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Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug–target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β 1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H 4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug–target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N , N -dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs. New targets for old drugs Most drugs are intended to be selective for a single protein target, but will commonly bind to several other targets too. Some 'off-target' events induce side effects of varying degrees of severity, though some may be essential for a drug's efficacy. A new strategy to identify potential off-target effects for known drugs is reported in this issue. The structures of 3,665 FDA-approved and investigational drugs were computationally screened against hundreds of protein targets as defined by the ligands that bind to them. Chemical similarities between the drugs and various sets of ligands predicted thousands of off-target associations, some of which were confirmed in pharmacological assays. This approach may help predict and explain the side effects of known drugs and drug candidates, and may also lead to the identification of new clinical applications for drugs that have been previously approved for use in humans. Drugs that are chemically quite similar often bind to biologically diverse protein targets, and it is unclear how selective many of these compounds are. Because many drug–target combinations exist, it would be useful to explore possible interactions computationally. Here, 3,665 drugs are tested against hundreds of targets; chemical similarities between drugs and ligand sets are found to predict thousands of unanticipated associations.

Background Minimally invasive pancreaticoduodenectomy (PD) remains an uncommon procedure, and the safety and efficacy remain uncertain beyond single institution case series. The aim of this study is to compare outcomes and costs between laparoscopic (LPD) and open PD (OPD) using a large population-based database. Methods The Nationwide Inpatient Sample database (a sample of approximately 20 % of all hospital discharges) was analyzed to identify patients who underwent PD from 2000 to 2010. Patient demographics, comorbidities, hospital characteristics, inflation-adjusted total charges, and complications were evaluated using univariate and multivariate logistic regression. Hospitals were categorized as high-volume hospitals (HVH) if more than 20 PD (open and laparoscopic) were performed annually, while those performing fewer than 20 PD were classified as low-volume hospitals. Results Of the 15,574 PD identified, 681 cases were LPD (4.4 %). Compared to OPD, patients who underwent LPD were slightly older (65 vs. 67 years; p  = 0.001) and were more commonly treated at HVH (56.6 vs. 66.1 %; p  < 0.001). Higher rates of complications were observed in OPD than LPD (46 vs. 39.4 %; p  = 0.001), though mortality rates were comparable (5 vs. 3.8 %, p  = 0.27). Inflation-adjusted median hospital charges were similar between OPD and LPD ($87,577 vs. $81,833, p  = 0.199). However, hospital stay was slightly longer in the OPD group compared to LPD group (12 vs. 11 days, p  < 0.001). Stratifying outcomes by hospital volume, LPD at HVH resulted in shorter hospital stays (9 vs. 13 days, p  < 0.001), which translated into significantly lower median hospital charges ($76,572 vs. $106,367, p  < 0.001). Conclusions Contrary to fears regarding the potential for compromised outcomes early in the learning curve, LPD morbidity in its first decade is modestly reduced, while hospital costs are comparable to OPD. In high-volume pancreatic hospitals, LPD is associated with a reduction in length of stay and hospital costs.

Background The role of neoadjuvant chemotherapy (NCT) for high-risk soft tissue sarcoma (STS) is questioned. This study aimed to define which patients may experience a survival advantage with NCT. Methods All the patients from the U.S. Sarcoma Collaborative database (2000–2016) who underwent curative-intent resection of high-grade, primary truncal/extremity STS size 5 cm or larger were included in this study. The primary end points were recurrence-free survival (RFS) and overall survival (OS). Results Of the 4153 patients, 770 were included in the study. The median tumor size was 10 cm, and 669 of the patients (87%) had extremity tumors. The most common histology was undifferentiated pleomorphic sarcoma (UPS), found in 42% of the patients. Of the 770 patients, 216 (28%) received NCT. The patients who received NCT had deeper, larger tumors ( p  < 0.001). Of the patients with tumors 5 cm or larger and 8 cm or larger, NCT was not associated with improved RFS or OS. However for the patients with tumors 10 cm or larger, NCT was associated with improved 5-year RFS (51% vs 40%; p  = 0.053) and 5-year OS (58% vs 47%; p  = 0.043). By location, the patients with extremity tumors 10 cm or larger but not truncal tumors had improved 5-yearr RFS (54% vs 42%; p  = 0.042) and 5-year OS (61% vs 47%; p  = 0.015) with NCT. According to histology, no subtype had improved RFS or OS with NCT, although the patients with UPS had a trend toward improved 5-year RFS (56% vs 42%; p  = 0.092) and 5-year OS (66% vs 52%; p  = 0.103) with NCT. Conclusion For the patients with high-grade STS, NCT was associated with improved RFS and OS when tumors were 10 cm or larger and located in the extremity. However, no histiotype-specific advantage was identified. Future studies assessing the efficacy of NCT may consider focusing on these patients, with added focus on histology-specific strategies.

