her that her risk of recurrence is very low and offer her observation
B . Offer her IP Cisplatin and IP/IV Paclitaxel chemotherapy
C . Tell her that she has a Carcinosarcoma and offer her Adriamycin/Ifosfamide x 6 cycles
D . Tell her that she has a Carcinosarcoma and offer her Gemcitabine/Docetaxel x 6 cycles
E . Carboplatin/Paclitaxel x 6 cycles
Your Answer : Option
Not Answered
Correct Answer : Option
E
Explanation:E) Carboplatin/Paclitaxel x 6 cycles
Carcinosarcomas consists of malignant epithelial and mesenchymal components. They account for <2% of malignant ovarian cancers. These are rare tumor that carry a poor prognosis.
Most pathologists consider these tumors to be a variant of poorly differentiated epithelial ovarian cancer (metaplastic carcinoma).
Patients with carcinosarcomas are not candidates for fertility-sparing surgery regardless of age or stage. Optimal surgical debulking is recommended for patients with these ovarian cancers.
Data has shown that Carcinosarcomas should be treated with adjuvant Carboplatin/Taxol for Stage I-IV Ovarian cancer.
Ovarian Carcinosarcoma:
Stage I-IV: Offer Carboplatin/Taxol (can give Docetaxel or Liposomal Doxorubicin instead of Taxol)
**Carboplatin/Ifosfamide can also be offered as adjuvant therapy
Reference: Leiser AL et al. Carcinosarcoma of the ovary treated with platinum and taxane: the memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol 2007;105(3):657-61
5.
A 59-year-old female is s/p maximal complete resection for a left parietal lobe brain tumor. Final pathology reveals an anaplastic oligodendroglioma. Further analysis of the tumor specimen reveals codeletion of 1p and 19q. A Brain MRI done 2 days after surgery confirms all the tumor has been surgically removed. Her Karnofsky performance status is >90. What adjuvant therapy do you offer?
A . Standard Radiation
B . Standard Radiation with BCNU wafer
C . Chemotherapy with Temozolamide
D . Standard Radiation therapy and neoadjuvant or adjuvant Lomustine, Procarbazine, and Vincristine (PCV) chemotherapy
E . Observation
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) Standard 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 the addition of adjuvant PCV x 6 cycles with RT vs. RT alone (59.4 Gy). A total of 368 patients were enrolled. The overall survival favored the RT/PCV group (42.3 vs. 30.6 mo; HR=0.75).
In the 80 patients who glioma harbored a 1p/19q codeletion, the overall survival favored PCV arm (Not reached vs. 112 mo; HR=0.56) . IDH mutational status was also of prognostic significance.
Gliomas that harbored the 1p/19q codeletion had 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 the median Overall survival was seen between either arm (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 NCCN panel recommends that PCV be administered after RT (as per EORTC 26951) since the intensive PCV regimen given prior to RT (RTOG 9402) was not tolerated as well.
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.
Of note, the 2016 WHO classification of tumors of the CNS has deleted oligoastrocytoma as a category.
https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf
Reference: Van den Bent MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951 J Clin Oncol 2013;31(3):344-50
6.
A 48-year-old male who is a 40-pack-year smoker comes to see you for limited stage small cell lung cancer. Staging reveals no distant disease and his Brain MRI is negative. He has a robust performance status. What treatment do you propose?
A . Lobectomy followed by adjuvant Carboplatin/Paclitaxel
B . Concurrent chemoradiation with Cisplatin/Etoposide (radiation given in daily fractions), followed by PCI
C . Concurrent chemoradiation with Carboplatin/Etoposide (radiation given in daily fractions), followed by PCI
D . Concurrent chemoradiation with Cisplatin/Etoposide (radiation given in bid fractions), followed by PCI
E . In a sequential manner, give chemotherapy with Cisplatin/Etoposide followed by radiation therapy. No brain radiation indicated as the brain MRI is negative
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation: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. This is an important distinction.
A seminal study (See the reference below) demonstrated that twice a day (hyperfractionated) radiation confers benefit over daily radiation:
--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 so this created some measure of controversy.
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 will hopefully shed light on how Radiation should be optimally administered.
This study is evaluating the following:
1) Administering RT 45 Gy in 30 treatments (bid in 3 weeks)
2) 70 Gy in 35 treatments (7 weeks)
3) 61.2 Gy given in 34 treatments (daily x 3 weeks, then bid x 2 weeks; this arm has been discontinued)
Of note, the randomized, phase III European CONVERT trial did not demonstrate superiority of 66 Gy (once daily) over 45 Gy (BID), but overall survival and toxicity were comparable.
