Clancy J. Clark

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial

BACKGROUND Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. METHODS In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. FINDINGS Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. INTERPRETATION A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. FUNDING Comprehensive Cancer Center of Wake Forest Baptist Medical Center.Background Pancreatic cancer statistics are dismal, with a five-year survival of less than 10%, and over 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma, including aerobic glycolysis, oxidative phosphorylation, glutaminolysis, lipogenesis and lipolysis, autophagic status, and anti-oxidative stress. CPI-613 is a novel anti-cancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumor cells, causing changes in mitochondrial enzyme activities and redox status which lead to apoptosis, necrosis and autophagy of tumor cells. Methods This is a phase 1 study to determine the maximum-tolerated dose (MTD) of CPI-613 when used in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2 and irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus and 2400 mg/m2 over 46 h) in combination with CPI-613 in patients with newly diagnosed metastatic pancreatic adenocarcinoma with good bone marrow, liver and kidney function and good performance status (NCT01835041 – closed to recruitment). A two-stage dose-escalation scheme (single patient and traditional 3+3 design) was applied. In the single patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2/day; the dose level was then escalated by doubling the previous dose if there was no toxicity greater than Grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxicity attributed as probably or definitely related to CPI-613 was ≥ Grade 2. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as used in the last cohort of the single patient dose-escalation stage. Secondary objectives were safety, preliminary efficacy, and tissue collection for future analyses. Response rates, progression-free survival and overall survival data were assessed in the patients treated at the MTD. Findings Twenty patients were enrolled April 22, 2013 – January 8, 2016. The MTD of CPI-613 was 500 mg/m2. The median number of treatment cycles administered at the MTD was 11 (interquartile range, 4–19). Two patients enrolled at a higher dose (1000 mg/m2) both experienced a DLT (dose limiting toxicity). There were 2 unexpected serious adverse events (SAEs), both for the first patient enrolled: 1) possible leaching due to infusion of CPI-613 via non-PVC tubing, and 2) the patient re- accessed her port at home after accidental de-access. Neither incident resulted in a negative clinical outcome. Expected SAEs were: thrombocytopenia, anemia and lymphopenia (all for Patient #2, with anemia and lymphopenia being a DLT); hyperglycemia (Patient #7); hypokalemia, hypoalbuminemia and sepsis (Patient #11); and neutropenia (Patient #20). There was no grade 5 toxicity. For the 18 patients treated at the MTD, the most common Grade 3–4 toxicities were hypokalemia (6/18, 33%), diarrhea (5/18, 28%) and abdominal pain (4/18, 22%). Sensorial neuropathy (17/18, 94%) was managed with dose de-escalation or discontinuation per standard of care. None of the patients experienced grade 4 or 5 neuropathy. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Among the 18 patients treated with the MTD, there were 3 patients with a complete response (CR), 1 with a non-CR/non-progressive disease, 7 with a partial response (PR), 3 with stable disease, and 4 with PD. The partial + complete response rate was 61% (11/18). Interpretation The treatment was well tolerated and all end points were met. The intriguing signal of efficacy will require validation in a phase 2 study. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center

Comparison of observed to predicted outcomes using the ACS NSQIP risk calculator in patients undergoing pancreaticoduodenectomy.

Postoperative outcomes predicted by the ACS NSQIP universal risk calculator have not been validated for specific procedures like pancreaticoduodenectomy (PD).

Circumportal pancreas: imaging findings in 40 patients

AbstractPurpose To analyze the CT and MR imaging features of circumportal pancreas (CP) with emphasis on the relative frequency of variants of parenchymal fusion, ductal anatomy, and vascular anatomy.MethodsA retrospective review of CT and MR imaging findings of 40 patients with CP was performed. CT and MR images were reviewed by two radiologists in consensus. The course of the pancreatic duct in relation to the portal vein (anteportal vs. retroportal), location of the circumvenous pancreatic parenchyma in relation to the splenic vein (suprasplenic vs. infrasplenic), presence or absence of a visible accessory duct posterior to the portal vein, presence of vascular variants, history of pancreatitis and pancreatic surgery were recorded. Cases were classified into four categories: anteportal suprasplenic, retroportal suprasplenic, anteportal infrasplenic, and retroportal infrasplenic.ResultsOne case of suprasplenic fusion was excluded from the classification due to non-visualization of the pancreatic duct. 32/39(82%) of cases were classified as anteportal suprasplenic, 2/39(5%) as retroportal suprasplenic, 4/39(10%) as anteportal infrasplenic, and 1/39(3%) as retroportal infrasplenic. There were 12 vascular variants including nine with an intraparenchymal course (through the pancreatic head) of the common hepatic artery, one with an intraparenchymal course of the right hepatic artery, two replaced right hepatic arteries from the superior mesenteric artery, and one with an intraparenchymal course of the left gastric vein.ConclusionCircumportal pancreas is an important pancreatic fusion anomaly with distinctive imaging features. The most common variant of CP is the anteportal suprasplenic subtype, with other subtypes being much less common. Intraparenchymal course of the common hepatic artery is a common variant associated with CP. Recognition of CP is important to avoid potential complications in patients who undergo pancreatic surgery.

Effect of epidural compared to patient-controlled intravenous analgesia on outcomes for patients undergoing liver resection for neoplastic disease

Epidural analgesia is routinely used for postoperative pain control following abdominal surgeries, yet data regarding the safety and efficacy of epidural analgesia is controversial.

