BackgroundPancreatic 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.MethodsThis 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.FindingsTwenty 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 neu...

Within the tumor microenvironment is a dynamic exchange between cancer cells and their surrounding stroma. This complex biologic system requires carefully designed models to understand the role of its stromal components in carcinogenesis, tumor progression, invasion, and metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a prototypic matricellular protein at the center of this exchange. Two decades of basic science research combined with recent whole genome analyses indicate that SPARC is an important player in vertebrate evolution, normal development, and maintenance of normal tissue homeostasis. Therefore, SPARC might also play an important role in the tumor microenvironment. Clinical evidence indicates that SPARC expression correlates with tumor progression, but tightly controlled animal models have shown that the role of SPARC in tumor progression is dependent on tissue and tumor cell type. In this Prospectus, we review the current understanding of SPARC in the tumor microenvironment and discuss current and future investigations of SPARC and tumor-stromal interactions that require careful consideration of growth factors, cytokines, proteinases, and angiotropic factors that might influence SPARC activity and tumor progression.

BACKGROUND Surgical site infections (SSIs) remain a major source of morbidity and cost after resection of intra-abdominal malignancies. Negative-pressure wound therapy (NPWT) has been reported to significantly reduce SSIs when applied to the closed laparotomy incision. This article reports the results of a randomized clinical trial examining the effect of NPWT on SSI rates in surgical oncology patients with increased risk for infectious complications. STUDY DESIGN From 2012 to 2016, two hundred and sixty-five patients who underwent open resection of intra-abdominal neoplasms were stratified into 3 groups: gastrointestinal (n = 57), pancreas (n = 73), or peritoneal surface (n = 135) malignancy. They were randomized to receive NPWT or standard surgical dressing (SSD) applied to the incision from postoperative days 1 through 4. Primary outcomes of combined incisional (superficial and deep) SSI rates were assessed up to 30 days after surgery. RESULTS There were no significant differences in superficial SSIs (12.8% vs 12.9%; p > 0.99) or deep SSI (3.0% vs 3.0%; p > 0.99) rates between the SSD and NPWT groups, respectively. When stratified by type of surgery, there were still no differences in combined incisional SSI rates for gastrointestinal (25% vs 24%; p > 0.99), pancreas (22% vs 22%; p > 0.99), and peritoneal surface malignancy (9% vs 9%; p > 0.99) patients. When performing univariate and multivariate logistic regression analysis of demographic and operative factors for the development of combined incisional SSI, the only independent predictors were preoperative albumin (p = 0.0031) and type of operation (p = 0.018). CONCLUSIONS Use of NPWT did not significantly reduce incisional SSI rates in patients having open resection of gastrointestinal, pancreatic, or peritoneal surface malignancies. Based on these results, at this time NPWT cannot be recommended as a therapeutic intervention to decrease infectious complications in these patient populations.

High mFI is associated with postoperative morbidity and mortality after PD and can aid in preoperative risk stratification.

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