Jonathan Hernandez

Survival After Pancreaticoduodenectomy is not Improved by Extending Resections to Achieve Negative Margins

Objective:This study was undertaken to determine the survival benefit of extending resections to obtain microscopically negative margins after positive intraoperative frozen sections. Summary Background Data:The impact of residual microscopic disease after pancreaticoduodenectomy is currently a point of controversy. It is, however, generally believed that microscopically positive margins negatively impact survival and this may be improved by ultimately achieving negative margins. Methods:Since 1995, patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma have been prospectively followed. Margin status has been codified as macro/microscopically negative (R0) or macroscopically negative/microscopically positive (R1). The impact of margin status on survival was evaluated utilizing survival curve analysis. Data are presented as median, mean ± SD where appropriate. Results:For pancreatic adenocarcinoma, 202 patients underwent pancreaticoduodenectomy. R0 resections were achieved in 158 patients, 17 of whom required extended resections to achieve complete tumor extirpation after an initially positive intraoperative frozen section (R1 → R0). R1 resections were undertaken in 44 patients. Median survival for patients undergoing R0 resections was 21 months, 26 ± 23.4 months versus 13 months, 17 ± 21.0 months for patients undergoing R1 resections (P = 0.02). Median survival for patients undergoing R1 → R0 resections was 11 months, 16 ± 17.3, (P = 0.001). Margin status had a significant correlation with “N” stage and AJCC stage but not “T” stage. Conclusion:Survival after pancreaticoduodenectomy is not improved by extending pancreatic resections to achieve negative margins after initially positive intraoperative frozen sections. Tumor-specific factors beyond the presence of disease at a surgical margin are responsible for the abbreviated survival seen in patients undergoing R1 resections.

The Learning Curve of Laparoendoscopic Single-Site (LESS) Cholecystectomy: Definable, Short, and Safe

BACKGROUND The applications of laparoendoscopic single-site (LESS) surgery, including cholecystectomy, are occurring quickly, although little is generally known about issues associated with the learning curve of this new technique including operative time, conversion rates, and safety. STUDY DESIGN We prospectively followed all patients undergoing LESS cholecystectomy, and compared operations undertaken at our institutions in cohorts of 25 patients with respect to operative times, conversion rates, and complications. RESULTS One-hundred fifty patients of mean age 46 years underwent LESS cholecystectomy. No significant differences in operative times were demonstrable between any of the 25-patient cohorts operated on at our institution. A significant reduction in operative times (p < 0.001) after completion of 75 LESS procedures was, however, identified with the experience of a single surgeon. No significant reduction in the number of procedures requiring an additional trocar(s) or conversion to open operations was observed after completion of 25 LESS cholecystectomies. Complication rates were low, and not significantly different between any 25-patient cohorts. CONCLUSIONS For surgeons proficient with multi-incision laparoscopic cholecystectomy, the learning curve for LESS cholecystectomy begins near proficiency. Operative complications and conversions were infrequent and unchanged across successive 25-patient cohorts, and were similar to those reported for multi-incision laparoscopic cholecystectomy after the learning curve.

Consensus statement of the consortium for LESS cholecystectomy

Many surgeons attempting Laparo-Endoscopic Single Site (LESS) cholecystectomy have found the operation difficult, which is inconsistent with our experience. This article is an attempt to promote a standardized approach that we feel surgeons with laparoscopic skills can perform safely and efficiently. This is a four-trocar approach consistent with the four incisions utilized in conventional laparoscopic cholecystectomy. After administration of general anesthesia, marcaine is injected at the umbilicus and a 12-mm vertical incision is made through the already existing anatomical scar of the umbilicus. A single four-trocar port is inserted. A 5-mm deflectable-tip laparoscope is placed through the trocar at the 8 o’clock position, a bariatric length rigid grasper is inserted through the trocar at the 4 o’clock position (to grasp the fundus), and a rigid bent grasper is placed through the 10-mm port (to grasp the infundibulum). This arrangement of the instruments promotes minimal internal and external instrument clashing with simultaneous optimization of the operative view. This orientation allows retraction of the gallbladder in a cephalad and lateral direction, development of a window between the gallbladder and the liver which promotes the “critical view” of the cystic duct and artery, and provides triangulation with excellent visualization of the operative field. The operation is concluded with diaphragmatic irrigation of marcaine solution to minimize postoperative pain. Standardization of LESS cholecystectomy will speed adoption, reduce intraoperative complications, and improve the efficiency and safety of the approach.

