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Objective Regret is a powerful motivating factor in medical decision making among patients and surgeons. Regret can be particularly important for surgical decisions, which often carry significant risk and may have uncertain outcomes. We performed a systematic review of the literature focused on patient and physician regret in the surgical setting. Methods A search of the English literature between 1986 and 2016 that examined patient and physician self-reported decisional regret was carried out using the MEDLINE/PubMed and Web of Science databases. Clinical studies performed in patients and physicians participating in elective surgical treatment were included. Results Of 889 studies identified, 73 patient studies and 6 physician studies met inclusion criteria. Among the 73 patient studies, 57.5% examined patients with a cancer diagnosis, with breast (26.0%) and prostate (28.8%) cancers being most common. Interestingly, self-reported patient regret was relatively uncommon with an average prevalence across studies of 14.4%. Factors most often associated with regret included type of surgery, disease-specific quality of life, and shared decision making. Only 6 studies were identified that focused on physician regret; 2 pertained to surgical decision making. These studies primarily measured regret of omission and commission using hypothetical case scenarios and used the results to develop decision curve analysis tools. Conclusion Self-reported decisional regret was present in about 1 in 7 surgical patients. Factors associated with regret were both patient- and procedure related. While most studies focused on patient regret, little data exist on how physician regret affects shared decision making.

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene ( CLOCK ), brain and muscle ARNT-Like 1 gene ( BMAL1 ), period ( PER ), and cryptochrome ( CRY ), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health–related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.

Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85–95%), with approximately 5–15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras -driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-Kras G12D ; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant Kras G12D gene. Although the driver gene mutation Kras G12D is present in anus of both sexes, only female KC mice develop Kras -mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer–one of the deadliest malignancies–have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.

Background While pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, many other histologic forms of pancreatic cancer are also recognized. These histologic variants portray unique characteristics in terms of patient demographics, tumor behavior, survival, and responsiveness to treatments. Materials and Methods Patients who underwent surgical resection of the pancreas for non-metastatic, invasive pancreatic cancer between 2004 and 2014 were selected from the National Cancer Data Base and categorized by histologic variant according to WHO classification guidelines. Patient demographics, tumor variables, treatment characteristics, and survival were compared between histologic groups and subgroups. Results A total of 57,804 patients met inclusion and exclusion criteria and were grouped into eight major histologic categories. Survival analysis by the histologic group showed median overall survival of 20.2 months for ductal adenocarcinoma, 20.5 months for squamous cell carcinoma, 26.8 months for mixed acinar-neuroendocrine carcinomas, 52.6 months for cystic mucinous neoplasms with an associated invasive carcinoma, 67.5 months for acinar cell carcinoma, and 69.3 months for mesenchymal tumors. Median survival was not reached for neuroendocrine tumors and solid-pseudopapillary neoplasms, with 5-year overall survival rates of 84% and 97% respectively. Conclusions Rare subtypes of pancreatic cancer present unique clinicopathologic characteristics and display distinct tumor biologies. This study presents data on demographic, prognostic, treatment, and survival outcomes between rare forms of pancreatic neoplasms in order to aid understanding of the natural history and behavior of these neoplasms, with the hope of serving as a reference in clinical decision-making and ability to provide accurate prognostic information to patients.

Introduction Improvements in the ability to predict pancreatic fistula could enhance patient outcomes. Previous studies demonstrate that drain fluid amylase on postoperative day 1 (DFA1) is predictive of pancreatic fistula. We sought to assess the accuracy of DFA1 and to identify a reliable DFA1 threshold under which pancreatic fistula is ruled out. Methods Patients undergoing pancreatic resection from November 1, 2011 to December 31, 2012 were selected from the American College of Surgeons-National Surgical Quality Improvement Program Pancreatectomy Demonstration Project database. Pancreatic fistula was defined as drainage of amylase-rich fluid with drain continuation >7 days, percutaneous drainage, or reoperation for a pancreatic fluid collection. Univariate and multi-variable regression models were utilized to identify factors predictive of pancreatic fistula. Results DFA1 was recorded in 536 of 2,805 patients who underwent pancreatic resection, including pancreaticoduodenectomy ( n  = 380), distal pancreatectomy ( n  = 140), and enucleation ( n  = 16). Pancreatic fistula occurred in 92/536 (17.2 %) patients. DFA1, increased body mass index, small pancreatic duct size, and soft texture were associated with fistula ( p  < 0.05). A DFA1 cutoff value of <90 U/L demonstrated the highest negative predictive value of 98.2 %. Receiver operating characteristic (ROC) curve confirmed the predictive relationship of DFA1 and pancreatic fistula. Conclusion Low DFA1 predicts the absence of a pancreatic fistula. In patients with DFA1 < 90 U/L, early drain removal is advisable.

