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Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication.

Background This study was designed to develop a more robust predictive model, beyond T-stage alone, for incidental gallbladder cancer (IGBC) for discovering locoregional residual (LRD) and distant disease (DD) at reoperation, and estimating overall survival (OS). T-stage alone is currently used to guide treatment for incidental gallbladder cancer. Residual disease at re-resection is the most important factor in predicting outcomes. Methods All patients with IGBC who underwent reoperation at 10 institutions from 2000 to 2015 were included. Routine pathology data from initial cholecystectomy was utilized to create the gallbladder cancer predictive risk score (GBRS). Results Of 449 patients with gallbladder cancer, 262 (58 %) were incidentally discovered and underwent reoperation. Advanced T-stage, grade, and presence of lymphovascular (LVI) and perineural (PNI) invasion were all associated with increased rates of DD and LRD and decreased OS. Each pathologic characteristic was assigned a value (T1a: 0, T1b: 1, T2: 2, T3/4: 3; well-diff: 1, mod-diff: 2, poor-diff: 3; LVI-neg: 1, LVI-pos: 2; PNI-neg: 1, PNI-pos: 2), which added to a total GBRS score from 3 to 10. The scores were separated into three risk-groups (low: 3–4, intermediate: 5–7, high: 8–10). Each progressive GBRS group was associated with an increased incidence LRD and DD at the time of re-resection and reduced OS. Conclusions By accounting for subtle pathologic variations within each T-stage, this novel predictive risk-score better stratifies patients with incidentally discovered gallbladder cancer. Compared with T-stage alone, it more accurately identifies patients at risk for locoregional-residual and distant disease and predicts long-term survival as it redistributes T1b, T2, and T3 disease across separate risk-groups based on additional biologic features. This score may help to optimize treatment strategy for patients with incidentally discovered gallbladder cancer.

Background Despite meticulous surgical techniques, calcitonin levels remain detectable in 40 % to 66 % of patients after initial surgery for medullary thyroid carcinoma (MTC), and the optimal surgical management for persistent or recurrent disease remains controversial. Previous studies suggest that biochemical cure, defined by normalization of postoperative calcitonin measurements, predicts disease-free survival. Reoperative approaches range from targeted removal of detectable disease to comprehensive compartment-oriented lymph node clearance. Methods A proportional meta-analysis of clinical case series of postoperative calcitonin clearance after reoperation for MTC was performed. Studies were obtained from PubMed, Embase, Scopus, and the Cochrane Library. Results Twenty-seven articles capturing data of 984 patients met the inclusion criteria for the meta-analysis. Overall, normalization of calcitonin after reoperation for MTC occurred in 16.2 % of patients [95 % confidence interval (CI) 14.0–18.5]. Stratified by operative procedure, targeted selective lymph node removal procedures had a normalization of calcitonin in 10.5 % of patients (95 % CI 6.4–14.7), while compartment-oriented procedures had a higher rate of normalization at 18.6 % (95 % CI 15.9–21.3). Conclusions The rate of calcitonin normalization after reoperation for MTC is enhanced through use of a meticulous compartment-oriented lymph node dissection. Compartment-oriented lymph node dissection results in calcitonin normalization in 18.6 % of reoperative MTC patients and is the procedure of choice in patients in whom the goal is biochemical cure.

Background The American Cancer Society projects there will be over 22,000 new cases, resulting in nearly 11,000 deaths, related to gastric adenocarcinoma in the US in 2014. The aim of the current study was to find clinicopathologic variables associated with disease-free survival (DFS) and overall survival (OS) following curative resection of gastric adenocarcinoma, and create a nomogram for individual risk prediction. Methods A nomogram to predict DFS and OS following surgical resection of gastric adenocarcinoma was constructed using a multi-institutional cohort of patients who underwent surgery for primary gastric adenocarcinoma at seven major institutions in the US between January 2000 and August 2013. Discrimination and calibration of the nomogram were tested by C-statistic, Kaplan–Meier curves, and calibration plots. Results A total of 719 patients who underwent surgery for primary gastric adenocarcinoma were included in the study. Using the backward selection of clinically relevant variables with Akaike information criteria, age, sex, tumor site, depth of invasion, and lymph node ratio (LNR) were selected as factors predictive of OS, while age, tumor site, depth of invasion, and LNR were incorporated in the prediction of DFS. A nomogram was constructed to predict OS and DFS using these variables. Discrimination and calibration of the nomogram revealed good predictive abilities (C-index, DFS 0.711; OS 0.702). Conclusion Independent predictors of recurrence and death following surgery for primary gastric adenocarcinoma were used to create a nomogram to predict DFS and OS. The nomogram was able to stratify patients into prognostic groups, and performed well on internal validation.