Corinne Faivre-Finn et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncology 2017.
Reference: Turrisi AT et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340(4):265-71
7.
A 52-year-old female has stage IV melanoma with both lung and liver lesions. The index liver lesion measures 5 cm in size. Biopsy of this lesion reveals a BRAF wild-type melanoma. A brain MRI is negative and there are no bone lesions. She was initially started on Nivolumab as frontline therapy and achieves a partial response. However, after 1 year of treatment her disease starts to progress.
Her recent baseline CT scan shows that the liver lesion measures 4.5 cm in size. She is started on Ipilimumab 3 mg/kg and the patient has had 2 cycles thus far. The patient has Grade 1 diarrhea. She presented to the ED for some vague abdominal pain. While in the ER, she has a CT scan performed and it that reveals that all the lesions are stable except that her index liver lesion has increased to 5.5 cm. What do you recommend?
A . Stop Ipilimumab and switch to Trametinib
B . Increase the dose of Ipilimumab to 10 mg/kg
C . Continue therapy
D . Switch to Dabrafenib
E . Add Dacarbazine to Ipilimumab
Your Answer : Option
Not Answered
Correct Answer : Option
C
Explanation:C) Continue therapy
It can take time before once sees a cancer respond to immunotherapy. One needs to be careful with stopping therapy too soon based on an interval CT imaging. Sometimes, responses can occur even after radiologic evidence of initial disease progression. Pseudoprogression refers to cancer that initially appears larger on a scan, perhaps due to tumor infiltration, but will eventually regress with time. The patient had a CT scan performed to evaluate her abdominal pain. It was not a definitive restaging scan.
The patient in this question has just started on immunotherapy. It would be premature to assume that the enlarging liver lesion represents true tumor progression. This patient should be continued on therapy. Responses to immunotherapy can sometimes be delayed.
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 naïve patients).
Reference: Graziani G et al. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 2012;65(1):9-22.
8.
Two years ago, a 56-year-old female had a large macular lesion located on her right upper back that had been progressively growing. She was referred to Dermatology who performs a biopsy. Pathology reveals a tumor that is CD34+. Further evaluation confirms a dermatofibrosarcoma protuberans (DFSP).
She has surgery of this lesion and achieves negative margins. No adjuvant therapy is given. She was disease free for 2 years until she recently developed dyspnea. CT chest reveals 12 lung lesions. One of these lung lesions is biopsied confirming DFSP. Further testing of the sarcoma reveals a t(17;22). Which therapy do you offer?
A . Hospice
B . Imatinib
C . Cisplatin + Etoposide
D . Carboplatin + Paclitaxel
E . Pembrolizumab
Your Answer : Option
Not Answered
Correct Answer : Option
B
Explanation:B) Imatinib
Dermatofibrosarcoma protuberans (DFSP) is a tumor that occurs of the dermis layer of the skin.
Up to 5% of these tumors can metastasize. These tumors can initially 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). This 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 (PDGFRB).
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 2- to 4-cm margins to investing fascia that are subsequently verified to be clear by traditional pathologic examination
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.
Of note, patients with unresectable (but locoregional) DFSP can be offered neoadjuvant imatinib in hopes of downstaging the tumor to enable resection.
Reference: Rutkowski P et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 2010;28(10):1772-9.
9.
A 48-year-old female presents with a left-sided neck mass for the past 4 weeks. She is in overall good health and has no known medical conditions. Her primary care physician performs a thorough workup and orders a neck ultrasound that reveals a 2 cm left cervical lymph node that appears concerning for malignancy.
The patient is set up for an incisional biopsy that reveals that she has a grade I follicular lymphoma. She is referred to Oncology who performs a bone marrow biopsy that is negative for lymphoma involvement. A PET-CT scan shows only FDG activity at the solitary left-sided neck lymph node. She is felt to have stage I disease. What do you offer for therapy?
A . Observation
B . R-CHOP
C . R-CVP
D . Radiation therapy
E . Lenalidomide and Rituximab
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) Radiation therapy
In general, follicular lymphomas do not present in a localized manner. When they do though, one should consider local therapy with radiation as some studies show that this can lead to a long-term remission.
