Evaluation of the Association of Perioperative UGT1A1 Genotype-Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma: A Phase 2 Clinical Trial.

Importance: Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value. Objective: To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. Design, Setting, and Participants: This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. Interventions: Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2 over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2 for UGT1A1 genotype 6/6, 135 mg/m2 for UGT1A1 genotype 6/7, or 90 mg/m2 for UGT1A1 genotype 7/7; and prophylactic peg-filgastrim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). Main Outcomes and Measures: Margin-negative resection rate and PRG. Results: A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] with ERBB2-positive tumors; 19 [53%] with UGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by UGT1A1 genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]). Conclusions and Relevance: In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02366819.

Update on adjuvant chemotherapy for early breast cancer.

Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come.

Off-pump coronary artery bypass and avoidance of hypothermic cardiac arrest improves early left ventricular function in patients with systolic dysfunction.

OBJECTIVE: Off-pump coronary artery bypass surgery (OPCAB) and beating-heart coronary artery bypass grafting (BH-CAB) performed with cardiopulmonary bypass support are used with increasing frequency in the treatment of coronary artery occlusive disease. The utility of OPCAB and BH-CAB in treating high-risk patients has been studied, but the effects of these procedures on ventricular function have not been thoroughly investigated. METHODS: Data were collected from a database encompassing all patients who underwent isolated coronary revascularization performed by a single surgeon between August 2002 and March 2007. All procedures (n = 507) began as OPCAB operations, but 99 were converted to BH-CAB during surgery. Each patient's ejection fraction (EF) was measured preoperatively and postoperatively (median, 5.0 days after surgery). RESULTS: We found that although the BH-CAB patients tended to be in worse health and to have a lower preoperative EF than the OPCAB patients, both groups of patients had similar improvements in postoperative EF (6.8% vs 5.4%; p = 0.65). In addition, multivariable linear regression showed that a lower preoperative EF, age ≥ 70 years, and cardiomegaly predicted less postoperative EF improvement after coronary revascularization by either OPCAB or BH-CAB. CONCLUSIONS: Both OPCAB and BH-CAB procedures produce significant and similar short-term improvement in EF in patients with coronary disease. This change in EF may account for the subjective clinical improvements seen early after both procedures.

Non-functioning pancreatic neuroendocrine tumors--a case report and review of literature.

PURPOSE: Neuroendocrine tumors of pancreas (PNET) are rare pancreatic neoplasms comprising 1-2% of all pancreatic tumors. The overall prognosis and long-term survival for PNET patients is far better than for patients with exocrine pancreatic cancer. PNETs are classified as functional or nonfunctional based on the presence or absence of a specific clinical syndrome associated with hormone oversecretion. METHODS: We present the case of a 36-year-old female with epigastric and right upper quadrant abdominal pain for 3 months associated with decreased appetite, early satiety and a 20-lb weight loss. On examination, she was cachectic with hepatomegaly. RESULTS: Laboratory assays showed elevated liver and pancreatic enzymes. On computed tomography (CT) scan of the abdomen and pelvis, there was a low-attenuation mass in the distal pancreatic tail measuring 4.7 × 2.4 cm with multiple liver masses, omental implants, left ovarian mass, and a small amount of ascites. CT-guided liver biopsy on pathology was consistent with a well-differentiated pancreatic neuroendocrine carcinoma with metastasis to the liver. Assays for biomarkers of pancreatic neuroendocrine tumors showed an elevated chromogranin A with normal to non-specific elevations of the rest. CONCLUSIONS: The patient and her family declined palliative chemoembolization of the liver lesions or palliative chemotherapy and desired home hospice. We describe here the presentation and course of the case as well as a literature review of PNET with particular emphasis on nonfunctioning PNETs.

Selective left anterior descending shunting provides effective off-pump myocardial protection.

BACKGROUND: Coronary artery shunting during off-pump coronary artery bypass OPCAB procedures has been addressed only infrequently. To assess the protective effect of shunting, we examined CABG patients' postoperative cardiac enzyme levels and preoperative and postoperative ejection fractions. METHODS: During OPCAB, we selectively shunted the left anterior descending coronary artery (LAD) to provide myocardial protection when ischemia developed. We prospectively gathered data from 408 consecutive patients who underwent OPCAB. Data on shunt status were available for 386 of these patients. A "flow-through" shunt providing perfusion to the distal LAD was used whenever ST-segment elevations greater than 2 mm occurred or when patients had hemodynamic compromise unexplained by cardiac manipulation. Ejection fraction was assessed 1 to 3 days preoperatively and again 3 to 10 days postoperatively. Creatine kinase (muscle/brain) levels were assessed postoperatively for 24 hours. RESULTS: During OPCAB, 99 patients required shunting for presumed ischemia. Thirty-day cardiac mortality was 1.4% (4 of 296 without a shunt; 0 of 90 with a shunt). In patients without a LAD shunt, the mean peak creatine kinase index was 5.3; in patients who needed a shunt, the index was 5.2. Mean ejection fraction improved from 0.536 to 0.589 in the shunted patients and from 0.53.5 to 0.586 in the nonshunted patients. CONCLUSIONS: Selective shunting of the LAD during OPCAB provides effective protection against myocardial ischemia when ischemia is detected by electrocardiogram or when hypotension develops that is unexplained by cardiac manipulation.