Sabha Ganai

Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice

Background:An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue.Methods:We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of the RecA promoter to radiation was measured using fluorometry and immunoblotting. TRAIL toxicity was determined using flow cytometry and by measuring caspase-3 activation. A syngeneic murine tumour model was used to determine bacterial accumulation and the response to expressed TRAIL.Results:After irradiation, engineered S. typhimurium secreted TRAIL, which caused caspase-3-mediated apoptosis and death in 4T1 mammary carcinoma cells in culture. Systemic injection of Salmonella and induction of TRAIL expression using 2 Gy γ-irradiation caused a significant delay in mammary tumour growth and reduced the risk of death by 76% when compared with irradiated controls. Repeated dosing with TRAIL-bearing Salmonella in conjunction with radiation improved the 30-day survival from 0 to 100%.Conclusion:These results show the pre-clinical utility of S. typhimurium as a TRAIL expression vector that effectively reduces tumour growth and extends host survival.

Local recurrence after transanal endoscopic microsurgery for rectal polyps and early cancers.

BackgroundTransanal endoscopic microsurgery (TEM) allows for local excision of rectal neoplasms with greater exposure than transanal excision and less morbidity than transabdominal approaches. This study examines the implications of the procedure with respect to predictors of recurrence.MethodsWe performed a retrospective analysis of 144 consecutive TEMs from 1993 to 2004.ResultsThe study comprises 107 patients presenting for TEM with benign disease and 32 patients with cancer. Patients had a mean age of 64 ± 14 (SD) years. TEM was performed for recurrent lesions in 17% of cases. Pathologic classification of the lesions after TEM was benign adenoma in 45%, adenoma with high-grade dysplasia (HGD) in 17%, cancer in 33%, and other in 4%. Complications occurred in 10%, and local recurrence occurred in 15% of patients. Median follow-up was 44 months, with a median time to recurrence of 14 months. Positive margins did not influence lesion recurrence. Recurrence of cancers correlated with the depth of tumor invasion (P < .05). On multivariate analysis, independent predictors of recurrence were lesion size and the presence of HGD within adenomas (P < .05). Five-year neoplastic recurrence probabilities were 11% for benign adenomas, 35% for adenomas with HGD, and 20% for cancers (P = .31); invasive recurrence probabilities were 0% for benign adenomas, 15% for adenomas with HGD, and 13% for cancers (P < .05).ConclusionsClose endoscopic follow-up is warranted after TEM for both benign and malignant disease, with special attention to lesions with HGD. TEM can be performed safely for early rectal cancer with careful patient selection.

In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis

Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis, the average distance of bacteria from tumor vasculature and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 h, and colonization was determined to delay tumor growth by 48 h. From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm. After 48 h, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 h, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

Using GIS for spatial analysis of rectal lesions in the human body

BackgroundGeographic Information Systems (GIS) have been used in a wide variety of applications to integrate data and explore the spatial relationship of geographic features. Traditionally this has referred to features on the surface of the earth. However, it is possible to apply GIS in medicine, at the scale of the human body, to visualize and analyze anatomic and clinical features.In the present study we used GIS to examine the findings of transanal endoscopic microsurgery (TEM), a minimally-invasive procedure to locate and remove both benign and cancerous lesions of the rectum. Our purpose was to determine whether anatomic features of the human rectum and clinical findings at the time of surgery could be rendered in a GIS and spatially analyzed for their relationship to clinical outcomes.ResultsMaps of rectal topology were developed in two and three dimensions. These maps highlight anatomic features of the rectum and the location of lesions found on TEM. Spatial analysis demonstrated a significant relationship between anatomic location of the lesion and procedural failure.ConclusionThis study demonstrates the feasibility of rendering anatomical locations and clinical events in a GIS and its value in clinical research. This allows the visualization and spatial analysis of clinical and pathologic features, increasing our awareness of the relationship between anatomic features and clinical outcomes as well as enhancing our understanding and management of this disease process.

Mapping the rectum: spatial analysis of transanal endoscopic microsurgical outcomes using GIS technology.

Transanal endoscopic microsurgery (TEM) is a technically challenging procedure hindered by rectal anatomic constraints. To study the relationship of lesion position with performance of TEM, a novel approach of spatial analysis using Geographic Information Systems (GIS) was developed. A retrospective review was conducted on 144 consecutive TEMs, analyzing clinical, pathologic, and positional characteristics. Two- and three-dimensional maps of rectal topology were developed. GIS was used for spatial analysis, accounting for regional position and clustering of lesions. Lesions were located at a mean distance of 9.3 ± 4.9 (SD) cm from the dentate line, with an average size of 3.1 ± 1.4 cm. Proximal regions were associated with prolonged operative time. Regions between the rectosigmoid junction and the peritoneal reflection were associated with peritoneal breach. In spatial regression analysis, regional characteristics that were significantly associated with operative time included distance, presence of cancers, and positive margins; peritoneal breach was significantly associated with lesion size and location; conversions were associated with distance (P < 0.05). Specific knowledge of lesion size and location in the context of anatomic relationships is important for optimizing operative intervention. GIS provides a valuable tool in organizing spatial information and can be extended into clinical research topics involving the distinction of anatomic relationships.

National Trends in General Surgery Resident Exposure to Complex Oncology-Relevant Cases

OBJECTIVE To evaluate trends in surgical resident exposure to complex oncologic procedures in order to determine whether additional fellowship training is necessary. DESIGN An observational study of national Accreditation Council for Graduate Medical Education case log statistical reports was conducted to determine the average number of cases for selected oncology-relevant procedures completed during training. Linear regression and Cusick trend tests were used to assess temporal trends with the null hypothesis assuming an estimated slope of zero. Instrumental variable estimation was used to study the effect of duty-hour restrictions on oncologic cases per year. SETTING United States general surgery residency training programs. PARTICIPANTS Graduating surgical residents completing their training between 2000 and 2016. RESULTS Across the study interval, mean case volume was 950.6 ± 29.7 (standard deviation) cases with 38.9 ± 3.1 complex oncologic cases per graduating resident. Decreasing trends were noted for average exposure to lymphadenectomies (-7.8 cases/decade; 95% confidence interval [CI] -8.8 to -6.8) and low rectal procedures (-0.9 cases/decade; 95% CI -1.2 to -0.6). There was no clinically important change in complex soft-tissue resections and foregut cases. A significant increase was seen in number of hepatopancreaticobiliary procedures (+3.9 cases/decade; 95% CI 3.1-4.7). Using instrumental variable estimation, there was a modest decline in cancer-relevant cases by 5.0 cases/decade (95% CI 4.5-5.6), while there was an increase in 38.5 total cases/decade (95% CI 10.4-66.7) associated with duty-hour restrictions. CONCLUSIONS Case numbers for several complex oncologic procedures remain low, justifying a need for further fellowship training depending on individual resident experience.