Observation, single agent Rituximab, Rituximab/Lenalidomide or Rituximab (Obinutuzumab) + 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 listed ISRT as the preferred therapy for patients with Stage I or contiguous Stage II Follicular lymphoma that is grade 1-2.
Reference: Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996;14(4):1282-90.
10.
A 59-year-old female with Chronic Phase CML has been on imatinib 400 mg daily for 18 months. Baseline evaluation revealed good-risk disease on the Hasford scoring system. During her 12 month evaluation, she was in MMR and FISH analysis revealed a CCyR.
During her 18 month evaluation, the Bcr-Abl transcript has increased to 12% and FISH showed presence of t(9;22). Bone marrow biopsy is performed and she has a cytogenetic relapse. Three of 20 metaphases harbor Ph+. She has been compliant with imatinib and has not been on any other medications. Mutational analysis of the BCR-ABL kinase domain reveals F317L. What do you recommend?
A . Increase Imatinib to 800 mg daily
B . Immediate Allogeneic SCT
C . Continue therapy, but recheck cytogenetics in 3 months
D . Continue therapy, but add Interferon to Imatinib
E . Switch to a different TKI
Your Answer : Option
Not Answered
Correct Answer : Option
E
Explanation:E) Switch to a different TKI
She patient has relapsed disease. This is defined by any sign of a loss of response (defined as hematologic or cytogenetic).
A 1-log increase in BCR-ABL1 transcript levels with loss of MMR should prompt bone marrow evaluation for loss of CCyR but it is not itself defined as a relapse.
At the 18 month follow-up mark, to see a cytogenetic relapse is disconcerting. According to the NCCN guidelines, having a BRC-ABL1 > 10% at the 3 month mark (or greater) connotes TKI resistance.
In situations like this, one needs to check for compliance and drug-drug interactions. Prior to switching therapy for a presumed TKI failure, one should check the mutational status of BCR-ABL. For second-line treatment for patients with TKI-resistant disease, one should switch to another alternate TKI (predicated the BCR-ABL1 mutation status) and evaluate for an allogeneic HCT.
There is a subset of BCR-ABL mutant clones associated with impaired responses to second-generation TKIs.
As an example, for patients who harbor a F317L mutation in BCR-ABL1, one would offer Nilotinib (Dasatinib and Bosutinib will not work against this mutation). If a patient has a G250E mutation, one would offer Dasatinib.
Depending on mutational status, some TKIs may work better:
E255K/V, F317V/I/C, 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
The following mutations confer resistance to the following TKIs:
--Bosutinib will not work if a patient has a BCR-ABL1 mutation in T315I, V299L, G250E or F317L
--Dasatinib will not work if a patient has a BCR-ABL1 mutation in T315I/A, F317L/V/I/C or V299L
--Nilotinib will not work if a patient has a BCR-ABL1 mutation in T315I, Y253H, E255K/V, F359V/C/I or G250E
https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf
Reference: Jabbour E et al. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer 2011;117(9):1800-11
11.
A 42-year-old female was recently diagnosed with likely stage II right breast cancer. On routine mammogram, she was found to have a 3 cm right-breast mass with no clinical evidence of axilla LAD. Genetic testing reveals that she harbors a BRCA1 mutation.
The patient undergoes a biopsy of the 3 cm mass and the results are pending. Which of the following is the most likely type of breast cancer that she has?
A . ER+, PR+, Her2-
B . ER+, PR-, Her2-
C . ER+, PR+, Her2+
D . ER-, PR-, Her-
E . ER-, PR-, Her2+
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation: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 in these genes disenable this function leading to an increased cancer risk.
There are several differences between BRCA1 and BRCA2 related tumors.
BRCA1-related 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
Reference: Hirshfield KM, Ganesan S. Triple-negative breast cancer: molecular subtypes and targeted therapy. Curr Opin Obstet Gynecol 2014;26(1):34-40
12.
A 45-year-old female with thyroid cancer comes to see you to discuss the benefit of Radioactive Iodine therapy. Recently, she had a total thyroidectomy for a Papillary thyroid cancer. She was found to have a unifocal, 0.6 cm classic papillary thyroid cancer with no vascular invasion or extrathyroid extension. Her post-operative unstimulated thyroglobulin is < 1 ng/mL. She has no detectable anti-Tg antibodies. She had no lymph nodes involved or distant metastases. What do you tell her regarding RAI treatment?
