Cancer prevention and therapy through the modulation of the tumor microenvironment

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer

The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone

<p>Abstract</p> <p>Background</p> <p>The standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC.</p> <p>Design</p> <p>The GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID. NCT00941655</p

A complicated case of vascular Pythium insidiosum infection treated with limb-sparing surgery

INTRODUCTION: Pythiosis is a serious life- and limb-threatening infection endemic to Thailand, but rarely seen in the Western hemisphere. Here, we present a unique case of vascular pythiosis initially managed with limb-sparing vascular bypass grafts complicated by a pseudoaneurysm in our repair. PRESENTATION OF CASE: The patient is a 17 year-old Jamaican male with severe aplastic anemia. He sustained a minor injury to his left leg while fishing in Jamaica, which evolved to become an exquisitely tender inguinal swelling. His physical exam and imaging were significant for arteriovenous fistula with limb ischemia. Pathology obtained during surgery for an extra-anatomic vascular bypass showed extensive invasion by Pythium insidiosum. He later developed a pseudoaneurysm at the site of proximal anastomosis and required urgent intervention. DISCUSSION: This patient presented with a rare, but classic case of vascular pythiosis, which was unrecognized at the time of presentation. A variety of therapeutic modalities have been used to treat this disease, including antibiotics, antifungals, and immunotherapy, but the ultimate management of vascular pythiosis is surgical source control. CONCLUSION: A high index of suspicion in susceptible patients is needed for timely diagnosis of vascular pythiosis to achieve optimal source control

Liver resections in metastatic gastric cancer

AbstractBackgroundThe 5-year survival of patients receiving standard-of-care chemotherapy for metastatic gastric cancer (MGC) to the liver is <2%. This review examines the published data on liver resections for MGC and analyses the rationale for potentially aggressive surgical management.MethodsA search of the PubMed and Scopus databases was used to identify studies published in English from 1990 to 2009 that reported on 10 or more patients who underwent liver resections for MGC. All available clinicopathologic data were analysed. In particular, we examined longterm survival and the characteristics of individuals surviving for >5 years.ResultsNineteen studies reported on 436 patients. Median 5-year survival was 26.5% (range: 0–60%). Overall, 13.4% (48/358) of patients were alive at 5 years and studies with extended follow-up reported that 4.0% (7/174) of patients survived for >10 years. Overall in-hospital mortality was 3.5% (12/340 patients); however, the median mortality rate across the studies was 0%. No prognostic factor was found to be consistently statistically significant across these small studies.ConclusionsDespite the limitations of any analysis of retrospective data for highly selected groups of patients, it would appear that liver resections combined with systemic therapy for MGC can result in prolonged survival