Background The proximal gastric margin dictates the extent of resection for gastric adenocarcinoma (GAC). The value of achieving negative margins via additional gastric resection after a positive proximal margin frozen section (FS) is unknown. Methods The US Gastric Cancer Collaborative includes all patients who underwent resection of GAC at seven institutions from 2000–2012. Intraoperative proximal margin FS data and final permanent section (PS) data were classified as R0 or R1, respectively; positive distal margins were excluded. The primary aim was to evaluate the impact on local recurrence of converting a positive proximal FS-R1 margin to a PS-R0 final margin by additional resection. Secondary endpoints were recurrence-free survival (RFS) and overall survival (OS). Results Of 860 patients, 520 had a proximal margin FS and 67 were positive. Of these, 48 were converted to R0 on PS by additional resection. R0 proximal margin was achieved in 447 patients (86 %), PS-R1 in 25 (5 %), and converted FS-R1-to-PS-R0 in 48 (9 %). The median follow-up was 44 months. Local recurrence was significantly decreased in the converted FS-R1-to-PS-R0 group compared to the PS-R1 group (10 vs. 32 %; p  = 0.01). Median RFS was similar between the FS-R1-to-PS-R0 and PS-R1 cohorts (25 vs. 20 months; p  = 0.49), compared to 37 months for the PS-R0 group. Median OS was similar between the FS-R1-to-PS-R0 conversion and PS-R1 groups (36 vs. 26 months; p  = 0.14) compared to 50 months for the PS-R0 group. On multivariate analysis, increasing T-stage and N-stage were associated with worse OS; the FS-R1-to-PS-R0 proximal margin conversion was not significantly associated with improved RFS ( p  = 0.68) or OS ( p  = 0.44). Conclusion Conversion of a positive intraoperative proximal margin frozen section during gastric cancer resection may decrease local recurrence, but it is not associated with improved RFS or OS. This may guide decisions regarding the extent of resection.

Background Current staging and treatment guidelines for gastric adenocarcinoma do not differentiate between linitis plastic (LP) and non-LP cancers. Significant controversy exists regarding the surgical management of LP patients. Methods Using the multi-institutional U.S. Gastric Cancer Collaborative database, 869 gastric cancer patients who underwent resection between 2000 and 2012 were identified. Clinicopathologic and outcomes data of 58 LP patients were compared to 811 non-LP patients. Results Stage III/IV disease was more common at presentation in LP patients compared with non-LP patients (90 vs. 44 %, p  < 0.01). Despite the fact that most LP patients underwent total gastrectomy (88 vs. 39 %, p  < 0.01), final positive margins were more common in LP patients (33 vs. 7 %, p  < 0.01). The use of frozen section allowed 15 intraoperative positive margins in 38 patients to be converted to negative final margins. Median overall survival (OS) was significantly worse in patients with LP (11.6 vs. 37.8 months, p  < 0.01). There was no difference in median OS of LP patients based on stage (I/II, 17.3 mo; III, 10.6 mo; IV, 12.0 mo; p  = 0.46). LP and non-LP patients who underwent optimal resection (negative margin and D2/3 lymphadenectomy) had better survival compared with those with nonoptimal resections. The median OS for optimally resected stage III LP ( n  = 22) and stage III non-LP ( n  = 185) patients was nearly identical (26.7 vs. 25.3 mo; p  = 0.69). Conclusions Future staging systems and treatment guidelines should differentiate between LP and non-LP gastric cancers. Long-term survival in select LP patients who undergo optimal resections is comparable to optimally resected non-LP patients.

Background Although the extent of resection frequently dictates the method of reconstruction following distal subtotal gastrectomy, it is unclear whether Roux-en-Y gastrojejunostomy compared with Billroth II gastrojejunostomy is associated with superior perioperative outcomes. Methods Patients who underwent resection for gastric cancer with Roux-en-Y or Billroth II reconstruction between 2000 and 2012 in seven academic institutions (US Gastric Cancer Collaborative) were identified. Patients who underwent total gastrectomy, gastric wedge, or palliative resections (metastatic disease or R2 resections) were excluded. Results Of a total of 965 patients, 447 met the inclusion criteria. A comparison between the Roux-en-Y ( n  = 257) and Billroth II ( n  = 190) groups demonstrated no differences in patient and tumor characteristics, except for Billroth II patients having a higher proportion of antral tumors (71 % vs. 50 %, p  < 0.001). Roux-en-Y operations were slightly longer (244 min vs. 212 min, p  < 0.001) and associated with somewhat higher blood loss (243 ml vs. 205 ml, p  = 0.033). However, there were no significant differences in the length of hospital stay (8 days vs. 7 days), readmission rate (17 % vs. 18 %), 90-day mortality (5.1 % vs. 4.7 %), incidence (39 % vs. 41 %) and severity of complications, dependency on jejunostomy tube feeding at discharge (13 % vs. 12 %), same-patient decrease in serum albumin level from the preoperative to the postoperative value at 30, 60, and 90 days, receipt of adjuvant therapy (50 % vs. 53 %), or 5-year survival (44 % vs. 41 %). Conclusions Although long-term quality-of-life parameters were not compared, this study did not show an advantage of Roux-en-Y gastrojejunostomy over Billroth II gastrojejunostomy in short-term perioperative outcomes. Both techniques should be regarded as equally acceptable reconstructive options following partial gastrectomy for gastric cancer.