A . She needs RAI as her age is a poor risk factor
B . Her tumor meets all the criteria not to offer RAI therapy
C . She does not need RAI as it is only given for patients with tumors >6 cm in size or positive lymph node involvement
D . She needs RAI as her gender puts her at a higher risk of recurrence
E . She does not need RAI as she had a thyroidectomy
Your Answer : Option
Not Answered
Correct Answer : Option
B
Explanation:B) Her tumor meets all the criteria not to offer RAI therapy
RAI as adjuvant therapy is not offered to every patient with 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 one would not offer her adjuvant RAI.
RAI does have toxicity, so you need to carefully evaluate if a patient will truly benefit from it as adjuvant therapy.
RAI is typically recommended if any of the following features are present:
1) Gross extrathyroidal extension
2) Primary tumor >4 cm
3) Postoperative unstimulated Tg> 10 ng/mL
4) Bulky or >5 positive lymph nodes
If a patient has a differentiated thyroid cancer, one would selectively recommend adjuvant RAI if any of the following features are seen:
Tumor 2-4 cm
High risk histology (ie, poorly differentiated, tall cell, columnar cell, hobnail variant, diffuse sclerosing, and insular)
Lymphatic invasion
Cervical lymph node metastases
Macroscopic multifocality (one focus > 1 cm)
Postoperative unstimulated thyroglobulin < 10 ng/mL
Microscopic positive margins
Detectable anti-Tg antibodies
Reference: Hay ID. Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma. J Surg Oncol 2006;94(8):692-700.
13.
A 35-year-old male presents to see a Hematologist for a second opinion for his iron disorder. His ferritin is elevated at 850 μg/L. His transferrin saturation is normal at 20%. An abdominal MRI is performed as he had some mild transaminitis. The MRI suggests iron loading in the liver. A liver biopsy is performed and he is found to have marked iron accumulation in the hepatic Kupffer cells.
He has no signs of end organ damage to the heart, endocrine glands or joints. He has 4 siblings, 2 of whom have the same type of disorder. This patient likely has a mutation in which of the following genes?
A . HFE
B . FPN
C . HJV
D . TfR2
E . HAMP
Your Answer : Option
Not Answered
Correct Answer : Option
B
Explanation:B) FPN
Classical Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene. Ferroportin’s role in the body is to transfer iron from the intestine and macrophages into the bloodstream.
Of import, in classical Ferroportin disease, mutations in FPN1 limit but does not impair iron export in enterocytes, but does severely affect the iron transfer in macrophages. This leads to iron trapping in tissue macrophages with reduced iron release to serum transferrin. Hence, patients with this disease have low transferrin saturation. They will often have normal/low transferrin saturation, mild anemia and mild organ disease.
A hallmark feature of classical Ferroportin disease is marked iron accumulation in hepatic Kupffer cells, moreso than in the hepatocytes. This is opposite to what is seen in classical hemochromatosis.
The differential diagnosis includes hereditary hemochromatosis, the syndrome commonly due to either HFE,TfR2, HJV, HAMP or gain of function mutation in FPN1. However, in these conditions, the elevated ferritin levels is seen in concert with a high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load.
These conditions (HFE, TfR2, HJV, HAMP or gain of function mutation in FPN1) share a similar pathogenic basis (lack of hepcidin function-activity), biochemical expressivity (high transferrin saturation and high serum ferritin), liver pathology features (iron accumulation in parenchymal cells with iron-spared Kupffer cells until late stage), damage and disease of distinct target organs (liver, heart, endocrine glands, joints).
An abdominal MRI for patient’s with Ferroportin disease can show iron loading in the spleen, spine and liver.
A non-aggressive phlebotomy regimen is recommended, with careful monitoring of the transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.
Of note, non-classical ferroportin disease occurs with mutations in ferroportin that are resistant to inhibition by the iron regulatory molecule hepcidin, retaining full iron export capability. Patients will normally have high levels of ferritin and hepcidin, increased transferrin saturation, and typical deposition of iron in the hepatic parenchyma. This has also been called hepatic-type ferroportin disease.
Reference: Antonello Pietrangelo et al. Ferroportin disease: pathogenesis, diagnosis and treatment. Haematologica 2017 Dec; 102(12): 1972–1984
14.
A 62-year-old male undergoes a splenectomy for a splenic marginal zone lymphoma. He has no history of Hepatitis C and his SPEP/IFE are WNL.
