Nikolai Bildzukewicz

Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.

736 Initial Experience With an Innovative Endoscopic Clipping System

There are few options for the treatment of fistulas, leaks, and perforations endoscopically. Here we describe our experience with an endoscopic clipping system. A retrospective review of all cases using the Over-The-Scope-Clip system (Ovesco Endoscopy AG, Tuebingen, Germany) was performed. The system was utilized in ten patients with gastrointestinal surgical complications. Four patients had gastric leaks following sleeve gastrectomy, one had a post-operative colonic leak, two had gastro-gastric fistulas following gastric bypass, and three had esophageal perforations. Two leak patients had complete resolution, one had a contained leak following clip placement that was clinically insignificant, and the fourth patient had a persistent leak despite two clipping procedures. Two patients had gastro-gastric fistulas following roux-en-y gastric bypass surgery and, while they both had initial success, the fistulas recurred. One patient presented with anastomotic leak following colon resection but the system was unable to reach the treatment site. Three patients were successfully treated for esophageal perforation. There were no complications. This over-the-scope endoscopic clip system is simple to use, safe, and successful in approximating tissue to treat traditionally difficult surgical complications. Further experience and longer follow-up are needed to assess its indications as related to defect size and location.

Gastric cancer in the young: An advanced disease with poor prognostic features

Gastric cancer in young patients is rare. We analyzed the clinicopathological features and prognosis of early‐onset gastric carcinoma.

Appendicitis Following Virtual Colonoscopy: a Case Report

Acute appendicitis is one of the most commonly treated surgical emergencies in the USA today, occurring in about 7 % of the population. Appendicitis is generally caused by obstruction of the appendiceal lumen. Common causes of this obstruction include lymphoid hyperplasia as well as obstruction from stool or fecaliths. Rare causes of obstruction include parasitic infections, foreign bodies, and neoplasms. Furthermore, appendicitis is a rare but known complication of optical colonoscopy. The true incidence of appendicitis following optical colonoscopy is unknown; there are only 12 cases reported in the literature. Colonoscopy remains the gold standard screening exam for colorectal cancer, but recently, optical colonoscopy has been challenged by advances in virtual colonoscopy (or CT colonography). While thought to be safer, virtual colonoscopy (VC) does share some of the same potential complications as optical colonoscopy. The most concerning risk for both optical and VC is colonic perforation. A thorough review of the literature was performed, and unlike optical colonoscopy, there are no reports of acute appendicitis following VC. Therefore, we present the first case of acute appendicitis following VC.

Lumbar, Pelvic, and Uncommon Hernias

Abstract This chapter discusses less common hernias of the abdominal wall and pelvis, which rarely come to the attention of a general surgeon. These include hernias of the lumbar triangles in the lower back, namely the superior lumbar hernia (or Grynfelt-Lesshaft hernia) and inferior lumbar hernia (or Petit hernia). Obturator hernias, characterized by the classic Howship-Romberg sign, will also be discussed. In addition, the extremely rare sciatic and perineal hernias will be reviewed.

Routine esophageal manometry is not useful in patients with normal videoesophagram

BackgroundVideoesophagram (VEG) and esophageal manometry (EM) are components of the preoperative evaluation for foregut surgery. EM is able to identify motility disorders and diminished contractility that may alter surgical planning. However, there are no clearly defined criteria to guide this. Reliable manometry is not always easily obtained, and therefore its necessity in routine preoperative evaluation is unclear. We hypothesized that if a patient has normal videoesophagram, manometry does not reveal clinically significant esophageal dysfunction.MethodsWe reviewed patients who underwent protocolized videoesophagram and manometry at our institution. Measures of esophageal motility including the mean distal contractile integral (DCI), mean wave amplitude (MWA), and percent of peristaltic swallows (PPS) were analyzed. The Chicago Classification was used for diagnostic criteria of motility disorders. Normal VEG was defined as stasis of liquid barium on less than three of five swallows.ResultsThere were 418 patients included. 231 patients (55%) had a normal VEG, and 187 patients (45%) had an abnormal VEG. In the normal VEG group, only 2/231 (0.9%) patients had both abnormal DCI and PPS, 1/231 (0.4%) patients had both abnormal DCI and MWA and no patients had both abnormal MWA and PPS. There were no patients with achalasia or absent contractility and 1 patient with ineffective esophageal motility (IEM) in the normal VEG group. This was significantly different from the abnormal VEG group which included 4 patients with achalasia, 1 with absent contractility and 22 with IEM (p < 0.0001). The negative predictive value of VEG was 99.6% and the sensitivity was 96.4%.ConclusionsA normal videoesophagram reliably excluded the presence of clinically significant esophageal dysmotility that would alter surgical planning. Routine manometry is not warranted in patients with normal videoesophagram, and should be reserved for patients with abnormal VEG.

Mo1107 Differences of LES Impedance Planimetry in Laparoscopic Sleeve Gastrectomy Versus Laparoscopic Conversion From Gastric Banding to Sleeve Gastrectomy

Background:Among the extra-esophagealmanifestations of GERD, dental erosion is currently considered one of the most frequent. These dental erosions have a characteristic localization and may sometimes be the first symptom of the GERD. Wireless nasopharyngeal pH metry (ResTech pH probe) is a minimally invasive device for detection of oropharyngeal acid reflux.Aim: To ascertain whether adult patients with dental erosions (DE) have a higher incidence of reflux into the nasopharynx compared with controls using the ResTech phH probe.Materials and methods: A cross-sectional study was conducted among patients whom attend to the dental service at the Health Services Research Center in our institution. Dental erosion was classified by means of severity and anatomic location, according to the Eccles and Jenkins dental (0=no erosion present [control group];grade 1=loss of surface detail, with change confined to the enamel; grade 2=exposure of dentin affecting less than one third of the crown; and 3=exposure of dentin affecting one third or more of the crown). In all subjects eating habits and dental medical history (CPO index) was obtained and GERD symptoms were assessed using the GERD-Q questionnaire and the ISR index. In all subjects a Restech Dx-pH was performed and separate pH thresholds of 0.05). DE subjects had a higher prevalence of positive GERD-Q questionnaires (92% vs 42%, p=0.002) and also higher scores (45 vs 6, p=0.01). DE subjects had more number of reflux episodes at pH 5.0 and 4.5 compared to HC (p<0.05, Figure) . A positive correlation was found between the # of reflux episodes (pH 5.0 and 4.5) with the GERD-Q score (p=0.50 and 0.57). Conclusion: A relationship between DE and GERD was established by precise and accurate measurement of pH changes in the oral cavity using ResTech pH metry. This method could be an ideal tool for evaluation of GRED as cause of DE.