Reconstruction after partial duodenectomy using a Roux-en-Y lateral duodenojejunostomy: a single center retrospective analysis

Oncologic resections of the second and third portions of the duodenum (D2 and D3) via partial duodenectomy can pose a challenging clinical problem. The duodenum must be repaired primarily or reconstructed. We have adopted a method of reconstruction using a Roux-en-Y duodenojejunostomy (D-J) in patients with extensive duodenal wall loss. We report our results in the first series of these cases. A retrospective review of patients who underwent post partial duodenectomy with reconstruction between June 2004 and March 2014 was performed. Five patients underwent partial duodenectomy with reconstruction. Two had resection for extrinsic tumors (colonic adenocarcinoma). Three had intrinsic duodenal tumors (one tubular adenoma, one adenocarcinoma and one gastrointestinal stromal tumor). All patients were reconstructed via retrocolic Roux-en-Y D-J. Mean estimated blood loss was 470 mL with median length of stay of 11 days. Post-operative complications included three intra-abdominal abscesses, one superficial wound infection and one gastrointestinal bleed. There were no anastomotic leaks, injuries to the ampulla of Vater or mortalities. In conclusion, partial duodenectomy of lateral D2/D3 with Roux-en-Y D-J is a relatively safe and effective alternative to partial duodenectomy with primary repair or pancreaticoduodenectomy for certain tumors of the duodenum

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

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

Genetic Drivers of Ileal Neuroendocrine Tumors

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes

Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as “reactivating” mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells’ response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials

Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer

Tumor protein p53 (TP53) is the most commonly mutated gene in human cancer. The majority of mutations are missense, and generate a defective protein that is druggable. Yet, for decades, the small-molecule restoration of wild-type (WT) p53 function in mutant p53 tumors (so-called p53 mutant ‘reactivation’) has been elusive to researchers. The p53 protein requires the binding of a single zinc ion for proper folding, and impairing zinc binding is a major mechanism for loss of function in missense mutant p53. Here, we describe recent work defining a new class of drugs termed zinc metallochaperones that restore WT p53 structure and function by restoring Zn2+ to Zn2+-deficient mutant p53

Repair of a Post-Hepatectomy Posterior Sectoral Duct Injury Secondary to Anomalous Bile Duct Anatomy Using a Novel Combined Surgical-Interventional Radiologic Approach

A 64-year-old woman with a completely transected posterior sectoral duct following extended hepatectomy underwent a combined operative procedure with interventional radiology and surgery to restore biliary-enteric drainage. The anterior and posterior sectoral ducts were identified, and catheters were inserted into both systems. The posterior sectoral catheter was placed intraoperatively through a preoperatively placed sheath, and a new tunnel was created through the regenerated liver surface. Biliary-enteric anastomoses were created over the stents

Does Major Pancreatic Surgery Have Utility in Nonagenarians with Pancreas Cancer?

This study aims to define the role of surgery and assess different therapies for nonagenarians with localized, nonmetastatic pancreatic adenocarcinoma (PDAC). The National Cancer Database (NCDB) was queried for patients ≥ 90 years of age with nonmetastatic, localized PDAC from 2004-2016. Postoperative mortality was assessed at 30 and 90 days in patients receiving pancreatoduodenectomy or total pancreatectomy. Overall survival (OS) was compared between three treatment groups: surgery alone, chemotherapy alone, and chemoradiation (chemoRT) alone. Of 380,524 patients with PDAC, 98 patients ≥ 90 years of age underwent curative-intent resection; 55% were female and 75% had a Charlson-Deyo comorbidity score of 0. A total of 17% received postoperative chemotherapy, 51.1% had poorly differentiated tumors with a median tumor size of 3 cm, 55.1% had positive lymph nodes, and 19.4% had positive resection margins. Postoperative median length of stay was 11 days. Postoperative 30- and 90-day mortality was 10.0% and 18.9%, respectively. Median OS for the surgery alone group was 11.6 months compared with 20.4 months in those receiving adjuvant therapy (p = 0.01). Among nonoperative PDAC patients, median OS in patients receiving chemotherapy only (n = 207) was 7.2 months, while chemoRT only (n = 100) was similar to surgery only (11 versus 11.6 months, p = 0.97). Even in well-selected nonagenarians, pancreatoduodenectomy or total pancreatectomy carries a high mortality rate. While adjuvant therapy after resection provides the best survival, it is seldom achieved, and chemoRT alone affords identical survival statistics as surgery alone. These data suggest it is reasonable to consider chemoRT as initial therapy, then reassess candidacy for resection if performance status allows