Over the past 8 years, he has been through several lines of therapy:
Rituximab
Bendamustine + Obinutuzumab
Zanubrutinib
Umbralisib
He achieved a partial response to each regimen prior to progression. His main clinical issue is severe LUQ pain due to worsening splenomegaly. For this reason, he was taken for a splenectomy. Prior to his surgery, he receives the 3 requisite immunizations. After the splenectomy, he starts bleeding in his abdomen and CT imaging reveals that he has developed retroperitoneal bleeding. His Hemoglobin is down to 5.2 g/dl and he needs several pRBC transfusions. He carries a history of IgA deficiency. How should the pRBC be modified to ensure that he receives a safe transfusion?
A . None; IgA deficiency is the most common human immunodeficiency
B . Need to give premedications with steroids prior to any pRBC transfusion
C . Gamma irradiate the blood products
D . Wash the pRBC
E . Leukoreduce the pRBC products
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) Wash the pRBC
IgA is concentrated mostly in the mucosal secretions and is believed to be important in the immune function 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.
There are two levels of severity of IgA deficiency that is recognized. A serum IgA level < 7 mg/dL is considered to be severe deficiency.
IgA deficiency is the most common human immunodeficiency. The presence of anti-IgA that occurs in an IgA deficient recipient can lead to anaphylaxis if blood products are administered. This occurs as the anti-IgA antibody of the host reacts against the IgA antigen seen on the donor red cell units.
Most patients with selective IgA deficiency do not form anti-IgA antibodies. These antibodies are usually only found in patients who have undetectable serum IgA.
Patients with selective IgA deficiency can develop urticaria, wheezing, shock and cardiac arrest after receiving transfusions. If this were to happen, one must stop the transfusion immediately. Patients may need Epinephrine. One critical point is that patients with IgA deficiency who are transfused with plasma products that carry IgA, 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: red blood cells, Platelets, FFP, Cryoprecipitate and IVIG.
By washing the donor red cell units with saline, centrifuge or removal of the supernatant), the IgA antibodies will be removed. However, this will shorten the shelf-life of red blood cells to less than 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)
Reference: Brown R et al. An evaluation of the DiaMed assays for immunoglobulin A antibodies (anti-IgA) and IgA deficiency. Transfusion 2008; 48(10): 2057-9
15.
A 58-year-old male presents to the ED with RLE pain and swelling. An Ultrasound reveals a DVT of the right posterior tibial vein. Prior to this clotting event, he came back from a long plane ride he took to Asia. He is up to date with his age-appropriate cancer screening tests. He has a history of Type II DM and his calculated CrCl=35 mL/min.
He has a history of HIT that occurred over 2 years ago with prophylactic enoxaparin that was being given during an inpatient admission that he had for pneumonia. However, he did not have any clotting event (no DVT, stroke) with that HIT episode. He just had thrombocytopenia during that time.
He needs to be started on anticoagulation for his current RLE DVT. Of the following choices, what is the best option for him?
A . IVC Filter
B . Coumadin 5 mg daily
C . Enoxaparin 1.5 mg/kg x 5 days along with Coumadin 5 mg daily
D . Xarelto 15 mg po bid x 3 weeks then 20 mg po daily
E . Heparin gtt x 5 days along with Coumadin 5 mg daily
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) Xarelto 15 mg po bid x 3 weeks then 20 mg po daily
Xarelto is a factor Xa inhibitor. It is an approved medication for the following Medical indications:
--To 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 a DVT and of PE
--DVT prophylaxis for DVT in patients who are undergoing knee/hip replacement surgery
Given this patient’s 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 the patient needs a bridge with a heparin product for at least 5 days.
One advantage of Xarelto is that no bridging therapy is needed and it can be started as monotherapy. Xarelto has been shown to be an effective medication for those patients with a history of HIT (or who have current HIT).
Mothers who are nursing mothers should discontinue the drug or discontinue nursing. Patients with renal impairment will need to avoid or adjust the dose based on CrCl and treatment 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 who have a CrCl <30 mL/min.
Reference: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022406s015lbl.pdf
16.
A 68-year-old male comes to see you after recently being diagnosed with a T2 N0 M0 (+Muscle invasion, Grade 1) transitional cell cancer of the bladder. CT of the A/P with no contrast shows no LAD or distant metastasis. A CXR is negative. He is quite healthy. However, he does have a long standing history of Type II DM and HTN. His baseline Creatinine Clearance is 25 ml/min. What treatment do you recommend for him?
