Scott T. Kelley

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

A Gene Expression Model of Intrinsic Tumor Radiosensitivity: Prediction of Response and Prognosis After Chemoradiation

PURPOSE Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. METHODS AND MATERIALS Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). RESULTS Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). CONCLUSIONS We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Dedifferentiation Precedes Invasion in the Progression from Barrett's Metaplasia to Esophageal Adenocarcinoma

Purpose: Adenocarcinoma arises in Barretts esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barretts epithelium. Experimental Design: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barretts epithelia from which three of the cancers had arisen. Pooled samples from the Barretts epithelia of six patients without cancer or dysplasia served as a reference. Results: Barretts epithelia from which cancer had arisen differed from the reference Barretts epithelia primarily by underexpression of genes, many of which function in governing cell differentiation. These changes in gene expression were found even in those specimens of Barretts epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barretts epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barretts epithelium differed from cancers that had arisen from a Barretts epithelium by having an even greater number of these overexpressed genes. Conclusions: Histologic progression from Barretts epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barretts epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.

Neoadjuvant chemoradiotherapy is not associated with a higher complication rate vs. surgery alone in patients undergoing esophagectomy.

Recent studies have claimed a higher rate of perioperative complications related to the use of neoadjuvant chemoradiotherapy in the treatment of esophageal cancer. We tested the hypothesis that neoadjuvant chemoradiotherapy has no significant effect on the perioperative complication rate. Data on 155 patients with esophageal carcinoma treated between 1996 and 2001 were collected in a prospective database. This included 61 patients (40%) treated with neoadjuvant chemoradiotherapy (group I) and 94 patients (60%) who underwent esophagectomy alone (group II). Neoadjuvant therapy consisted of two courses of cisplatinum and continuous-infusion 5-fluorouracil with radiation followed by esophagectomy. Ivor-Lewis esophagectomy was performed in 146 (94%) and a transhiatal resection in nine (6%). The two groups (I vs. II) were comparable in terms of age (61.3±11 years vs. 64.8 ±11 years), diagnosis (adenocarcinoma: 82% vs. 83%; squamous cell carcinoma:11% vs. 16%), and stage (stage 0 to I: 39% vs. 38%; stage II: 25% vs. 34%; stage III: 30% vs. 24%; and stage IV: 6% vs. 4%). The neoadjuvant group had 23 complete responses, 11 partial responses, and 27 nonresponses. There were 39 complications (25.1%) for the cohort, which included three deaths (1.9%) and four anastomotic leaks (2.6%) demonstrated by Gastrografin swallow (1 in group I vs. 3 in group II. Only one leak required reoperation (group II); all others responded to conservative treatment. Group I had 14 complications (22.9%) vs. 25 (26.5%) in group II (P = NS). Groups were comparable with respect to the rate of pulmonary events (4.9% vs. 6.3 %), arrhythmias (6.5% vs. 8.5%), and stricture formation (6.5% vs. 7.4%). Neoadjuvant chemoradiotherapy in patients with esophageal cancer was not associated with increased perioperative morbidity or mortality. Complete response to chemoradiotherapy also did not affect the complication rate (26% vs. 22%).

Management of persistent gastroesophageal anastomotic strictures with removable self-expandable polyester silicon-covered (Polyflex) stents: an alternative to serial dilation.

BACKGROUND A benign gastroesophageal anastomotic stricture occurs in up to 42% of patients after transhiatal esophagectomy for esophageal cancer. Management of anastomotic strictures may require extended periods of serial endoscopic dilation, with significant risk, cost, and inconvenience for the patient. OBJECTIVE To determine if placement of removable self-expandable polyester silicon-covered (Polyflex) stents (SEPSs) prolonged the interval between endoscopic interventions in the management of persistent anastomotic stricture. DESIGN Retrospective cohort study. SETTING National Cancer Institute designated comprehensive cancer center. PATIENTS Eight patients after a transhiatal esophagectomy referred for management of benign persistent anastomotic strictures. INTERVENTIONS Serial balloon and bougie dilations and SEPS placement. MAIN OUTCOME MEASUREMENT The interval between endoscopic interventions and the number of endoscopic interventions before and after SEPS placement. RESULTS Over a 365-day period, 13 SEPS were placed in 8 patients with benign persistent anastomotic strictures after a transhiatal esophagectomy. A SEPS placement delayed the interval between endoscopic interventions from a mean of 7 days before stent insertion to 62 days after insertion (P < .008). The median number of preinsertion interventions was 4 and was reduced to 1 after insertion (P < .005). LIMITATION The small number of patients. CONCLUSIONS A SEPS placement did not result in stricture resolution or stabilization after SEPS removal. The SEPS migration rate was much higher in our patients with postesophagectomy anastomotic strictures than previously reported for other types of strictures. However, a SEPS placement did significantly delay the interval between endoscopic interventions in patients with persistent gastroesophageal anastomotic strictures after transhiatal esophagectomy. SEPS placement should be considered as an alternative to continued serial dilation in patients with persistent anastomotic strictures after transhiatal esophagectomy.

Are patients with esophageal cancer who become PET negative after neoadjuvant chemoradiation free of cancer

BACKGROUND Esophageal cancer continues to increase in incidence. Many patients are presenting with stage II or greater disease and proceeding to neoadjuvant chemoradiation therapy before resection. Approximately 30% of patients will achieve a complete response and might not benefit from proceeding to resection. This study will examine the ability of PET to predict patients with a complete pathologic response. STUDY DESIGN A query of our IRB-approved esophageal database revealed 81 patients who underwent a pre- and postchemoradiation PET scan and then proceeded to esophageal resection. Statistical analysis was performed to determine the ability of PET to predict a complete pathologic response. RESULTS When comparing posttherapy PET with final pathology, it was determined that PET could not consistently differentiate a complete pathologic response from patients who still had persistent disease. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 61.8%, 43.8%, 70%, 35%, and 56%, respectively, for patients with a complete PET response after neoadjuvant therapy. CONCLUSIONS A complete PET response after neoadjuvant chemoradiation is not substantially predictive of a complete pathologic response. Patients should still be referred for resection unless distant metastases are identified.

Somatostatin receptor profiling in hepatic metastases from small intestinal and pancreatic neuroendocrine neoplasms : Immunohistochemical approach with potential clinical utility

BACKGROUND The expression of somatostatin receptors (SSTRs) on endocrine tumor (ET) cells forms the basis for somatostatin analog treatment of patients with SSTR-positive, hormonally active ETs. In patients with SSTR-negative ETs, the clinical response is generally absent or suboptimal, while nonfunctioning ETs with SSTR positivity show a variable response to such therapy. METHODS We retrospectively studied SSTR subtype expression in hepatic metastases from 14 adult patients with primary endocrine carcinomas (ECAs) of the small intestine and pancreas and compared SSTR subtype expression among the primary and metastatic ECAs. Polyclonal antibodies against the 5 SSTR subtypes were used on formalin-fixed, paraffin sections from each primary and metastatic ECA. Both qualitative and semiquantitative evaluation of the stained ECA sections was carried out. RESULTS Eleven (61%) of 18 hepatic metastases from small intestinal and pancreatic ECAs were positive for SSTR-1, 15 (83%) for SSTR-2, 13 (72%) for SSTR-3, 10 (56%) for SSTR-4, and 15 (83%) for SSTR-5. Among 11 hepatic ECA metastases from small intestinal ECAs (carcinoids), 7 (63%) expressed SSTR-1, 9 (81%) expressed SSTR-2, 8 (72%) expressed SSTR-3, 6 (54%) expressed SSTR-4, and 10 (91%) expressed SSTR-5. Of 7 hepatic ECA metastases from pancreatic ECAs, 4 expressed SSTR-1, 6 expressed SSTR-2, and 5 expressed SSTR-3 and SSTR-5 each. We also observed the immunohistochemical evidence of heterogeneity of expression of various SSTR subtypes in the primary enteropancreatic ECAs and their hepatic metastases. CONCLUSIONS SSTR subtype expression needs to be correlated to somatostatin analog therapy. Immunohistochemical profiling of various SSTR subtypes as a part of routine surgical pathologic analysis of enteropancreatic ETs may become a useful predictor of responsiveness of ETs to various SSTR analogs.

