Morbidity and Mortality after Pancreaticoduodenectomy in Patients with Borderline Resectable Type C Clinical Classification

Background

We previously described the clinical classification of patients with resectable pancreatic tumor anatomy but marginal performance status (PS) or reversible comorbidities as “borderline resectable type C” (BR-C). This study was designed to analyze the incidence and risk factors for post-pancreaticoduodenectomy (PD) morbidity/mortality in a multi-institutional cohort of BR-C patients.

Methods

Elective PDs were evaluated from the 2005-10 ACS-NSQIP database. BR-C was defined as age?≥?80, poor PS, weight loss?>?10 %, pulmonary disease, recent myocardial infarction/angina, stroke history, and/or preoperative sepsis. Variables associated with 30-day postoperative major complications (PMC) and mortality were analyzed.

Results

A total of 3,033/8,266 (36.7 %) patients were BR-C. BR-C patients were more likely to suffer PMC (31.3 vs. 26.2 %) and mortality (4.1 vs. 2.3 %). BR-C patients with PMC suffered 50 % higher mortality versus non-BR-C patients with PMC (11.5 vs. 7.7 %) (all p?<?0.001). For BR-C patients, multivariate analysis identified the following risk factors for PMC or mortality: albumin?<?3.5 g/dL, dyspnea, preoperative sepsis, age?≥?80, poor PS, anesthesia score?≥?4, and intraoperative transfusion?≥?4 units.

Conclusions

Nationwide, one third of patients undergoing PD are medically borderline. These BR-C patients are at higher risk for and less able to be rescued from PMC. Surgeons should identify and optimize comorbidities and utilize prehabilitation to address functional deficits before elective PD.     

Organochlorine pesticides exposure in female adolescents: potential impact on sexual hormones and interleukin-1 levels

The objective of this study was to assess the potential impact of organochlorine pesticides (OCPs) on IL-1 axis in exposed female adolescents through an observational cross-sectional study. The study was conducted in Sary-Agach District (OCPs exposed girls) and Sairam District (OCPs unexposed controls), South Kazakhstan. The study included 524 female adolescents aged 10–17 years (OCPs exposed, n?=?253; OCPs unexposed, n?=?271). The main outcome was assessment of OCPs blood levels (correlating to pubertal development and sexual hormonal status) and IL-1 levels. The delayed sexual development and the hormonal profile in OCPs exposed female adolescents correlated to the blood levels of OCPs. Interestingly, serum IL-1α and IL-1β in girls living in contaminated areas correlated to OCPs blood levels as well. Both OCPs and IL-1 blood levels in exposed female adolescents resulted to be increased, but further research is required to establish if that might represent an additional factor contributing to puberty disorders and/or reproductive health issues.     

Clinicopathological analysis of ATRX,DAXX and NOTCH receptor expression in angiosarcomas

Aims

Multiple genetic alterations, including alternative lengthening of telomeres (ALT) and NOTCH mutations, have been described in angiosarcoma. Loss of α‐thalassaemia/mental retardation syndrome X‐linked (ATRX) and death domain‐associated protein 6 (DAXX) expression is frequently associated with the ALT phenotype. Additionally, inhibition of NOTCH signalling induces the development of malignant vascular tumours in mice, indicating a tumour suppressive role of the NOTCH pathway in the pathogenesis of angiosarcoma. The aim of this study was to evaluate the immunohistochemical expression of ATRX, DAXX and NOTCH receptors (NOTCH1 and NOTCH2) in a large cohort of angiosarcomas, and study their clinicopathological and prognostic significance.

Methods and results

One hundred and forty cases of angiosarcoma were stained for ATRX, DAXX, NOTCH1 and NOTCH2. ATRX loss (<10% labelling) was seen in seven of 118 (6%) cases, and was more frequent in deep soft tissue tumours than in other body sites (P = 0.004). Angiosarcomas with ATRX loss were associated with worse event‐free survival than angiosarcomas with retained ATRX expression (P = 0.003). DAXX was retained in all specimens examined. Decreased NOTCH1 expression (≤1+ intensity) was seen in 29 of 123 (24%) cases, and was associated with a cutaneous site of origin (P = 0.013) and advanced disease (P = 0.026). NOTCH2 expression was decreased in 16 of 103 (16%) cases, was associated with visceral tumours (P = 0.001), and correlated with worse disease‐specific survival (P = 0.033).

Conclusions

ATRX, NOTCH1 and NOTCH2 expression varies in angiosarcomas and shows significant correlations with site of origin and poor clinical outcome, thus highlighting the biological heterogeneity within this tumour type.     

Adjuvant/Perioperative Therapy in Pancreatic and Periampullary Cancer

The delivery of postoperative combined modality adjuvant therapy for completely resected pancreatic adenocarcinoma was initially shown to be beneficial based on a prospective, randomized trial published 30 years ago. Since then, oncologists have debated whether chemotherapy alone, chemoradiation, or both are optimal adjuvant therapies following pancreatectomy for pancreatic ductal adenocarcinomas (PDAC). No global consensus has emerged, and there is no one superior modality despite randomized trials in part, to poor trial design, poor patient selection, and poor therapy options itself. We need to have a disciplined approach to the selection of patients for pancreatectomy, pathologic assessment of surgical resection margins, and postoperative (pre-treatment) imaging. In the era of the multidetector CT optimized for pancreatic imaging, tumors of “borderline resectability” have emerged as a distinct subset of PDAC. The attempt to standardize the definition of borderline resectable is a work in progress and modified with time. This distinction (between resectable and borderline resectable) is essential to minimize potentially confounding results of clinical trials. Additionally, preoperative therapy is not only preferred but mandatory in a large population of borderline resectable patients. Ultimately, as we develop more effective systemic therapies for PDAC, proceeding with surgery after a period of induction therapy will be even more compelling especially if there is a clear positive impact on overall survival.     

Patterns of self-reported symptoms in pancreatic cancer patients receiving chemoradiation

Pancreatic cancer is a lethal disease characterized by multiple disease-related symptoms. Chemoradiation therapy is a standard of treatment for locally advanced pancreatic cancer. Although shown to prolong survival, there is little information about treatment-related symptoms or the palliative benefits of chemoradiation. We assessed symptoms of patients with locally advanced pancreatic cancer receiving chemoradiation to determine the prevalence, and co-occurrence, of symptoms and to identify the extent to which symptoms interfered with function. Forty-eight patients were treated with chemoradiation on a Phase I protocol. Patients received radiotherapy (50.4 Gy in 28 fractions), capecitabine (median dose 825 mg/m(2) twice daily), and bevacizumab (2.5-10 mg/kg). Symptom severity and its interference with function were prospectively assessed (at presentation, during, and after chemoradiation) in 43 consenting patients using the M.D. Anderson Symptom Inventory. Results showed that 95% of patients reported at least one of the 13 symptoms assessed at presentation. The most commonly reported symptoms of moderate to severe (>or=5 on a 0-10 scale) intensity at presentation were lack of appetite (24%), pain (19%), fatigue (19%), and sleep disturbance (10%). We observed an increase in patients reporting moderate to severe fatigue, nausea, and sleep disturbance during chemoradiation. McNemar tests for paired binary observations showed the proportion of patients reporting moderate to severe symptoms significantly (P<0.001) decreased after chemoradiation at 94 days follow-up (lack of appetite=7%, pain=7%, fatigue=13%, sleep disturbance=7%). This study demonstrates the feasibility and usefulness of symptom assessment in chemoradiation protocols. Future studies with larger cohorts are needed to further characterize multiple symptoms associated with chemoradiation.     

Multipulse drug permeation across a membrane driven by a chemical pH-oscillator.

Chemical pH-oscillators provide a potential means for modulating the delivery of acidic or basic drugs across lipophilic membranes. Previous attempts to exploit this notion were not completely successful due to quenching of the pH oscillator in the presence of the drug, most likely by a buffering mechanism. Here we show that multiple, periodic pulses of drug flux across a membrane can be achieved when the concentration of drug is sufficiently low. Advantage is taken of a pH oscillator system whose periodicity is slower than that of previously considered oscillators.