Renuka Iyer

Higher Frequencies of GARP+CTLA-4+Foxp3+ T Regulatory Cells and Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Are Associated with Impaired T-Cell Functionality

The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations.

A Phase II Study of Gemcitabine and Capecitabine in Advanced Cholangiocarcinoma and Carcinoma of the Gallbladder: A Single-Institution Prospective Study

AimTo determine the clinical benefit response (CBR), time to tumor progression (TTP), overall survival, and effect on quality of life (QOL) of gemcitabine and capecitabine in patients with advanced biliary cancer.MethodsGemcitabine (1000 mg/m2 IV over 30 minutes on days 1 and 8) and capecitabine (650 mg/m2 orally twice daily for 14 days) were administered and repeated every 21 days. All patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Pancreatic Cancer Module (EORTC QLQ-C30-PAN 26) questionnaire on day 1 of each cycle. Cumulative QOL scores were calculated. The two-stage design required 17 patients to evaluate the confirmed response at nine weeks.ResultsTwelve patients with a median age of 54 years were enrolled. A median of eight cycles per patient were completed. With a median follow-up of 18.2 months, the CBR (two partial response and five stable disease) was 58% [95% confidence interval (CI) 28–85%]. Four out of seven patients with CBR had no decline in QOL with chemotherapy. The probability of survival at one year was 0.58. Median TTP and overall survival were 9.0 and 14.0 months, respectively. Nine patients had grade 3 or 4 toxicities. There were no treatment-related deaths.ConclusionsGemcitabine and capecitabine at this dose and schedule are well tolerated and effective and may offer clinical benefit and maintain QOL in patients with advanced biliary cancer. This regimen merits further investigation in the neoadjuvant setting.

Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers ☆

BACKGROUND Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival. PATIENTS AND METHODS Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08. MP-TF activity levels were measured using a TF-dependent FXa generation assay. RESULTS The study population comprised 117 patients, including pancreatic (n=80), biliary (n=34) or unknown primary histologically consistent with PBC (n=3). Of these, 52 patients (44.5%) experienced thromboembolism, including pulmonary embolism (n=15), deep venous thrombosis (n=21) and other arterial or venous events (n=32). Mean TF was 2.15 (range 0.17- 31.01) pg/mL. Median survival was 98.5 days for MP-TF activity ≥ 2.5 pg/mL versus 231 days for MP-TF activity<2.5 pg/mL (p<0.0001). In multivariate analysis, elevated MP-TF activity was associated with both VTE (OR 1.4, 95% CI 1.1-1.6) and mortality (HR 2.5, 95% CI 1.4-4.5). CONCLUSIONS Elevated circulating MP-TF activity is associated with thrombosis and worsened survival in patients with PBC. MP-TF activity as a prognostic biomarker warrants further prospective evaluation.

Current Understanding of the Molecular Biology of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene knock-out/knock-in studies indicate that inactivation of factors including MEN1 and abnormal PI3K/mTOR signaling uncouples endocrine cell cycle progression from the control of environmental cues such as glucose, leading to islet cell overgrowth. In addition, accumulating evidence suggests that further impairment of endothelial-endocrine cell interactions contributes to tumor invasion and metastasis. Recent phase III clinical trials have shown that therapeutic interventions, such as sunitinib and everolimus, targeting those signal transduction pathways improve disease-free survival rates. Yet, cure in the setting of advanced disease remains elusive. Further advances in our understanding of the molecular mechanisms of PanNETs and improved preclinical models will assist in developing personalized therapy utilizing novel drugs to provide prolonged control or even cure the disease.

Controversies in the Multimodality Management of Locally Advanced Esophageal Cancer: Evidence-Based Review of Surgery Alone and Combined-Modality Therapy

Most patients with esophageal cancer present with locoregional disease, and the optimal initial management is controversial. The current National Comprehensive Cancer Network (NCCN) practice guidelines support diverse treatment options for locoregional disease, including surgical resection alone, definitive chemoradiation therapy, and preoperative combined-modality (neoadjuvant/trimodality) therapy. Many cancer centers worldwide favor a neoadjuvant approach, although the evidence supporting this practice is inconsistent. A concise review of the literature is presented. The topics discussed do not necessarily reflect each author’s opinions or clinical practices.

Rituximab-based therapy for gemcitabine-induced hemolytic uremic syndrome in a patient with metastatic pancreatic adenocarcinoma: a case report.

PurposeThe purpose of this report is to describe the management and outcome of an unusual complication of a commonly used chemotherapeutic agent. Gemcitabine is a known risk factor for hemolytic uremic syndrome (HUS), which can often have a rapidly fatal clinical course despite intervention with steroids, plasmapheresis and hemodialysis.MethodsA retrospective report of the first case of gemcitabine-related HUS, in a patient with metastatic pancreatic adenocarcinoma, treated with a variety of standard therapies in addition to rituximab is presented. The hematologic response parameters and clinical outcomes to each of the therapies given are described.ResultsChemotherapy-induced HUS was aggressively treated with plasmapheresis, high-dose steroids, vincristine and rituximab. Platelet recovery and clinical improvement coincided with administration of rituximab. In addition, aggressive supportive measures to manage renal failure (hemodialysis) and labile hypertension, allowed this patient to have an extended survival as a result of successful therapy for this complication despite an underlying rapidly fatal malignancy.ConclusionThis case highlights the importance of timely application of aggressive measures even in patients with known diagnosis of a fatal malignancy as these interventions can prolong life and be of palliative benefit.