BackgroundAdrenocortical carcinoma (ACC) is a rare but aggressive malignancy, and many prognostic factors that influence survival remain undefined. Individually, the GRAS (Grade, Resection status, Age, and Symptoms of hormone hypersecretion) parameters have demonstrated their prognostic value in ACC. This study aimed to assess the value of a cumulative GRAS score as a prognostic indicator after ACC resection.MethodsA retrospective cohort study of adult patients who underwent surgical resection for ACC between 1993 and 2014 was performed using the United States Adrenocortical Carcinoma Group (US-ACCG) database. A sum GRAS score was calculated for each patient by adding one point each when the criteria were met for tumor grade (Weiss criteria ≥ 3 or Ki67 ≥ 20%), resection status (micro- or macroscopically positive margin), age (≥ 50 years), and preoperative symptoms of hormone hypersecretion (present). Overall survival (OS) and disease-free survival (DFS) by cumulative GRAS score were analyzed by the Kaplan–Meier method and log-rank test.ResultsOf the 265 patients in the US-ACCG database, 243 (92%) had sufficient data available to calculate a cumulative GRAS score and were included in this analysis. The 265 patients comprised 23 patients (10%) with a GRAS of 0, 52 patients (21%) with a GRAS of 1, 92 patients (38%) with a GRAS of 2, 63 patients (26%) with a GRAS of 3, and 13 patients (5%) with a GRAS of 4. An increasing GRAS score was associated with shortened OS (p < 0.01) and DFS (p < 0.01) after index resection.ConclusionIn this retrospective analysis, the cumulative GRAS score effectively stratified OS and DFS after index resection for ACC. Further prospective analysis is required to validate the cumulative GRAS score as a prognostic indicator for clinical use.

Background Minimally invasive liver surgery is a growing field, and a small number of recent reports have suggested that laparoscopic liver resection (LLR) is feasible even in patients with cirrhosis. However, parenchymal transection of the cirrhotic liver is challenging due to fibrosis and portal hypertension. There is a paucity of data regarding the technical modifications necessary to safely transect the diseased parenchyma. Methods Patients undergoing LLR by a single surgeon between 2008 and 2015 were reviewed. Patients with cirrhosis were compared to those without cirrhosis to examine differences in surgical technique, intraoperative characteristics, and outcomes (including liver-related morbidity and general postoperative complication rates). Results A total of 167 patients underwent LLR during the study period. Forty-eight (29 %) had cirrhosis, of which 43 (90 %) had hepatitis C. Most had Child–Pugh class A disease (85 %). Compared to noncirrhotics, patients with cirrhosis were older, had more comorbidities, and were more likely to have hepatocellular carcinoma. Precoagulation before parenchymal transection was used more frequently in cirrhotics (65 vs. 15 %, P  < 0.001), and mean portal triad clamping time was longer (32 vs. 22 min, P  = 0.002). There were few conversions to open surgery, though hand-assisted laparoscopy was used as an alternative to converting to open in three patients with cirrhosis. Blood loss was relatively low for both groups. Although there were more postoperative complications among cirrhotics (38 vs. 13 %, P  = 0.001), this was almost entirely due to a higher rate of minor (Clavien–Dindo I or II) complications. Liver-related morbidity, major complications, and mortality rates were similar. Conclusions LLR is safe for selected patients with cirrhosis. The added complexity associated with the division of diseased liver parenchyma may be overcome with some form of technique modification, including more liberal use of precoagulation, portal triad clamping, or a hand-assist port.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. When diagnosed in advanced stages of the disease, the outcomes of surgical resection are not well understood. The objective of this study is to determine the impact of surgery in patients with advanced ACC. Using the Surveillance, Epidemiology and End Results database, we identified patients diagnosed with Stage III and IVACC between 1988 and 2009. A total of 320 patients with Stage III and IV disease were included in our analysis. In patients treated with surgical resection, the Stage III 1- and 5-year survival rates were 77 and 40 per cent, respectively, whereas the Stage IV 1- and 5-year survival rates were 54 and 27.6 per cent, respectively. Patients treated without surgery had poor survival at 1 year for both Stage III (13%) and Stage IV (16%) ( P < 0.01 compared with the surgical groups). Lymph node dissection was performed in 26 per cent of the patients with advanced ACC and was associated with improved survival in univariate analysis of Stage IV patients. Overall, our results indicate that favorable survival outcomes can be achieved even in patients with Stage III and IV disease and surgery should be considered in patients with advanced ACC.

Consumer groups campaign for cost transparency believing that patients will select hospitals accordingly. We sought to determine whether the cost of pancreaticoduodenectomy (PD) should be considered in choosing a hospital. Using the Nationwide Inpatient Sample database, we analyzed charges for patients who underwent PD from 2000 to 2010. Outcomes were stratified by hospital volume. A total of 15,599 PDs were performed in 1,186 hospitals. The median cost was $87,444 (interquartile range $16,015 to $144,869). High volume hospitals (HVH) had shorter hospital stay (11 vs 15 days, P < .001) and mortality (3% vs 7.6%, P < .001). PD performed at low volume hospitals had higher charges compared with HVH ($97,923 vs $81,581, P < .001). On multivariate analysis, HVH was associated with a lower risk of mortality, while extremes in hospital costs, cardiac comorbidity, and any complication were significant predictors of mortality. Although PDs performed at HVH are associated with better outcomes and lower hospital charges, costs should not be the primary determinant when selecting a hospital.