Martin D. McCarter

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial

BACKGROUNDnGastrointestinal 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 alpha 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.nnnMETHODSnWe 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.nnnFINDINGSnAll 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.nnnINTERPRETATIONnAdjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.nnnFUNDINGnUS National Institutes of Health and Novartis Pharmaceuticals.

Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial.

Objective:To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). Background:GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. Methods:This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). Results:After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. Conclusions:Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246)

Microscopically Positive Margins for Primary Gastrointestinal Stromal Tumors: Analysis of Risk Factors and Tumor Recurrence

BACKGROUNDnLittle 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.nnnSTUDY DESIGNnWe 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.nnnRESULTSnSeventy-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.nnnCONCLUSIONSnApproximately 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.

Germinal Center T Follicular Helper Cells Are Highly Permissive to HIV-1 and Alter Their Phenotype during Virus Replication

HIV-1 replication is concentrated within CD4+ T cells in B cell follicles of secondary lymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helper cells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the major HIV-1 virus–producing cells in vivo has not been established. In this study, we investigated TFH permissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses. Using flow cytometry, higher percentages of GC TFH (CXCR5highPD-1high) and CXCR5+programmed cell death-1 (PD-1)low cells were GFP+ than non-GC TFH (CXCR5+PD-1intermediate) or extrafollicular (EF) (CXCR5−) cells. When sorted prior to spinoculation, however, GC TFH were substantially more permissive than CXCR5+PD-1low or EF cells, suggesting that many GC TFH transition to a CXCR5+PD-1low phenotype during productive infection. In situ hybridization on inguinal lymph node sections from untreated HIV-1–infected individuals without AIDS revealed higher frequencies of HIV-1 RNA+ cells in GC than non-GC regions of follicle or EF regions. Superinfection of HIV-1–infected individuals’ lymph node cells with GFP reporter virus confirmed the permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% of CXCR5+CD4+ cells were located in follicles. Within sorted lymph node cells from four HIV-infected individuals, CXCR5+ subsets harbored 11–66-fold more HIV-1 RNA than CXCR5− subsets, as determined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and, to a lesser extent, CXCR5 during HIV-1 replication. These data further implicate GC TFH as the major HIV-1–producing cells in chronic asymptomatic HIV-1 infection.

Extraskeletal osteosarcoma: analysis of outcome of a rare neoplasm

Purpose. Extraskeletal osteosarcoma represents an unusual soft-tissue sarcoma that historically is reported to carry an exceptionally poor prognosis.The objectives of this study were to use a prospectively gathered sarcoma database to test the prevailing clinical bias and more accurately describe the natural history, characterize the prognostic features, estimate survival and evaluate treatment strategies for this unusual sarcoma. Patients and methods. From a large database of nearly 4000 sarcomas at a single institution, 15 patients with pathologically confirmed extraskeletal osteosarcoma were analysed. Results and discussion. Extraskeletal osteosarcoma usually occurs as a large, deep, high-grade lesion in the lower extremity of older patients. Overall and disease-specific survival at 5 years was 50%, with a median follow-up of 35 months (range 3– 200 months). Use of adjuvant chemotherapy or radiation therapy did not appear to influence survival, but an effect may have been missed by the relatively low numbers in each group.When matched to a comparable group of patients with stage III extremity sarcomas, there was no significant difference in overall or disease-specific survival between groups. Treatment for extraskeletal osteosarcoma should follow established guidelines for treatment of soft-tissue sarcomas, with the decision regarding adjuvant therapy to be based on individual risk factors.

