Sumana Narayanan

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Abstract Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.

Outcomes of microwave ablation for colorectal cancer liver metastases: A single center experience

Surgical management of colorectal cancer liver metastases continues to evolve to optimize oncologic outcomes while maximizing parenchymal preservation. Long‐term data after intraoperative microwave ablation are limited. This study investigates outcomes and patterns of recurrence in patients who underwent intraoperative microwave ablation.

Treatment of Diaphragmatic Hernia Occurring After Transhiatal Esophagectomy

BackgroundPostesophagectomy diaphragmatic hernia (DH) is an uncommon problem but an important one to recognize and treat because of the risk of significant complications such as incarceration and strangulation. Diaphragmatic hernia appears to occur more frequently following transhiatal esophagectomy (THE) than after transthoracic procedures, likely because of the enlargement of the diaphragmatic hiatus required to perform THE.MethodsAfter 199 consecutive esophagectomies were performed at Rutgers Robert Wood Johnson University Hospital between January 2000 and June 2013, ten patients were identified with DH; all underwent diaphragmatic hernia repair (DHR). All patients who underwent esophagectomy during this time period were cataloged in a prospectively maintained database that was then retrospectively reviewed. All DH were repaired using a novel biologic plug mesh technique.ResultsTen esophagectomy patients developed DH; nine post-THE and one post-McKeown esophagectomy. One patient was excluded from analysis because of atypical presentation. Demographic data were similar between esophagectomy patients who developed DH and those who did not. Administration of neoadjuvant chemoradiation correlated with development of DH, but did not reach statistical significance. Complications directly related to DHR were few and mostly infectious, including empyema and pneumonia, and were more likely to occur in those who presented with acute obstruction. One patient presented with dysphagia post repair.ConclusionsDiaphragmatic hernia development post esophagectomy is an uncommon complication, but can have devastating results when there is bowel compromise. Repair by plugging the diaphragmatic hiatus with a biologic mesh is a safe and effective method for closing the defect and results in few complications.

Genomic characterization of colitis-associated colorectal cancer

BackgroundInflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, idiopathic, repeated inflammatory disease. Colorectal cancer (CRC) that develops in patients with IBD is known as colitis-associated colorectal cancer (CAC), but the underlying carcinogenic mechanism remains unclear. Genomic analysis of sporadic CRC has been well described based on next-generation sequencing (NGS) data. Using NGS, we compared all exons of 415 cancer-associated genes in patients in Japan and the USA who had CRC and found similar genomic alteration patterns among the two populations. However, genomic analysis of CAC has not been thoroughly investigated.Main bodyThe molecular pathogenesis of CAC shares many features with sporadic CRC, but there are distinct variations in the time and frequency of some alterations. Gene alterations in CAC are gradually being elucidated using genomic sequencing analyses. Some studies have shown that gene alteration patterns differ between UC and CD. The carcinogenesis of CAC depends on unique environmental, genetic, and immunological factors.ConclusionsIn this review, we have discussed the differences in genomic alterations between sporadic CRC and CAC. NGS in patients with IBD has the potential to detect early CAC and to suggest therapeutic targets.

ASO Author Reflections: “From Computer to Bedside”: A New Translational Approach to Immunogenomics

Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Surgical Oncology, Mount Sinai Medical Center, Miami, FL; Department of Surgery, The State University of New York Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY; Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan; Department of Surgery, Yokohama City University, Yokohama, Japan; Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan