Summary Background Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived ...growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. Methods We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov , number NCT00041197. Findings All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum–maximum 0–56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% 95% CI 96–100 vs 83% 78–88 at 1 year; hazard ratio HR 0·35 0·22–0·53; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 3% vs 0), abdominal pain (12 3% vs six 1%), and diarrhoea (ten 2% vs five 1%) in the imatinib group and hyperglycaemia (two <1% vs seven 2%) in the placebo group. Interpretation Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. Funding US National Institutes of Health and Novartis Pharmaceuticals.
Abstract Background Previous studies have demonstrated improved in-hospital mortality following hepatic resection for hepatocellular carcinoma (HCC) at teaching hospitals. The objective of this study ...was to evaluate if resection of HCCs at academic cancer programs (ACP) is associated with improved 10-year survival. Study Design Using the NCDB (1998-2011), we evaluated patients undergoing hepatic resection for HCC at ACPs, comprehensive community cancer programs (CCCPs), and community cancer programs (CCPs). High volume cancer programs (HVCPs) were defined as performing ≥10 hepatectomies per year. Multivariate Cox proportional hazard models by stepwise selection were applied to estimate hazard ratios (HR) of predictors of survival. The Kaplan-Meier method was used to generate survival curves at each facility type and survival rates were compared using the log-rank test. Results We identified 12,757 patients undergoing hepatic resection for HCC at ACPs (n=8,404), CCPs (n=483), and CCCPs (n=3,870). Sixty-two percent (n=5,191) of patients treated at ACPs were at high volume institutions compared to 11.6% (n=446) and 0% of CCCPs and CCPs, respectively (p<0.0001). On multivariable analysis, patients undergoing hepatic resection at transplant centers (p<0.0001) and HVCPs had significantly improved survival (p<0.0001). Adjusted 10-year survival rates were 28.7% at high volume ACPs, 28.2% at high volume CCCPs, 24.9% at low volume CCCPs, 25.1% at low volume ACPs, and 21.3% at CCPs (p=<0.0001 ). Conclusions Patients undergoing hepatic resection for HCC at HVCPs had a significantly improved 10-year survival. Regionalization of HCC treatment to HVCPs may improve long-term survival.
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of ...homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.
IMPORTANCE: To our knowledge, this study reports on the largest cohort of long-term survivors (LTSs) (≥10 years) following a diagnosis of pancreatic ductal adenocarcinoma (PADC) and identifies the ...characteristics associated with LTS. OBJECTIVE: To determine patient, tumor, surgical, and sociodemographic characteristics associated with LTS. DESIGN, SETTING, AND PARTICIPANTS: A nationwide retrospective cohort study of patients with invasive PADC (International Classification of Diseases for Oncology, Third Edition codes 8140/3, 8500/3, 8021/3, and 8035/3) was conducted using data collected in the National Cancer Database (NCDB). A multivariable logistic regression model of factors significantly associated with LTS was developed and used to generate a nomogram predicting the likelihood of surviving at least 10 years from initial diagnosis. Data collected from more than 1500 academic centers and community hospitals in the United States and Puerto Rico were assessed. Patients included were those with histologically proven PADC who underwent pancreatic surgical resection aimed at removal of the primary tumor between January 1, 1998, and December 31, 2002 (n = 11 917). The initial cohort (n = 70 915) excluded noninvasive tumors or tumors with unknown histology (n = 11 696) and was limited to patients who underwent surgical resection (n = 47 302 excluded). Analysis was conducted from January 1, 1998, to December 31, 2011. EXPOSURES: Pancreatic ductal adenocarcinoma. MAIN OUTCOMES AND MEASURES: Long-term survival, defined as surviving at least 10 years from initial diagnosis. RESULTS: Of the 11 081 patients with complete survival information, 431 individuals (3.9%) were LTSs. Significant predictors of LTS included (determined using odds ratio OR; 95% CI), in order of importance, lymph node positivity ratio (0%: 4.6; 3.4-6.4), adjuvant chemotherapy (2.4; 2.0-3.0), pathologic T stage (T1: 3.1; 1.8-5.6), patient age (50-60 years: 3.4; 1.8-6.7), tumor grade (well differentiated: 2.2; 1.5-3.0), surgical margin (negative: 1.9; 1.4-2.6), pathologic M stage (M = X: 5.6; 2.1-22.8), tumor size (<2 cm: 1.7; 1.2-2.5), educational level (>86% high school graduates: 1.7; 1.2-2.4), and insurance status according to the patient’s zip code (private: 2.0; 95% CI, 0.9-5.1). The model C index was 0.768. Based on our nomogram, patients with the most favorable characteristics had an 18.1% chance of LTS. Furthermore, survival curves demonstrated that the probability of dying following initial diagnosis of PADC reached a plateau of approximately 10% per year after 7 years of survival. CONCLUSIONS AND RELEVANCE: Although PADC remains a deadly disease, long-term survival is possible, even beyond the 10-year mark. Our adjusted analysis identified lymph node ratio, administration of adjuvant chemotherapy, and pathologic T stage as being the top 3 variables associated with LTS of PADC. In addition, our easy-to-use nomogram may be able to identify potential LTS among patients with resected PADC.
