Trevan D. Fischer

Autophagy Suppresses Age-Dependent Ischemia and Reperfusion Injury in Livers of Mice

BACKGROUND & AIMS As life expectancy increases, there are greater numbers of patients with liver diseases who require surgery or transplantation. Livers of older patients have significantly less reparative capacity following ischemia and reperfusion (I/R) injury, which occurs during these operations. There are no strategies to reduce the age-dependent I/R injury. We investigated the role of autophagy in the age dependence of sensitivity to I/R injury. METHODS Hepatocytes and livers from 3- and 26-month-old mice were subjected to in vitro and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins (Atg). Mitochondrial dysfunction was visualized using confocal and intravital multi-photon microscopy of isolated hepatocytes and livers from anesthetized mice, respectively. RESULTS Immunoblot, autophagic flux, genetic, and imaging analyses all associated the increase in sensitivity to I/R injury with age with decreased autophagy and subsequent mitochondrial dysfunction due to calpain-mediated loss of Atg4B. Overexpression of either Atg4B or Beclin-1 recovered Atg4B, increased autophagy, blocked the onset of the mitochondrial permeability transition, and suppressed cell death after I/R in old hepatocytes. Coimmunoprecipitation analysis of hepatocytes and Atg3-knockout cells showed an interaction between Beclin-1 and Atg3, a protein required for autophagosome formation. Intravital multi-photon imaging revealed that overexpression of Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in livers of older mice after I/R. CONCLUSIONS Loss of Atg4B in livers of old mice increases their sensitivity to I/R injury. Increasing autophagy might ameliorate liver damage and restore mitochondrial function after I/R.

Disconnected pancreatic duct syndrome: disease classification and management strategies.

BACKGROUND Disconnected pancreatic duct syndrome (DPDS) typically complicates acute necrotizing pancreatitis (ANP) and presents as a pseudocyst months after the initial episode of pancreatitis. However, our experience suggests that the presentation of DPDS may be quite varied and might require significant evaluation and judgment before surgical intervention. We sought to determine the presentations of DPDS and assess the management of the various forms of presentation. STUDY DESIGN A retrospective review of all patients with DPDS between July 2005 and June 2011 was performed. Patients were included when CT scan demonstrated a clear disconnected pancreas that was confirmed at operation. Medical records were reviewed in detail to determine clinical presentation, management, and outcomes. RESULTS Of the 50 patients identified, 66% were male, with a mean age of 53 ± 16 years. Mortality was 2% and 3 patients (6%) required late reoperation. The DPDS presented in 3 forms: diagnosed concurrently with ANP (concurrent DPDS; n = 28); delayed presentation with a pseudocyst (delayed DPDS; n = 15); and as a consequence of chronic pancreatitis (CP) (CP DPDS; n = 7). Concurrent DPDS was treated with necrosectomy including body/tail resection within 60 days of onset and complicated by a grade B/C fistula in 36%. Delayed DPDS required distal pancreatectomy 440 days after diagnosis, with a 7% fistula rate. Chronic pancreatitis DPDS was treated with lateral pancreatojejunostomy at 417 days with no fistulas. CONCLUSIONS Disconnected pancreatic duct syndrome presents concurrently with ANP, in a delayed fashion, or infrequently in the setting of CP. Prompt recognition and classification with appropriate operative therapy results in low mortality and nonoperatively managed pancreatic fistulas.

Role of autophagy in differential sensitivity of hepatocarcinoma cells to sorafenib