Akt expression may predict favorable prognosis in cholangiocarcinoma.

Background:  Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase‐2 (COX‐2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co‐expression of these proteins has not been reported. Co‐expression may reflect cross‐talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co‐expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome.

Massive hyperdiploidy and tetraploidy in acute myelocytic leukemia and myelodysplastic syndrome

Massive hyperdiploidy (>50 chromosomes) and tetraploidy (4n) are rare cytogenetic abnormalities in myelocytic malignancies, and their significance is unknown. We report on 11 patients with acute myelocytic leukemia (AML) and two patients with a myelodysplastic syndrome (MDS) with massive hyperdiploidy (10 patients) or tetraploidy (3 patients) seen at our institution over a 12-year period. Eleven patients were male and two were female. Age range was 44-84 years (median, 70 years). Only one AML patient had a previous MDS, and no patient had therapy-related disease. One or more copies of chromosomes 8 and 19 were gained in eight patients each; other frequently gained chromosomes included 13, 15, and 21. Eight patients had structural abnormalities in addition to chromosome gain; del(5q) was most common (five patients). Eleven patients received induction chemotherapy, but only four achieved complete remission. Survival ranged from 1 to 22 months, with a median of 6 months. We conclude that massive hyperdiploidy and tetraploidy are infrequent abnormalities in AML and MDS, are seen primarily in de novo disease in older male patients and are associated with a low remission rate and short survival. Massive hyperdiploidy and tetraploidy define a prognostically unfavorable cytogenetic group in de novo AML.

Pilot study of gefitinib, oxaliplatin, and radiotherapy for esophageal adenocarcinoma: tissue effect predicts clinical response.

Purpose:Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer is associated with poor prognosis. Preclinical studies indicate synergism between the EGFR inhibitor gefitinib and oxaliplatin or radiotherapy (RT). We report here early results of a planned phase I/II study of gefitinib, oxaliplatin, and RT for locally advanced, unresectable esophageal cancer. Methods and Materials:The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m2 on days 1, 15, and 29, and RT (50.4 Gy in 28 1.8-Gy fractions). Four-quadrant biopsies were obtained at 1-cm intervals along the length of the tumor before and after treatment and the specimens were immunostained for EGFR, Erk, Akt, and their phosphorylated (activated) forms. Results:Enrollment was halted at 6 evaluable cases [all male; median age, 72.5 years (range, 51–75); and all with Eastern Cooperative Oncology Group performance status of 1]. All 6 tumors were adenocarcinomas; 5 were stage III and 1 stage IVA. Oxaliplatin was given at 85 mg/m2 in 3 cases and at 100 mg/m2 in 3 cases. Gefitinib therapy lasted a median 24 weeks; the median number of oxaliplatin doses was 6.5. Best responses were mucosal complete response (n = 1), partial response (n = 1), stable disease (n = 1), and progressive disease (n = 3). EGFR was expressed by tumor in 5 cases and Erk and Akt in 6 cases before treatment; no changes were noted after treatment. EGFR expression did not correlate with survival or response. No grade 4 toxicities were noted; grade 3 toxicities were diarrhea (n = 1), vomiting (n = 1), fatigue (n = 1), and constipation (n = 2). Median overall and disease-free survival times were 10.8 months and 8.4 months. Conclusions:Gefitinib in combination with oxaliplatin and RT was tolerable, but had limited clinical activity and did not down-regulate total or activated EGFR, Akt, or Erk in esophageal tumor samples.

Treatment of locally advanced unresectable pancreatic cancer: a 10-year experience

PURPOSE We retrospectively analyzed the results of patients with locally advanced unresectable pancreatic cancer (LAPC) treated with either chemoradiation (CRT) or chemotherapy alone over the past decade. METHODS AND MATERIALS Between December 1998 and October 2009, 116 patients with LAPC were treated at our institution. Eighty-four patients received concurrent chemoradiation [RT (+) group], primarily 5-flourouracil based (70%). Thirty-two patients received chemotherapy alone [RT (-) group], the majority gemcitabine based (78%). Progression-free survival (PFS) and overall survival (OS) were calculated from date of diagnosis to date of first recurrence and to date of death or last follow-up, respectively. Univariate statistical analysis was used to determine significant prognostic factors for overall survival. RESULTS Median patient age was 67 years. Sixty patients were female (52%). Median follow-up was 11 months (range, 1.6-59.4 months). The RT (+) group received a median radiation dose of 50.4 Gy, was more likely to present with ECOG 0-1 performance status, and experienced less grade 3-4 toxicity. PFS was 10.9 versus 9.1 months (P=0.748) and median survival was 12.5 versus 9.1 months (P=0.998) for the RT (+) and RT (-) groups respectively (P=0.748). On univariate analysis, patients who experienced grade 3-4 toxicity had worse overall survival than those who did not (P=0.02). CONCLUSIONS Optimal management for LAPC continues to evolve. Patients who developed treatment-related grade 3-4 toxicity have a poorer prognosis. Survival rates were not statistically significant between chemotherapy and chemoradiotherapy groups.