Background Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently emerged as a treatment choice for patients with colorectal liver metastases (CLM) and inadequate future liver remnant (FLR). The aim of this study was to define the results of ALPPS compared with two-stage hepatectomy (TSH) for patients with CLM. Materials and methods A meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Identification of eligible studies was performed using three distinct databases through February 2017; Medline, ClinicalTrials.gov and Cochrane library—Cochrane Central Register of Controlled Trials using a syntax including medical subject headings terms “portal vein ligation,” “PVE,” “staged hepatectomy,” “staged liver resection,” “liver resection,” “two-stage hepatectomy,” “TSH,” “in situ liver transection with portal vein ligation,” “associating liver partition and portal vein ligation for staged hepatectomy” and “ALPPS”. Results Among the 634 records identified, 9 studies comparing ALPPS with TSH met the inclusion criteria. These studies included 657 patients with unresectable CLM (ALPPS, n  = 186 vs TSH, n  = 471). There was no difference in final postoperative FLR between ALPPS versus TSH (mean difference: 31.72, 95% CI: −27.33 to 90.77, p  = 0.29). The kinetic growth rate was faster with the ALPPS versus TSH (mean difference 19.07 ml/day, 95% CI 8.12–30.02, p  = 0.0006). TSH had a lower overall and major morbidity versus ALPPS (overall morbidity: RR: 1.39, 95% CI: 1.07–1.8, p  = 0.01; I 2 : 58%, p  = 0.01; major morbidity: RR: 1.57, 95% CI: 1.18–2.08, p  = 0.002; I 2 : 0%, p  = 0.44). Overall survival was comparable following ALPPS versus TSH. Conclusion While ALPPS may be a suitable approach for patients, the higher morbidity and mortality should be considered when determining the operative approach for patients with extensive CLM.

Introduction Colorectal liver metastases develop in 50% of patients diagnosed with colorectal cancer. Surgical resection for colorectal liver metastasis typically involves either anatomical resection (AR) or parenchymal-sparing hepatectomy (PSH). The objective of the current study was to analyze data on parenchymal versus non-parenchymal-sparing hepatic resections for CLM. Methods A systematic review of the literature regarding parenchymal-sparing hepatectomy was performed. MEDLINE/PubMed, Cochrane, and EMBASE databases were searched for publications containing the following medical subject headings (MeSH): “Colorectal Neoplasms,” “Neoplasm Metastasis,” “Liver Neoplasms” and “Hepatectomy”. Besides, the following keywords were used to complete the literature search: “Hepatectomy,” “liver resection,” “hepatic resection,” “anatomic/anatomical,” “nonanatomic/ nonanatomical,” “major,” “minor,” “limited,” “wedge,” “CRLM/CLM,” and “colorectal liver metastasis.” Data was reviewed, aggregated, and analyzed. Results Two thousand five hundred five patients included in 12 studies who underwent either PSH ( n  = 1087 patients) or AR ( n  = 1418 patients) were identified. Most patients had a primary tumor that originated in the colon (PSH 52.2–74.4% vs. AR 53.9–74.3%) ( P  = 0.289). The majority of studies included a large subset of patients with only a solitary tumor with a reported median tumor number of 1–2 regardless of whether the patient underwent PSH or AR. Median EBL was no different among patients undergoing PSH (100–896 mL) versus AR (200–1489 mL) for CLM ( P  = 0.248). There was no difference in median length-of-stay following PSH (6–17 days) versus AR (7–15 days) ( P  = 0.747). While there was considerable inter-study variability regarding margin status, there was no difference in the incidence of R0 resection among patients undergoing PSH (66.7–100%) versus AR (71.6–98.6%) ( P  = 0.58). When assessing overall survival, there was no difference whether resection of CLM was performed with PSH (5 years OS: mean 44.7%, range 29–62%) or AR (5 years OS: mean 44.6%, range 27–64%) ( P  = 0.97). Conclusion PSH had a comparable safety and efficacy profile compared with AR and did not compromise oncologic outcomes. PSH should be considered an appropriate surgical approach to treatment for patients with CLM that facilitates preservation of hepatic parenchyma.

BackgroundFibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc’s role in FLC tumour growth remains enigmatic.ObjectiveWe sought to determine the protein kinase-mediated signalling networks that drive growth and proliferation in FLC.DesignWe integrated a combination of newly established preclinical models of FLC and an unbiased polypharmacology-based approach to identify downstream kinases involved in DNAJ-PKAc-mediated FLC cell growth. We validated our findings in multiple patient-derived mouse models and patient tumours.ResultsFunctional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc’s centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumour growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues.ConclusionOur findings underscore the role of DNAJ-PKAc in rewiring signalling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.

[This corrects the article DOI: 10.1371/journal.pgen.1011216.].