AIM To investigate the role of sorafenib (SFN) in autophagy of hepatocellular carcinoma (HCC). We evaluated how SFN affects autophagy signaling pathway in human HCC cell lines. METHODS Two different human HCC cell lines, Hep3B and Huh7, were subjected to different concentrations of SFN. Cell viability and onset of apoptosis were determined with colorimetric assay and immunoblotting analysis, respectively. The changes in autophagy-related proteins, including LC3, ULK1, AMPK, and LKB, were determined with immunoblotting analysis in the presence or absence of SFN. To assess autophagic dynamics, autophagic flux was measured with chloroquine, a lysosomal inhibitor. The autophagic responsiveness between different HCC cell lines was compared under the autophagy enhancing conditions. RESULTS Hep3B cells were significantly more resistant to SFN than Huh7 cells. Immunoblotting analysis revealed a marked increase in SFN-mediated autophagy flux in Huh7 cells, which was, however, absent in Hep3B cells. While both starvation and rapamycin enhanced autophagy in Huh7 cells, only rapamycin increased autophagy in Hep3B cells. Immunoblotting analysis of autophagy initiation proteins showed that SFN substantially increased phosphorylation of AMPK and consequently autophagy in Huh7, but not in Hep3B cells. CONCLUSION The autophagic responsiveness to SFN is distinct between Hep3B and Huh7 cells. Resistance of Hep3B cells to SFN may be associated with altered autophagy signaling pathways.

Improved Breast Cancer Care Quality Metrics After Implementation of a Standardized Tumor Board Documentation Template

PURPOSE Cancer treatment requires a coordinated multidisciplinary treatment approach, which led to the development of the Rapid Quality Reporting System by the Commission on Cancer. However, the lack of immediate availability of documented treatment plans and the inefficiency of global medical record reviews represent significant barriers to adherence reporting and the timely implementation of quality improvement measures. METHODS Adherence to national guidelines in the areas of radiation treatment, chemotherapy, and hormone therapy was assessed after breast conservation surgery (BCS). Adherence rates within 1 year of BCS were analyzed 10 weeks before and after the implementation of a standardized documentation template at weekly multidisciplinary breast cancer conferences. RESULTS Documented adherence rates increased postimplementation in patients undergoing consideration for both radiation treatment and hormone therapy within 1 year of BCS (89% v 65%; P = .045% and 85% v 62%; P = .002, respectively). No change was observed in patients undergoing evaluation for cytotoxic chemotherapy (80% v 85%; P = 1.00). CONCLUSION The addition of a documentation template to multidisciplinary breast cancer conferences resulted in increased recorded adherence rates to national guidelines. This template provided a means of both accurate and efficient documentation of evidence-based practice, which represents a concept with broad application in quality improvement. Although evaluation of the project was not continued beyond the pilot stage, current quality measure scores remain within the same range.

Adjuvant Radiation is Associated with Improved Survival for Select Patients with Non-metastatic Adrenocortical Carcinoma

BackgroundAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy for which surgery is the mainstay of treatment and for which adjuvant radiation is infrequently employed; however, small, single-institution series suggest adjuvant radiation may improve outcomes.MethodsAll patients with non-metastatic ACC treated with either surgery alone or surgery followed by adjuvant radiation were identified in the 2004–2013 National Cancer Database. Factors associated with receipt of radiation and the impact of adjuvant radiation on survival were determined by multivariable analysis.ResultsOf 1184 patients, 171 (14.4%) received adjuvant radiation. Patient demographics were similar between the two groups, but those receiving radiation were more likely to have had positive margins following surgery (37.4 vs. 14.6%; p < 0.001), evidence of vascular invasion (14.0 vs. 5.1%; p = 0.05), and receive concurrent chemotherapy (57.3 vs. 28.8%; p < 0.001). After adjustment for tumor and other treatment factors, only positive margins following surgery was associated with an increased likelihood of receiving adjuvant radiation (odds ratio 3.84, 95% confidence interval [CI] 1.95–7.56). Radiation therapy did not confer a difference in median overall survival in the general cohort. However, for patients with positive margins, adjuvant radiation was associated with a 40% decreased yearly risk of death after adjustment for concurrent chemotherapy (hazard ratio 0.60, 95% CI 0.40–0.92; p = 0.02). This survival advantage was not evident for other traditional high-risk features.ConclusionAdjuvant radiation appears to decrease the risk of death in ACC patients with positive margins following surgical resection, but only a small percentage are currently receiving radiation. Multidisciplinary treatment with surgery and radiation should be considered for these patients.

