By the pricking of my thumbs, something wicked this way comes: sporadic cancers versus eponymous hereditary cancer predisposition syndromes.

Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation-an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum-was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown.

Patterns of Failure for Lymph Node-Positive Resected Pancreatic Adenocarcinoma After Adjuvant Radiotherapy or Gemcitabine-based Chemotherapy Alone.

PURPOSE: The purpose of this study was to investigate the effect of radiotherapy on local control and mordibity for patients with resected lymph node-positive pancreatic cancer as compared to gemcitabine-based chemotherapy alone. MATERIALS AND METHODS: Sixty-nine patients received adjuvant therapy for pancreatic adenocarcinoma with lymph node involvement after surgical resection and met the inclusion criteria for this analysis. Forty (58 %) patients received postoperative radiotherapy (PORT) to a median dose of 50.4 Gy with capecitabine or 5-fluorouracil concurrently in all but one case; 15 patients also received gemcitabine prior to PORT. Twenty-nine (42 %) patients received gemcitabine-based chemotherapy without PORT for a median of 6 cycles. RESULTS: The median overall survival for patients receiving PORT was 24.4 months compared to 25.6 months for patients not receiving PORT (p = 0.943). At 2 years, the rate of local control was 57 % for patients receiving PORT compared to 37 % for those who did not (p = 0.034). At 2 years, the rate of palliative local interventions was 16 % for patients receiving PORT compared to 18 % for patients who did not (p = 0.821). CONCLUSION: The use of PORT was associated with improved local control in the gemcitabine era for patients with resected, node-positive, pancreatic adenocarcinoma. The rates of overall survival and palliative interventions did not differ between the two groups.

Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.

PURPOSE: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. RESULTS: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. CONCLUSION: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Peripheral neuropathy associated with capecitabine.

5-fluorouracil (5-FU)-associated peripheral neuropathy is an uncommon event. Capecitabine (CAP) is a pro-drug of 5-FU and peripheral neuropathy associated with CAP has not been reported. During analysis of 28 patients receiving CAP with concomitant radiation (XRT) for pancreatic cancer (resected or locally advanced), two patients developed signs and symptoms consistent with peripheral neuropathy. Patients received CAP 1200-1600 mg/m2 in two divided doses with XRT (total 5040-5400 Gy) x 6 weeks, followed by 4 weeks rest, then 6 cycles of CAP 2000-2500 mg/m2 in two divided doses x 14 days every (q) 3 weeks. Patients were assessed weekly during CAP-XRT and q 3 weeks during CAP alone. Patient A reported right leg weakness (foot drop) during week 4 of CAP-XRT (1600 mg/m2). Patient B developed perioral and upper extremity paresthesias during the fourth cycle of CAP alone (2500 mg/m2). Dihydropyrimidine dehydrogenase (DPD) activity was measured by radioisotopic assay using lysates of peripheral blood mononuclear cells. Neurologic examination revealed right foot drop in Patient A and was unremarkable in Patient B. Central nervous system imaging was negative. Electromyogram and nerve conduction studies showed sensorimotor peripheral neuropathy in both patients. DPD activity was normal in both patients. There was no evidence of disease progression. Neurologic symptoms resolved after stopping CAP for 4 weeks in Patient A, with no recurrence after reinitiating CAP alone at 2000 mg/m2. Patient B continued at 80% of standard dose (2000 mg/m2) and symptoms resolved without further intervention. We conclude peripheral neuropathy with 5-FU is rare. Neurotoxicity occurs most often with intermittent high dose 5-FU as bolus injection or 24- to 48-h infusions. The etiology of neurotoxicity in our two patients remains unclear; however, as CAP is rapidly metabolized to 5-FU in patients with normal liver function, it is likely that 5-FU or its active metabolites (fluoro-beta-alanine) were contributing factors. Knowledge regarding potential adverse effects of CAP is paramount and dose modification is indicated with development of neurotoxicity.