Gene expression profiling of colorectal mucinous adenocarcinomas

PURPOSE: Although mucinous adenocarcinomas represent 6% to 19% of all colorectal adenocarcinomas, little is known about the genome-wide alterations associated with this malignancy. We have sought to characterize both the gene expression profiles of mucinous adenocarcinomas and their clinicopathologic features. METHODS: Tumors from 171 patients with primary colorectal cancer were profiled using the Affymetrix HG-U133Plus 2.0 GeneChip with characterization of clinicopathologic data. Gene ontology software was used to identify altered biologic pathways. RESULTS: Twenty (11.7%) mucinous adenocarcinomas and 151 (89.3%) nonmucinous adenocarcinomas were identified. Mucinous adenocarcinomas were more likely to be diagnosed with lymph node (LN) metastases (75% vs 51%, P = .04) and at a more advanced stage (85% vs 54%, P = .006) but long-term survival (5-y survival 58.9% vs 58.7%, P = NS) was similar. Mucinous adenocarcinomas displayed 182 upregulated and 135 downregulated genes. The most upregulated genes included those involved in cellular differentiation and mucin metabolism (eg, AQP3 + 4.6, MUC5AC +4.2, MUC2 + 2.8). Altered biologic pathways included those associated with mucin substrate metabolism (P = .002 and .02), amino acid metabolism (P = .02), and the mitogen-activated protein kinase cascade (P = .02). DISCUSSION: Using gene expression profiling of mucinous adenocarcinomas, we have identified the differential upregulation of genes involved in differentiation and mucin metabolism, as well as specific biologic pathways. These findings suggest that mucinous adenocarcinomas represent a genetically distinct variant of colorectal adencarcinoma and have implications for the development of targeted therapies.

Surgery residency training programmes have greater impact on outcomes after pancreaticoduodenectomy than hospital volume or surgeon frequency

BACKGROUND Hospital volume of pancreaticoduodenectomy (PD) and surgeon frequency of PD have been shown to impact outcomes. The impact of surgery residency training programmes after PD is unknown. This study was undertaken to determine the impact of surgery training programmes on outcomes after PD, as well as their importance relative to hospital volume and surgeon frequency of PD. METHODS The State of Florida Agency for Healthcare Administration Database was queried for patients undergoing PD during 2002-2007. Measures of outcome were compared for patients undergoing PD at centres with vs. without surgery residency training programmes. RESULTS A total of 2345 PDs were identified, of which 1478 (63%) were undertaken at training centres and 867 (37%) were performed at non-training centres. Patients undergoing PD at training centres had shorter lengths of stay, lower hospital charges and lower in-hospital mortality. Relative to surgeon frequency of PD, training centres had a greater favourable impact on hospital length of stay, hospital charges and in-hospital mortality (P < 0.001 for each, ancova). Relative to hospital volume of PDs undertaken, training centres had a greater impact on hospital charges (P < 0.001, ancova). CONCLUSIONS Surgery residency training programmes have a favourable effect on outcomes following PD and their impact on outcome is greater than the impact of hospital volume or surgeon frequency of PD.

Surgeons Can Favorably Influence Career Choices and Goals for Students Interested in Careers in Medicine

BACKGROUND This study was undertaken to determine the impact of an academic summer research, shadowing, and mentorship program on students interested in medicine and surgery. STUDY DESIGN Forty-four (92%) of 48 participants of a summer research, shadowing, and mentorship program returned blinded questionnaires that focused on the programs impact on their scholarly skills, career choices, and goals. The program interfaced academic surgeons with students interested in careers in medicine and enabled students to participate in research projects, attend daily lectures, and shadow physicians in the operating room, clinic, and hospital. Proficiency in scholarly skills, before and after the program, was scored by the participants using a Likert scale (0 = none to 10 = proficient). RESULTS Ninety-three percent of participants were in or had completed college; only 7% had advanced degrees. With the program, proficiency in all categories assessed improved considerably, including medical terminology, abstract writing, statistical analysis, graph and table construction, article writing, and video production. During the last 5 years, participants coauthored 112 national presentations (29 video presentations), 46 published abstracts, and 57 peer-reviewed published articles. Ninety-two percent developed more favorable opinions of a career in medicine; 8% believed the experience deterred them from a career in medicine because of lifestyle and studious demands. Seventy-seven percent believed the program promoted a career in surgery; 82% believed it elevated their goals to become leaders in American medicine. CONCLUSIONS Shadowing opportunities, mentoring, and didactic teaching of scholarly skills for college and graduate students foster academic productivity and elevation of career goals. Academic surgeons can favorably influence career choices and goals for students interested in careers in medicine and surgery.