Local pancreatic head resection: the search for optimal indications through quality of life assessments

BACKGROUND Local pancreatic head resection (LPHR) for chronic pancreatitis has had limited adoption in the United States perhaps because of sparse outcomes and quality of life data. METHODS Forty-four patients underwent LPHR and retrospective evaluation of patient outcomes and quality of life assessment was performed. RESULTS The mean age was 49 ± 11 years (50% men) with chronic alcohol use as the etiology in 79% of patients. One patient (2%) died within 90 days. The intensive care unit stay was 1.8 ± 3.1 days and postoperative length of stay was 12.6 ± 9.4 days with 96% of patients discharged home. Ten (22%) patients had major perioperative complications. Biliary stricture was the most common late complication (14%). Quality of life assessment results showed that global status (47/100) and physical (66/100), cognitive (68/100), and social (52/100) functions were acceptable. Prevalent postoperative symptoms were pain (52/100), insomnia (56/100), and digestive disturbance (60/100). CONCLUSIONS LPHR is safe and effective for a substantial proportion of patients with chronic pancreatitis. Further refinement in the selection of patients most likely to benefit from this operation is warranted.

Resectable Distal Pancreas Cancer: Time to Reconsider the Role of Upfront Surgery

BackgroundNeoadjuvant chemotherapy (NAC) is increasingly utilized to optimize survival in proximal pancreatic adenocarcinoma. However, few studies have explored the impact of NAC in distal pancreas cancer.MethodsPatients with resectable pancreatic adenocarcinoma of the body or tail treated with either upfront pancreatectomy or NAC followed by surgery were identified in the 2006–2014 National Cancer Database. Trends in utilization, predictors of use, and impact of NAC on overall survival were determined.ResultsOf 1485 patients, 176 (11.9%) received NAC. Use of NAC increased from 9.3% in 2006 to 16.9% in 2013 [odds ratio 1.14; 95% confidence interval (CI) 1.05–1.24; p = 0.001]. NAC patients were younger, had higher clinical stage, and preoperative CA 19-9 levels (all p < 0.05). After adjustment for patient-, tumor-, and treatment-related factors, increased clinical stage was the greatest independent predictor of neoadjuvant approach (p < 0.001). On multivariable analysis, survival benefit from NAC did not reach threshold of significance (95% CI 0.66–1.04; p = 0.10) for the entire cohort. However, NAC was associated with a significant survival advantage in clinical stage III with a 51% decreased yearly risk of death (adjusted hazard ratio 0.49; 95% CI 0.25–0.98; p = 0.04). A trend towards improved survival with NAC was observed among stage IIA (p = 0.09) and IIB (p = 0.07) patients.ConclusionsNeoadjuvant chemotherapy is associated with improved overall survival in Stage III distal pancreatic adenocarcinoma and shows promise in earlier stage disease. However, only a small percentage of patients receive NAC. Prospective evaluation of NAC in distal pancreatic adenocarcinoma is warranted based on these findings.

Pediatric Thyroid Cancer

Pediatric differentiated thyroid cancer makes up approximately 10% of all thyroid malignancies and is the second most common cancer in adolescents aged 15–19. There should be a high index of suspicion of any thyroid nodule that present in childhood as malignancy rates can be as high as 25–50%. Most DTCs in children are well-differentiated tumors but present with a higher frequency of multifocality, nodal involvement, extrathyroidal extension, and distant metastases. Long-term survival is excellent but recurrence rates can approach 40–50% over 40–50 years. Treatment generally involves a total thyroidectomy; more extensive surgery and the use of radioiodine need to strike a balance between maintaining the low disease-specific mortality currently experienced by children with DTC and reducing potential complications from therapy that ensures a good quality of life during a very long survivorship. Risk stratification is similar to adults, but re-stratification based on response to therapy 1–2 years after treatment appears to be the most reliable at predicting future recurrence and dictating the level of surveillance. Future research should focus on long-term survivorship issues and validating risk stratification systems.