A . Neoadjuvant Cisplatin based chemotherapy followed by a cystectomy
B . Concurrent chemoradiation
C . Cystectomy alone
D . Radiation alone
E . Choice B or C
Your Answer : Option
Not Answered
Correct Answer : Option
E
Explanation:E) Choice B or C
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 or concurrent chemoradiation with 5-FU/Mitomycin C (after a maximal debulking TURBT). Concurrent chemoradiation does has Category 1 evidence to offer in this setting as does neoadjuvant Cisplatin-based chemotherapy followed by a radical cystectomy. However, given his renal dysfunction, he is not a candidate for Cisplatin.
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 will still will give Cisplatin if the GFR is < 45 ml/min. Some will use split dose cisplatin in this situation. Some will not give Cisplatin if the CrCl is <60 mL/min.
Dialysis: Give 50% of the dose. Dialysis should be performed within 3 hours after giving the dose
Reference: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
17.
A 14-year-old male has a history of severe Hemophilia A, with Factor VIII levels < 1%. He developed right knee bleeding at the age of 1 and subsequently he had been receiving prophylaxis with Factor VIII, 30 units/kg three times a week. Despite this, he still has required many Factor VIII infusions for breakthrough bleeding episodes.
When he was around 8 years old, he was found to have an inhibitor and he has required bypassing agents to control his bleeding. Despite this, he continues to have several bleeds every year especially in his bilateral knees. Which medication would you consider adding at this time as prophylaxis to help control his bleeding?
A . None
B . Factor IX infusions
C . Rituximab
D . IVIG
E . Emicizumab
Your Answer : Option
Not Answered
Correct Answer : Option
E
Explanation: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.
Johannes Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017; 377:809-818
https://www.uptodate.com/contents/search (Accessed May 2019)
Reference: Mahlangu J et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018;379(9):811.
18.
A 64-year-old year-old male has recently completed concurrent chemoradiation for his Stage IIIB lung adenocarcinoma. He received Cisplatin/Etoposide during the radiation. He tolerated therapy quite well with no major side effects. A restaging CT scan 4 weeks after completing therapy shows reduction of his tumor mass. No new or distant metastatic disease was seen. Which therapy should be given at this time as part of consolidation therapy?
A . Single agent Alimta
B . Cisplatin and Etoposide x 2 cycles
C . Keytruda
D . Durvalumab
E . Observation
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation:D) Durvalumab
Most patients with Stage III unresectable, NSCLC have disease progression despite receiving 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.
Reference: Scott J. Antonia et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med 2017; 377:1919-1929
19.
A 62-year-old male presents with right flank pain. A CT C/A/P is ordered and he is found to have a right kidney mass. No other sites of disease are noted. He undergoes a nephrectomy and he is found to have a collecting duct cancer. Unfortunately, 1 year later he is found to have widely metastatic disease. A biopsy of a lung lesion reveals a collecting duct cancer. Next generation sequencing reveals no actionable mutations. Which therapy do you offer?
A . Sutent
B . Pazopanib
C . Axitinib
D . Gemzar + Platinum
E . Everolimus
Your Answer : Option
Not Answered
Correct Answer : Option
D
Explanation: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.
Reference: S Dason et al. Management of renal collecting duct carcinoma: a systematic review and the McMaster experience. Curr Oncol 2013 Jun; 20(3): e223–e232.
20.
A 66-year-old male presents to see Hematology/Oncology for diffuse LAD that has slowly developed over the past 6 months. His exam reveals LAD in his cervical neck, axilla and inguinal area. He has a palpable spleen. He denies having any constitutional B symptoms.
An excisional biopsy is performed of his cervical lymph node. Lymphoma is confirmed. The lymphoma is: CD10-, CD5+, CD23-, Cyclin D1- and SOX11+. His Ki67 is 20%.
A PET-CT is performed that shows disease throughout his body. What is the most likely lymphoma that this patient has?
A . Follicular lymphoma
B . CLL/SLL
C . Mantle cell lymphoma
D . DLBCL
E . Marginal zone lymphoma
Your Answer : Option
Not Answered
Correct Answer : Option
C
Explanation: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 Mantle cell displaying an 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 D1 negative variant. Data sets have demonstrated that Cyclin D1 negative MCL patients are clinically and biologically similar to the conventional cyclin D1(+) MCL.
The prognostic role of SOX11 has shown conflicting results.
Reference: Lena Nordström et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study. Br J Haematol 2014 Jul; 166(1): 98–108