Background The effect of routine drainage after abdominal surgery with enteric anastomoses is controversial. In particular, the role of peritoneal drain (PD) placement after total gastrectomy for adenocarcinoma is not well established. Methods Patients who underwent total gastrectomy for gastric adenocarcinoma (GAC) at seven institutions from the US Gastric Cancer Collaborative, from 2000 to 2012, were identified. The association of PD placement with postoperative outcomes was analyzed. Results Overall, 344 patients were identified and 253 (74 %) patients received a PD. The anastomotic leak rate was 9 %. Those with PD placement had similar American Society of Anesthesiologists score, tumor size, TNM stage, and the need for additional organ resection when compared with their counterparts. No difference was observed in the rate of any complication (54 vs. 48 %; p   =  0.45), major complication (25 vs. 24 %; p   =  0.90), or 30-day mortality (7 vs. 4 %; p   =  0.51) between the two groups. In addition, no difference in anastomotic leak (9 vs. 10 %; p   =  0.90), the need for secondary drainage (10 vs. 9 %; p   =  0.92), or reoperation (13 vs. 8 %; p   =  0.28) was identified. On multivariate analysis, PD placement was not associated with decreased postoperative complications. Subset analysis, stratified by patients who did not undergo concomitant pancreatectomy ( n   =  319) or those who experienced anastomotic leak ( n   =  31), similarly demonstrated no association of PD placement with reduced complications or mortality. Conclusions PD placement after total gastrectomy for GAC is associated with neither a decrease in the frequency and severity of adverse postoperative outcomes, including anastomotic leak and mortality, nor a decrease in the need for secondary drainage procedures or reoperation. Routine use of PDs is not warranted.

Background Postoperative complications (POCs) can negatively impact survival after oncologic resection. POCs may also decrease the rate of adjuvant therapy completion. We evaluated the impact of complications on gastric cancer survival and analyzed the combined effect of complications and adjuvant therapy on survival. Methods We analyzed 824 patients from 7 institutions of the U.S. Gastric Cancer Collaborative who underwent curative resection for gastric adenocarcinoma between 2000 and 2012. POC were graded using the modified Clavien–Dindo system. Survival probabilities were estimated using the method of Kaplan and Meier and analyzed using multivariate Cox regression. Results Median follow-up was 35 months. The overall complication rate was 41 %. The 5-year overall survival (OS) and recurrence-free survival (RFS) of patients who experienced complications were 27 and 23 %, respectively, compared with 43 and 40 % in patients who did not have complications ( p  < 0.0001 for OS and RFS). On multivariate analysis, POC remained an independent predictor for decreased OS and RFS (HR 1.3, 95 % CI 1.1–1.6, p  = 0.03 for OS; HR 1.3, 95 % CI 1.01–1.6, p  = 0.03 for RFS). Patients who experienced POC were less likely to receive adjuvant therapy (OR 0.5, 95 % CI 0.3–0.7, p  < 0.001). The interaction of complications and failure to receive adjuvant therapy significantly increased the hazard of death compared with patients who had neither complications nor adjuvant therapy (HR 2.3, 95 % CI 1.6–3.2, p  < 0.001). Conclusions Postoperative complications adversely affect long-term outcomes after gastrectomy for gastric cancer. Not receiving adjuvant therapy in the face of POC portends an especially poor prognosis following gastrectomy for gastric cancer.

Background Survival estimates following surgical resection of gastric adenocarcinoma are traditionally reported as survival from the date of surgery. Conditional survival (CS) estimates, however, may be more clinically relevant by accounting for time already survived. We assessed CS following surgical resection for gastric adenocarcinoma. Methods We analyzed 807 patients who underwent resection for gastric adenocarcinoma from 2000 to 2012 at seven participating institutions in the U.S. Gastric Cancer Collaborative. Cox proportional hazards models were used to evaluate factors associated with overall survival. Three-year CS estimates at “ x ” year after surgery were calculated as follows: CS 3  = S ( x +3) /S ( x ). Results Overall 1-, 3-, and 5-year overall survival rates after gastric resection were 42, 34, and 30 %, respectively. Using CS estimates, the probability of surviving an additional 3 years given that the patient had survived at 1, 3, and 5 years were 56, 71, and 82 %, respectively. Patients with higher risk at baseline (i.e., stage III or IV disease, lymphovascular invasion) demonstrated the greatest increase in CS over time. Conclusions Survival estimates following surgical resection of gastric adenocarcinoma is dynamic; the probability of survival increases with time already survived. Patients with worse prognostic features at the time of surgery had the greatest increases in CS over time. Conditional survival estimates provide important information about the changing probability of survival over time and should be used among patients with resected gastric adenocarcinoma to guide subsequent follow-up strategies.