Correlations Between Neoadjuvant Treatment, Anemia, and Perioperative Complications in Patients Undergoing Esophagectomy for Cancer

INTRODUCTION The influence of preoperative hemoglobin levels on outcomes of patients undergoing esophagectomy for cancer is not clearly defined. The goal of this article was to explore the association between combined modality therapy, preoperative anemia status, and perioperative blood transfusion and risk of postoperative complications among patients undergoing esophageal resection. METHODS From a retrospective esophageal database, 413 patients were identified. Anemia was defined according to the World Health Organization classification of <13 g/dL or <12 g/dL for men or women, respectively. Statistical analysis was performed with analysis of variance, Pearsons chi(2), or Fisher exact test as appropriate. The independent association of anemia, blood transfusion, and combined modality treatment on risk of postoperative complications were examined using multiple logistic regression. RESULTS Information on combined modality treatment, preoperative hemoglobin levels, and blood transfusion was available for 413 patients, of whom 57% received combined modality treatment. Overall 197 (47.6%) patients were preoperatively found to be anemic, and those who had received combined modality treatment were more likely to be anemic (60.6% versus 30.7%, P < 0.001). Anemic patients required more blood transfusions than nonanemic patients (46.7% versus 29.6%, P < 0.001). Seventy-five percent of patients who required transfusion during the hospital stay had received combined modality treatment (P = 0.01). Combined modality treatment and anemia were not associated with increased risk of complications. Patients with any perioperative complication and surgical site infections were more likely to have received blood transfusion compared to patients without complications (OR = 1.73; 95% CI 1.04-2.87 and OR = 2.98; 95% CI 1.04-8.55; respectively). CONCLUSIONS Overall, we determined that administration of neoadjuvant treatment to esophageal cancer patients was not associated with an increased rate of perioperative complications. Preoperative anemia did not predict worsened short-term outcomes, but increased the chances of red blood cell transfusion, which were significantly associated with higher overall complications and increased risk of surgical site infections. These data confirm previous studies that allogenic red blood cell transfusions are independent risk factors for increased morbidity and mortality and should be minimized during surgery for esophageal cancer.

Erratum: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement (Annals of Surgical Oncology 14 (128-133)DOI: 10.1245/s10434-006-9185-7)

J. Esquivel, R. Sticca, P. Sugarbaker, E. Levine, T. D. Yan, R. Alexander, D. Baratti, D. Bartlett, R. Barone, P. Barrios, S. Bieligk, P. Bretcha-Boix, C. K. Chang, F. Chu, Q. Chu, S. Daniel, E. deBree, M. Deraco, L. Dominguez-Parra, D. Elias, R. Flynn, J. Foster, A. Garofalo, F. N. Gilly, O. Glehen, A. Gomez-Portilla, L. Gonzalez-Bayon, S. Gonzalez-Moreno, M. Goodman, V. Gushchin, N. Hanna, J. Hartmann, L. Harrison, R. Hoefer, J. Kane, D. Kecmanovic, S. Kelley, J. Kuhn, J. LaMont, J. Lange, B. Li, B. Loggie, H. Mahteme, G. Mann, R. Martin, R. A. Misih, B. Moran, D. Morris, L. Onate-Ocana, N. Petrelli, G. Philippe, J. Pingpank, A. Pitroff, P. Piso, M. Quinones, L. Riley, L. Rutstein, S. Saha, S. Alrawi, A. Sardi, S. Schneebaum, P. Shen, D. Shibata, J. Spellman, A. Stojadinovic, J. Stewart, J. Torres-Melero, T. Tuttle, V. Verwaal, J. Villar, N. Wilkinson, R. Younan, H. Zeh, F. Zoetmulder, and G. Sebbag