Safety of an Enhanced Recovery Pathway for Patients Undergoing Open Hepatic Resection

Background Enhanced recovery pathways (ERP) have not been widely implemented for hepatic surgery. The aim of this study was to evaluate the safety of an ERP for patients undergoing open hepatic resection. Methods A single-surgeon, retrospective observational cohort study was performed comparing the clinical outcomes of patients undergoing open hepatic resection treated before and after implementation of an ERP. Morbidity, mortality, and length of hospital stay (LOS) were compared between pre-ERP and ERP groups. Results 126 patients (pre-ERP n = 73, ERP n = 53) were identified for the study. Patient characteristics and operative details were similar between groups. Overall complication rate was similar between pre-ERP and ERP groups (37% vs. 28%, p = 0.343). Before and after pathway implementation, the median LOS was similar, 5 (IQR 4–7) vs. 5 (IQR 4–6) days, p = 0.708. After adjusting for age, type of liver resection, and ASA, the ERP group had no increased risk of major complication (OR 0.38, 95% CI 0.14–1.02, p = 0.055) or LOS greater than 5 days (OR 1.21, 95% CI 0.56–2.62, p = 0.627). Conclusions Routine use of a multimodal ERP is safe and is not associated with increased postoperative morbidity after open hepatic resection.

Resection of a Giant Primary Synovial Sarcoma of the Inferior Vena Cava Extending Into the Right Atrium With Caval Reconstruction Under Cardiopulmonary Bypass and Circulatory Arrest

BACKGROUND Synovial sarcoma primarily arises in para-articular locations of the extremities. However, numerous unique sites of origin have been reported. There are only 5 known cases of primary intravascular synovial sarcoma. METHODS We present the second reported case of synovial sarcoma arising from the inferior vena cava (IVC) in a 41-year-old woman with progressive fatigue, abdominal distension, and lower-extremity swelling. This is the first known case with a monophasic histological subtype. RESULTS The tumor arose from the retrohepatic IVC with cephalad extension into the right atrium. Excision required cardiopulmonary bypass and deep hypothermic circulatory arrest, followed by bovine pericardial patch reconstruction of the IVC. CONCLUSIONS Primary synovial sarcoma of the IVC is rare. The use of cardiopulmonary bypass with or without deep hypothermic circulatory arrest may be required if there is tumor extension into the heart. Bovine pericardium is an excellent material for caval reconstruction.

Modified frailty index predicts postoperative outcomes in older gastrointestinal cancer patients

Frailty disproportionately impacts older patients with gastrointestinal cancer, rendering them at increased risk for poor outcomes. A frailty index may aid in preoperative risk stratification. We hypothesized that high modified frailty index (mFI) scores are associated with adverse outcomes after tumor resection in older, gastrointestinal cancer patients.

Expected and Unexpected Consequences of the Affordable Care Act: The Impact on Patients and Surgeons-Pro and Con Arguments.

The Patient Protection and Affordable Care Act (PPACA), called the Affordable Care Act (ACA) or “ObamaCare” for short, was enacted in 2010. The Public Policy and Advocacy Committee of the Society for Surgery of the Alimentary Tract (SSAT) hosted a debate with an expert panel to discuss the ACA and its impact on surgical care after the first year of patient enrollment. The purpose of this debate was to focus on the impact of ACA on the public and surgeons. At the core of the ACA are insurance industry reforms and expanded coverage, with a goal of improved clinical outcomes and reduced costs of care. We have observed supportive and opposing views on ACA. Nonetheless, we will witness major shifts in health care delivery as well as restructuring of our relationship with payers, institutions, and patients. With the rapidly changing health care landscape, surgeons will become key members of health systems and will likely need to lead transition from solo-practice to integrated care systems. The full effects of the ACA remain unrealized, but its implementation has begun to change the map of the American health care system and will surely impact the practice of surgery. Herein, we provide a synopsis of the “pro” and “con” arguments for the expected and unexpected consequences of the ACA on society and surgeons.

Retrieval of Microencapsulated Islet Grafts for Post-transplant Evaluation.

Microencapsulation of islets is a procedure used to immunoisolate islets in order to obviate the need for immunosuppression of islet transplant recipients. Although microencapsulated islets have routinely been transplanted in the peritoneal cavity, the ideal site for their engraftment remains to be determined. The omentum, a highly vascularized tissue, has been proposed as an alternative site for microencapsulated islet transplantation. An added benefit to the omentum is that implanted microcapsules can be easily retrieved for post-transplant evaluation. This chapter describes a collagenase-based procedure for the retrieval of microencapsulated islets following the harvest of omentum pouch site of transplantation.

Trends in the Use of Endoscopic Retrograde Cholangiopancreatography for the Management of Chronic Pancreatitis in the United States.

Goals:The aim of this study was to characterize current trends in the use of endoscopic retrograde cholangiopancreatography (ERCP) in the United States for patients hospitalized with chronic pancreatitis. Background:Historically, ERCP was the primary tool for diagnostic and therapeutic management of chronic pancreatitis. With increased availability of magnetic resonance imaging and endoscopic ultrasound, indications for ERCP are being redefined. Study:We performed a retrospective cohort study using the Nationwide Inpatient Sample from 1998 to 2010. We identified patients with a primary discharge diagnosis of chronic pancreatitis who underwent ERCP. We excluded patients diagnosed with biliary, gallbladder, or pancreatic neoplasm and patients who underwent gallbladder or pancreatic operation during the same admission. We analyzed patient and hospital characteristics, length of stay, and in-hospital mortality, and adjusted for weighted sample schema. Results:During the study period, 29,318 patients with chronic pancreatitis (mean age 52 y, 57.2% female) underwent ERCP during their hospitalization. The majority of patients were white (56.1%). The majority of procedures were performed at large (72.4%), urban (95.2%), and academic (69.0%) hospitals. Mean hospital charges were