Characteristics of 10-Year Survivors of Pancreatic Ductal Adenocarcinoma

IMPORTANCEnTo 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.nnnOBJECTIVEnTo determine patient, tumor, surgical, and sociodemographic characteristics associated with LTS.nnnDESIGN, SETTING, AND PARTICIPANTSnA 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 (nu2009=u200911,917). The initial cohort (nu2009=u200970,915) excluded noninvasive tumors or tumors with unknown histology (nu2009=u200911,696) and was limited to patients who underwent surgical resection (nu2009=u200947,302 excluded). Analysis was conducted from January 1, 1998, to December 31, 2011.nnnEXPOSURESnPancreatic ductal adenocarcinoma.nnnMAIN OUTCOMES AND MEASURESnLong-term survival, defined as surviving at least 10 years from initial diagnosis.nnnRESULTSnOf 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 (Mu2009=u2009X: 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 patients 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.nnnCONCLUSIONS AND RELEVANCEnAlthough 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.

HIV-1 Infection of Human Intestinal Lamina Propria CD4+ T Cells In Vitro Is Enhanced by Exposure to Commensal Escherichia coli

Microbial translocation has been linked to systemic immune activation in HIV-1 disease, yet mechanisms by which microbes may contribute to HIV-associated intestinal pathogenesis are poorly understood. Importantly, our understanding of the impact of translocating commensal intestinal bacteria on mucosal-associated T cell responses in the context of ongoing viral replication that occurs early in HIV-1 infection is limited. We previously identified commensal Escherichia coli-reactive Th1 and Th17 cells in normal human intestinal lamina propria (LP). In this article, we established an ex vivo assay to investigate the interactions between Th cell subsets in primary human LP mononuclear cells (LPMCs), commensal E. coli, and CCR5-tropic HIV-1Bal. Addition of heat-killed E. coli to HIV-1–exposed LPMCs resulted in increases in HIV-1 replication, CD4 T cell activation and infection, and IL-17 and IFN-γ production. Conversely, purified LPS derived from commensal E. coli did not enhance CD4 T cell infection. E. coli exposure induced greater proliferation of LPMC Th17 than Th1 cells. Th17 cells were more permissive to infection than Th1 cells in HIV-1–exposed LPMC cultures, and Th17 cell infection frequencies significantly increased in the presence of E. coli. The E. coli-associated enhancement of infection was dependent on the presence of CD11c+ LP dendritic cells and, in part, on MHC class II-restricted Ag presentation. These results highlight a potential role for translocating microbes in impacting mucosal HIV-1 pathogenesis during early infection by increasing HIV-1 replication and infection of intestinal Th1 and Th17 cells.

Neoadjuvant FOLFIRINOX Application in Borderline Resectable Pancreatic Adenocarcinoma: A Retrospective Cohort Study

Abstract5-Fluorouracile, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) has not been extensively used in the neoadjuvant setting because of concerns with safety and toxicity. We evaluated our institutional experience with neoadjuvant FOLFIRINOX in borderline resectable pancreatic adenocarcinoma (BRPAC). The primary endpoints were completion of therapy to surgery and negative resection margin (R0) rate.Patients with BRPAC treated with neoadjuvant FOLFIRINOX were retrospectively analyzed. Between August 2011 and September 2013, 20 patients with BRPAC treated with neoadjuvant FOLFIRINOX were identified.Most patients (88.8%) completed FOLFIRINOX therapy and underwent resection. Abutment of venous structures was identified in 13 cases (72.2%), while short segment portal vein encasement in 3 cases (16.6%) with concomitant arterial involvement in 3 cases (16.6%). Isolated superior mesenteric artery abutment was identified in 2 cases (11.2%). Patients received a median of 4 cycles of FOLFIRINOX. There was 1 case of progression. Vascular resection was performed in 9 cases (52.9%). Preoperative radiation therapy was used in 8 patients (44%). All patients underwent margin negative resection (R0). Histopathologic treatment response was evident in 10 cases (58.8%).Neoadjuvant FOLFIRINOX was generally safe and the expected toxicity did not prevent surgery allowing for a high rate of R0 resection.

Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report

BackgroundNon-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it.Case presentationA thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, big insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT.ConclusionOptimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established.

Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection

BackgroundEarly HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1-induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1BaL or mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated.ResultsThe majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up-regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gram-negative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation.ConclusionsGram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis.