Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis.

Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers.

Cutting both ways: the innate immune response to oncolytic virotherapy.

Oncolytic viruses (OVs), above and beyond infecting and lysing malignant cells, interact with the immune system in complex ways that have important therapeutic significance. While investigation into these interactions is still in its early stages, important insights have been made over the past two decades that will help improve the clinical efficacy of OV-based management strategies in cancer care moving forward. The inherent immunosuppression that defines the tumor microenvironment can be modified by OV infection, and the subsequent recruitment and activation of innate immune cells, in particular, is central to this. Indeed, neutrophils, macrophages, natural killer cells, and dendritic cells, as well as other populations such as myeloid-derived suppressor cells, are key to the immune escape that allows tumors to survive, but their natural response to infection can be exploited by virotherapy. While stimulation of innate immune cells by OVs can initiate antitumor responses, related antiviral activity can limit virus spread and direct cytopathogenic effects. In this review, we highlight how each innate immune cell population influences this balance of antitumor and antiviral forces during virotherapy, some of the important molecular pathways that have been identified, and specific therapeutic targets that have emerged through this work. We discuss the importance of OV-based combination therapies in optimizing antiviral and antitumor innate immune responses stimulated by virotherapy toward tumor eradication, and how these processes vary depending on the tumor and OV in question. Rather than concentrating on a particular OV species in the review, we present the range of effects that have been documented across OV types to emphasize the context-specific nature of these interactions and how this is important in the design of future OV-based treatment approaches.

Deletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development.

Vaccinia virus (VV) has emerged as a promising platform for oncolytic virotherapy. Many clinical VV candidates, such as the double-deleted VV, vvDD, are engineered with deletions that enhance viral tumor selectivity based on cellular proliferation rates. An alternative approach is to exploit the dampened interferon-based innate immune responses of tumor cells by deleting one of the many VV immunomodulatory genes expressed to dismantle the antiviral response. We hypothesized that such a VV mutant would be attenuated in non-tumor cells but retain the ability to effectively propagate in and kill tumor cells, yielding a tumor-selective oncolytic VV with significant anti-tumor potency. In this study, we demonstrated that VVs with a deletion in one of several VV immunomodulatory genes (N1L, K1L, K3L, A46R, or A52R) have similar or improved in vitro replication, spread, and cytotoxicity in colon and ovarian cancer cells compared to vvDD. These deletion mutants are tumor selective, and the best performing candidates (ΔK1L, ΔA46R, and ΔA52R VV) are associated with significant improvement in survival, as well as immunomodulation, within the tumor environment. Overall, we show that exploiting the diminished antiviral responses in tumors serves as an effective strategy for generating tumor-selective and potent oncolytic VVs, with important implications in future oncolytic virus (OV) design.

Modeling oncolytic virus dynamics in the tumor microenvironment using zebrafish.

We have adapted a zebrafish (Danio rerio) tumor xenograft model for use in the study of oncolytic virotherapy. Following implantation of mammalian cancer cells into the perivitelline space of developing zebrafish embryos, both local and intravenous oncolytic virus treatments produce a tumor-specific infection with measurable antitumor effects. Tumor cells are injected at 48 h post fertilization, with oncolytic virus treatment then being administered 24 h later to allow for an initial period of tumor development and angiogenesis. Confocal fluorescent imaging is used to quantify dynamics within the tumor environment. The natural translucency of zebrafish at the embryo stage, coupled with the availability of strains with fluorescent immune and endothelial cell reporter lines, gives the model broad potential to allow for real time, in vivo investigation of important events within tumors throughout the course of virotherapy. Zebrafish xenografts offer a system with biologic fidelity to processes in human cancer development that influence oncolytic virus efficacy, and to our knowledge this is the first demonstration of the model's use in the context of virotherapy. Compared with other models, our protocol offers a powerful, inexpensive approach to evaluating novel oncolytic viruses and oncolytic virus-based combination therapies, with potential application to investigating the impacts of virotherapy on immune response, tumor vasculature, and metastatic disease.

Impairments in Bowel Function, Social Function and Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be associated with decreases in quality of life (QOL). Bowel-related QOL (BR-QOL) after CRS-HIPEC has not been previously studied. The objectives of the current study were to examine the effect of different types of bowel resection during CRS-HIPEC on overall QOL and BR-QOL. METHODS: A prospective cohort study was performed. QOL data were collected using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR-29 questionnaires at 3, 6, and 12 months after CRS-HIPEC. Patients were divided into groups that underwent no bowel resection, non-low anterior resection (LAR) bowel resection, LAR, and LAR with stoma. Primary outcomes were global QOL and BR-QOL. RESULTS: Overall, 158 patients were included in this study. Bowel resections were performed in 77% of patients, with 31% undergoing LAR. Global QOL was not significantly different between groups. LAR patients (with and without stoma) had significantly worse BR-QOL, embarrassment, and altered body image, with LAR + stoma patients having the largest impairments in these domains. Trends toward higher levels of impotence and anxiety were also seen in LAR patients. Although global QOL improved over time, impairments in BR-QOL and sexual and social function did not significantly improve over time. CONCLUSIONS: Although global QOL after CRS-HIPEC was not affected by the type of bowel resection, the use of LAR and ostomies was associated with clinically meaningful and persistent impairments in BR-QOL and related functional domains. Generic QOL questionnaires may not adequately capture these domains; however, targeted questionnaires in these patients may help improve QOL after CRS-HIPEC.

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials.

Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).

Management of complex polyps of the colon and rectum.

PUPRPOSE: Benign polyps that are technically challenging and unsafe to remove via polypectomy are known as complex polyps. Concerns regarding safety and completeness of resection dictate they undergo advanced endoscopic techniques, such as endoscopic mucosal resection or surgery. We provide a comprehensive overview of complex polyps and current treatment options. METHODS: A review of the English literature was conducted to identifyarticles describing the management of complex polyps of the colon and rectum. RESULTS: Endoscopic mucosal resection is the standard of care for the majority of complex polyps. Only polyps that fail endoscopic mucosal resection or are highly suspicious of invasive cancer but which cannot be removed endoscopically warrant surgery. CONCLUSION: Several factors influence the treatment of a complex polyp; therefore, there cannot be a "one-size-fitsall" approach. Treatment should be tailored to the lesion's characteristics, the risk of adverse events, and the resources available to the treating physician.

Complement inhibition enables tumor delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies.

The systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. While pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. For the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway. We show that this phenotype can be capitalized upon to deliver maraba virus pseudotyped with the lymphocytic choriomeningitis virus glycoprotein in a Fischer rat model in the face of neutralizing antibody through the use of complement modulators. This finding changes the understanding of the humoral immune response to arenaviruses, and also describes methodology to deliver viral vectors to their therapeutic sites of action without the interference of neutralizing antibody.

Impact of Major Complications on Patients' Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for selected patients with peritoneal surface malignancies (PSM). Although it can have significant morbidity, perioperative mortality is low. Little is known about whether major complications after CRS/HIPEC have a lasting impact on patients' quality of life (QOL). METHODS: We retrospectively reviewed data from a prospectively collected database on patients treated with CRS/HIPEC for PSM (2011-2014). Patients with CRS/HIPEC and 6-month QOL evaluation were included. Major perioperative complications (Clavien-Dindo grade 3/4) were the primary independent variable. QOL was evaluated using the validated EORTC QLQ-C30 score. The primary outcome was 6-month global health score. Secondary outcomes were individual functional and symptom domains. RESULTS: Forty-two patients were analyzed. Median age was 57.5; 64 % were female. Origin of PSM was appendix (55 %), colorectal (38 %), mesothelioma (5 %), and small bowel (2 %). Fourteen patients (33 %) had major (grade 3/4) complications. Median length of stay was 16 days; patients experiencing major complications had significantly increased length of stay (35.5 vs. 13 days, p < 0.01). Major complications included intra-abdominal abscess (9.5 %), bleeding (9.5 %), symptomatic pleural effusion (7.1 %), anastomotic leaks (7.1 %), and renal failure (2.4 %). The average global health score at 6 months was 68.1. The worst-rated symptom scores at 6 months were diarrhea (39.8) and fatigue (35.4). There were no significant differences in 6-month QOL scores between patients with and without major complications, globally or in specific domains. CONCLUSIONS: Although major complications are common after CRS/HIPEC, QOL at 6 months recovers and is similar to those without major complications.

Direct Lymph Node Vaccination of Lentivector/Prostate-Specific Antigen is Safe and Generates Tissue-Specific Responses in Rhesus Macaques.

Anti-cancer immunotherapy is emerging from a nadir and demonstrating tangible benefits to patients. A variety of approaches are now employed. We are invoking antigen (Ag)-specific responses through direct injections of recombinant lentivectors (LVs) that encode sequences for tumor-associated antigens into multiple lymph nodes to optimize immune presentation/stimulation. Here we first demonstrate the effectiveness and antigen-specificity of this approach in mice challenged with prostate-specific antigen (PSA)-expressing tumor cells. Next we tested the safety and efficacy of this approach in two cohorts of rhesus macaques as a prelude to a clinical trial application. Our vector encodes the cDNA for rhesus macaque PSA and a rhesus macaque cell surface marker to facilitate vector titering and tracking. We utilized two independent injection schemas demarcated by the timing of LV administration. In both cohorts we observed marked tissue-specific responses as measured by clinical evaluations and magnetic resonance imaging of the prostate gland. Tissue-specific responses were sustained for up to six months-the end-point of the study. Control animals immunized against an irrelevant Ag were unaffected. We did not observe vector spread in test or control animals or perturbations of systemic immune parameters. This approach thus offers an "off-the-shelf" anti-cancer vaccine that could be made at large scale and injected into patients-even on an out-patient basis.

Peritoneal Carcinomatosis from Colon Cancer: A Systematic Review of the Data for Cytoreduction and Intraperitoneal Chemotherapy.

A systematic review of the literature on the management of peritoneal carcinomatosis (PC) from colon cancer with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) was undertaken using OVID Medline. Forty-six relevant studies were reviewed. Mean weighted overall morbidity following CRS and IPC was 49% (range 22-76%) and mortality was 3.6% (range 0-19%). Median overall survival ranged from 15 to 63 months, and 5-year overall survival ranged from 7 to 100%. This represents an improvement over historical treatment with systemic chemotherapy alone, even in the era of modern chemotherapeutic agents. Quality of life following surgery is initially decreased but improves with time and approaches baseline. Available data appear to support the treatment of PC from colon cancer with CRS and IPC. There is a large amount of variability among studies and few high-quality studies exist. Further studies are needed to standardize techniques.

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection.

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.

Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer.

Metastatic colorectal cancer (CRC) is complex clinical challenge for which there are limited treatment options. Chemotherapy with or without surgery provides moderate improvements in overall survival and quality of life; nevertheless the 5-year survival remains below 30%. Oncolytic vaccinia virus (VV) shows strong anti-tumour activity in models of CRC, however transient delays in disease progression are insufficient to lead to long-term survival. Here we examined the efficacy of VV with oxaliplatin or SN-38 (active metabolite of irinotecan) in CRC cell lines in vitro and VV with irinotecan in an orthotopic model of metastatic CRC. Synergistic improvements in in vitro cell killing were observed in multiple cell lines. Combination therapy was well tolerated in tumour-bearing mice and the median survival was significantly increased relative to monotherapy despite a drug-dependent decrease in the mean tumour titer. Increased apoptosis following in vitro and in vivo combination therapy was observed. In vitro cell cycle analysis showed increases in S-phase cells following infection occurred in both infected and uninfected cell populations. This corresponded to a 4-fold greater increase in apoptosis in the uninfected compared to infected cells following combination therapy. Combination treatment strategies are among the best options for patients with advanced cancers. VV is currently under clinical investigation in patients with CRC and the data presented here suggest that its combination with irinotecan may provide benefit to a subset of CRC patients. Further, investigation of this combination is necessary to determine the tumour characteristics responsible for mediating synergy.

Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques.

Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.

Evidence for differential viral oncolytic efficacy in an in vitro model of epithelial ovarian cancer metastasis.

Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses-Myxoma virus, double-deleted vaccinia virus, and Maraba virus-using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis.

First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity.

Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.

Oncolytic vaccinia virus as an adjuvant treatment to cytoreductive surgery for malignant peritoneal mesothelioma.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Oncolytic viruses are a promising new therapy for cancer because of their ability to kill tumor cells with minimal toxicity to normal tissues. This experimental study aimed to examine the potential of modified vaccinia virus (VV) to treat MPM when administered alone or as an adjuvant treatment to surgery. METHODS: Two aggressive murine mesothelioma cell lines (AC29, AB12), were used. Cell viability and viral cytopathic effects were assessed using MTS and crystal violet assays. Immunocompetent mice were injected intraperitoneally with MPM cells and treated with intraperitoneal VV. Tumor-bearing mice also underwent cytoreductive surgery (CRS) followed by VV (or control) therapy. RESULTS: The cytotoxic effects of VV on MPM cell lines was significantly increased compared with the control non-cancer cell line. In both orthotopic models, VV induced tumor regression, prolonging median and long-term survival. VV treatment after incomplete CRS was not superior to VV alone; however, when mice with microscopic disease were treated with VV, further prolongation of median and long-term survivals was observed. CONCLUSIONS: VV selectively kills MPM cells in vitro and leads to improved survival and cures in immunocompetent murine models. Higher efficacy of the virus in the microscopic disease context suggests the use of the virus as an adjuvant treatment to complete surgical resection. These promising results justify further studies of VV in humans as a novel treatment for MPM.