HPV L1 capsid protein detection and progression of anal squamous neoplasia.

The progression of cervical intraepithelial lesions to invasive cancer is associated with corresponding reductions in human papillomavirus (HPV) L1 capsid antigen (L1) expression. We sought to determine whether a similar loss of L1 occurs during anal carcinogenesis using immunohistochemistry on paraffin-embedded sections as well as INNO-LiPA HPV Genotyping (Innogenetics, Gent, Belgium) technology to determine HPV infection status. We analyzed 31 squamous cell carcinomas (SCCs), 26 SCCs in situ (SCC-IS), and 11 normal anal mucosae from 36 patients. High-risk HPV subtypes were detected in all patients. L1 nuclear staining was identified in 38% of SCC-IS; however, there was no detection in normal anal mucosae, SCC, or recurrent SCC. Of those SCC-IS associated with a concomitant invasive SCC, only 15% demonstrated nuclear L1 expression as compared to 62% of isolated SCC-IS (P = .02). Nuclear expression of L1 is lost in the progression of anal SCC-IS to SCC and may serve as a possible prognostic marker of enhanced malignant potential.

TNFα gene delivery therapy for solid tumors

Importance of the field: Multimodality therapy, including adjuvant and neoadjuvant chemotherapy and radiotherapy, is now the mainstay of treatment for the majority of non-hematologic cancers. Host toxicity can, however, be significant, which may contribute to local and/or systemic failures. Novel adjunctive treatments that can limit systemic exposure while synergizing with standard therapy hold promise in the fight against an increasing number of cancers. Areas covered in this review: We discuss a TNFα gene delivery system used to generate high levels of intratumoral TNFα, while limiting systemic exposure. The delivery system utilizes a replication-deficient adenoviral vector. When injected intratumorally and activated by external beam radiation, infected cells synthesize and locally secrete large amounts of TNFα. What the reader will gain: This review will provide the reader with a thorough understanding of the gene-based TNFα delivery system with special emphasis on product characteristics, mechanisms of action, clinical efficacy, safety and tolerability. Take home message: The TNFα gene delivery system holds promise as an adjunctive agent for improved local control and increasing resectability rates for many solid tumors. The completion of several ongoing randomized trials will help to better define the role for TNFα gene delivery therapy in the treatment of solid tumors.

The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer

HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.

Medical comorbidities should not deter the application of laparoscopic fundoplication.

IntroductionLaparoscopic Nissen fundoplication offers significant improvement in gastroesophageal reflux disease (GERD) symptom severity and frequency. This study was undertaken to determine the impact of preoperative medical comorbidities on the outcome and satisfaction of patients undergoing fundoplication for GERD.MethodsPrior to fundoplication, patients underwent esophageal motility testing and 24-h pH monitoring. Before and after fundoplication, the frequency and severity of reflux symptoms were scored using a Likert scale. Medical comorbidities were classified by organ systems, and patients were assigned points corresponding to the number of medical comorbidities they had. In addition, all patients were assigned Charlson comorbidity index (CCI) scores according to the medical comorbidities they had. A medical comorbidity was defined as a preexisting medical condition, not related to GERD, for which the patient was receiving treatment. Analyses were then conducted to determine the impact of medical comorbidities as well as CCI score on overall outcome, symptom improvement, and satisfaction.ResultsSix hundred and ninety-six patients underwent fundoplication: 538 patients had no medical comorbidities and 158 patients had one or more medical comorbidities. Preoperatively, there were no differences in symptom severity and frequency scores between patients with or without medical comorbidities. Postoperatively, all patients had improvement in their symptom severity and frequency scores. There were no differences in postoperative symptom scores between the patients with medical comorbidities and those without. The majority of patients were satisfied with their overall outcome; there was no relationship between the number of medical comorbidities and satisfaction scores. These findings were mirrored when patients’ CCI scores were compared with satisfaction, overall outcome, and symptom improvement.ConclusionThese results promote further application of laparoscopic Nissen fundoplication, even for patients with medical comorbidities.