Background
Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal ...adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling.
Aims
We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC.
Methods
Normal human esophageal epithelium, Barrett’s esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers.
Results
sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls.
Conclusions
sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition’s ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.
Background Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series ...contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. Study Design We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. Results Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio HR 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. Conclusions Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years.
Immune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related ...mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness.
We tested this strategy by designing a randomized phase II clinical trial treating advanced melanoma patients with either Ipilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA). Clinicaltrails.gov identifier (NCT02403778). The frequency of circulating MDSCs and the activation of CD8(+) T cells was measured by flow cytometry. Expression of immunosuppressive genes was measured with quantitative real time-PCR. T cell suppressive functions were measured by mixed lymphocyte reaction.
Here we show that in vitro treatment with ATRA decreases immunosuppressive function of MDSCs in mixed lymphocyte reactions. Additionally, ATRA reduces the expression of immunosuppressive genes including PD-L1, IL-10, and indoleamine 2,3‑dioxygenase by MDSCs. Furthermore, the addition of ATRA to standard of care Ipilimumab therapy appears safe, as ATRA did not increase the frequency of grade 3 or 4 adverse events. Finally, ATRA significantly decreased the frequency of circulating MDSCs compared to Ipilimumab treatment alone in advanced-stage melanoma patients.
These results illustrate the importance of MDSCs in immunotherapy resistance and provide evidence that targeting MDSCs in cancer patients may augment immunotherapeutic approaches.
•ATRA decreases MDSC immunosuppressive gene expression and immunosuppressive function.•ATRA decreases the frequency of circulating MDSCs.•The combination of ATRA and Ipilimumab appears to be safe.•ATRA increases the frequency of circulating mature myeloid cells.
Background Obesity is associated with an increased risk of postoperative complications after colectomy for cancer, but it is unclear which specific complications occur more frequently in obese ...patients. Our objective was to assess the association of body mass index (BMI) on short-term outcomes after colectomy for cancer. Study Design Using the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) dataset, we identified patients who underwent colectomy for malignancy at 121 hospitals. Logistic regression models were developed to assess risk-adjusted 30-day outcomes by BMI while adjusting for preoperative risk factors. Results There were 3,202 patients identified: 33.4% normal weight (BMI 18.5 to 24 kg/m2 ), 35.1% overweight (BMI 25 to 29 kg/m2 ), 19.0% obese (BMI 30 to 34 kg/m2 ), and 12.4% morbidly obese (BMI ≥ 35 kg/m2 ). Compared with normal weight patients, complications occurred more frequently in the morbidly obese (31.8% versus 20.5%, odds ratio OR 1.75, 95% CI 1.33 to 2.31). Specifically, the morbidly obese had a higher risk of surgical site infection (20.7% versus 9.0%; OR 2.66, 95% CI 1.91 to 3.73), dehiscence (3.3% versus 1.1%; OR 3.51, 95% CI 1.55 to 7.95), pulmonary embolism (1.3% versus 0.3%; OR 6.98, 95% CI 1.62 to 30.06), and renal failure (3.0% versus 1.5%; OR 2.75, 95% CI 1.21 to 6.26). Pneumonia, urinary tract infection, stroke, cardiac arrest, myocardial infarction, deep venous thrombosis, length of stay, sepsis, and 30-day mortality did not differ significantly by BMI. Conclusions Compared with normal weight patients, morbidly obese patients had a higher risk of surgical site infection, dehiscence, pulmonary embolism, and renal failure, but not other complications or mortality. Quality initiatives should include these specific complications.
Although the concept of cancer stem cells (CSCs) is well‐accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the ...existence of human melanoma cells that fulfill the criteria for CSCs (self‐renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH‐positive melanoma cells are more tumorigenic than ALDH‐negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH‐positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH‐positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug‐induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH‐positive CSCs from patient‐derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)‐driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer. STEM Cells2012;30:2100–2113
In patients with advanced esophageal or gastric cancer, it is highly likely that palliation of symptoms will become a focus of treatment. Dysphagia and obstruction are the most common complaints, and ...many of these patients can be treated with endoscopic interventions to alleviate symptoms. Bleeding, perforation, and nutritional issues are common problems. Attempts at palliation should be guided by thoughtful discussions regarding patients' goals of care. Owing to the high morbidity and mortality in patients with limited life expectancy, a strategy of working from the least invasive to the most invasive interventions should be guided by the patient's goals.
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