Mucinous tumor of the appendix with limited peritoneal spread: is there a role for expectant observation?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is now the standard management for mucinous tumors of appendiceal origin at many centers. We examined the role of expectant observation (EO) in patients who had undergone an initial resection at the time of referral to our center and who had limited residual disease. METHODS: We performed a retrospective review of patients referred to Mount Sinai/Princess Margaret Hospitals, Toronto, for consideration of surgical management of peritoneal malignancy between January 1998 and December 2009. One hundred and three patients with primary mucinous appendiceal malignancy were identified. EO, consisting of regularly scheduled imaging and clinical review, was selected for asymptomatic patients with low-grade tumor and no/limited disease on imaging. Overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Management consisted of supportive care in 7 patients, systemic chemotherapy in 7, referral for CRS with HIPEC in 8, CRS without HIPEC at our center in 51, and EO in 30. In the CRS group, 5-year OS was 74 % and PFS was 56 %; both OS and PFS were predicted by extent of residual disease after cytoreduction (p = 0.014 and p = 0.011, respectively). In the EO group, 5-year OS and PFS were 95 and 82 %, respectively. Two patients in the EO group subsequently underwent CRS for progression on imaging. CONCLUSIONS: In well-selected patients who have undergone initial resection for low-grade mucinous tumor of the appendix with limited peritoneal spread, a formal program of observation can result in excellent 5-year OS and PFS. Longer-term follow-up will help define the benefits and risks of this approach.

Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) represents a significant clinical challenge for which there are few treatment options. Oncolytic viruses are ideal candidates for PC treatment because of their high tumor specificity, excellent safety profile and suitability for peritoneal delivery. Here, we described the use of vvDD-SR-RFP, a recombinant vaccinia virus, in xenograft and syngeneic models of colorectal PC. Colorectal cancer cell lines were highly susceptible to vvDD-SR-RFP replication and cytotoxicity. Intraperitoneal delivery of vvDD-SR-RFP on Day 12 to mice with colorectal carcinomatosis significantly improved survival whereas survival was not improved following virus treatment on Day 8, when tumors were smaller. Immunohistochemistry revealed early tumors had a poorly distributed network of blood vessels and lower proliferation index compared to later tumors. Virus infection was also restricted to tumor rims following Day 8 treatment, whereas it was disseminated in tumors treated on Day 12. Additionally, direct infection of tumor endothelium was observed and virus infection correlated with a loss of endothelial staining and induction of cell death. Our results demonstrate that tumor vasculature has a critical role in virus delivery and tumor response. This will have significant implications in the clinical setting, both in understanding timing of therapies and in designing combination treatment strategies.

Physicians' awareness of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer carcinomatosis.

BACKGROUND: Recent trials have shown that cytoreductive surgery and heated intraperitoneal chemotherapy (S+HIPEC) for colorectal cancer carcinomatosis (CRC-C) leads to 5-year, disease-free survival rates of more than 30%. Since these data represent a substantial change in the management of CRC-C, the objectives of this study were to determine physicians' awareness of S+HIPEC for CRC-C and physician characteristics predictive of awareness of S+HIPEC for CRC-C. METHODS: This study was a mailed, cross-sectional survey of general surgeons and medical oncologists in Ontario. RESULTS: The response rate was 44.0% (214 of 487). Most respondents were men and younger than 50 years. There was an even split between those at academic and community hospitals. Overall, 46% of respondents were aware of S+HIPEC for CRC-C, and multivariate analysis showed that there were no physician characteristics predictive of awareness of S+HIPEC for CRC-C. CONCLUSION: Physician awareness of S+HIPEC for CRC-C is low. Therefore, strategies to improve patient and physician knowledge about S+HIPEC for CRC-C are important to ensure appropriate treatment for patients.

CONTEXTE: Des essais récents ont démontré que la chirurgie de réduction tumorale combinée à la chimiothérapie intrapéritonéale hyperthermique (S+HIPEC) contre la carcinomatose du cancer colorectal (C-CCR) produit des taux de survie sans maladie de 5 ans qui dépassent 30 %. Comme ces données représentent une modification importante de la prise en charge de la C-CCR, l'étude visait à déterminer si les médecins connaissent la technique S+HIPEC contre la C-CCR et les caractéristiques des médecins qui prédisent une connaissance de la technique S+HIPEC contre la C-CCR. MÉTHODES: L'étude consistait en un sondage transversal postal mené auprès de chirurgiens généraux et de médecins oncologues de l'Ontario. RÉSULTANTS: Le taux de réponse a atteint 44,0 % (214 sur 487). La plupart des répondants étaient des hommes de moins de 50 ans. La répartition entre les hôpitaux universitaires et les hôpitaux communautaires était égale. Dans l'ensemble, 46 % des répondants connaissaient la technique S+HIPEC contre la C-CCR et une analyse à variables multiples a montré qu'il n'y avait pas de caractéristiques des médecins qui pouvaient prédire la connaissance de la technique S+HIPEC contre la C-CCR. CONCLUSIONS: Les médecins connaissent peu la technique S+HIPEC contre la C-CCR. Des stratégies visant à améliorer la connaissance de la technique S+HIPEC contre la C-CCR chez les patients et les médecins sont importantes pour assurer le traitement approprié des patients.