[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer remains a malignancy with high morbidity and mortality despite improvements to diagnosis, staging, chemotherapy, radiation, and surgery. Neoadjuvant therapy (NT) may improve oncologic outcome in many patients, however the degree to which patients benefit remains unclear. We examined the relationship between pathologic response to NT and magnitude of benefit in patients with esophageal cancer.
Using a comprehensive esophageal cancer database, we identified patients who underwent esophagectomy between 1994 and 2008. Pathologic response was denoted as complete (pCR), partial (pPR), and nonresponse (NR). Clinical and pathologic data were compared using Fisher's exact and chi-square when appropriate, while Kaplan-Meier estimates were used for survival analysis.
We identified 347 patients who underwent esophagectomy, and 262 (75.5%) were treated with NT. The median age was 66 years (28-86 years) with median follow-up of 20 months (1-177 months). There were 106 (40.5%) patients exhibiting pCR, 95 (36.3%) with pPR, and 61 (23.3%) with NR. The rate of R0 resections was higher amongst pCR (100%) compared with 94.7% in pPR (P = 0.02) and 87.5% in NR (P = 0.0007). There were 15 (14.2%) recurrences in pCR, 22 (23.7%) in pPR, and 17 (28.8%) in NR (P = 0.04). Patients achieving pCR had 5-year disease-free survival (DFS) and overall survival (OS) of 52% and 52%, respectively, compared with 36% and 38% in pPR and 22% and 19% in NR (P < 0.0001, P < 0.0001).
Esophageal cancer patients frequently succumb to their disease. However, patients treated with neoadjuvant therapy who achieve pCR have a higher rate of R0 resections, fewer recurrences, and improved 5-year OS and DFS.
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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).
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.
International journal of radiation oncology, biology, physics 11/2009; 75(2):489-96. DOI:10.1016/j.ijrobp.2009.06.014 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iatrogenic esophageal perforation during endoscopy in the setting of malignancy is an uncommon but often devastating complication and presents a formidable challenge to the surgeon. We sought to determine the efficacy of a self-expanding plastic stent for esophageal perforation before neoadjuvant chemoradiation in a single patient. A 74-year-old woman with a T4N0 adenocarcinoma at the gastroesophageal junction was perforated during upper endoscopy. We elected to manage the perforation with a silicone-covered, self-expanding Polyflex stent. Subsequent studies revealed good positioning of the stent with exclusion of the perforation from the esophageal lumen. The patient subsequently underwent neoadjuvant chemoradiation therapy with cisplatin, 5-flourouracil, and external beam radiation (2640 Gy) followed by minimally invasive, hand-assisted transhiatal esophagogastrectomy. We describe the first case of endoscopic stenting for locally advanced, perforated esophageal cancer for the purposes of administering neoadjuvant chemoradiation as a bridge to definitive surgery. This patient was able to resume oral nutrition after stenting and during neoadjuvant therapy, experiencing no major complications from chemoradiation. Chemoradiation does not necessarily preclude the use of endoscopically placed covered plastic esophageal stents as a bridge to resection, even in the face of iatrogenic perforation.
The American surgeon 01/2009; 74(12):1215-7. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer represents a major public health problem worldwide. Several minimally invasive esophagectomy (MIE) techniques have been described and represent a safe alternative for the surgical management of esophageal cancer in selected centers with high volume and expertise in them. This article reviews the most recent and largest series evaluating MIE techniques. Recent larger series have shown MIE to be equivalent in postoperative morbidity and mortality rates to conventional surgery. MIE has been associated with less blood loss, less postoperative pain, and decreased intensive care unit and hospital length of stay compared with conventional surgery. Despite limited data, conventional surgery and MIE have shown no significant difference in survival, stage for stage. The myriad of MIE techniques complicates the debate of defining the optimal surgical approach for treating esophageal cancer. Randomized controlled trials comparing MIE with conventional open esophagectomy are needed to clarify the ideal procedure with the lowest postoperative morbidity, best quality of life after surgery, and long-term survival.
Journal of the National Comprehensive Cancer Network: JNCCN 11/2008; 6(9):879-84. · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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, Pearson's 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.
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).
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.
Journal of Surgical Research 07/2008; 153(1):114-20. DOI:10.1016/j.jss.2008.06.005 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Journal of the American College of Surgeons 06/2008; 206(5):879-86; discussion 886-7. DOI:10.1016/j.jamcollsurg.2007.12.027 · 4.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
Retrospective cohort study.
National Cancer Institute designated comprehensive cancer center.
Eight patients after a transhiatal esophagectomy referred for management of benign persistent anastomotic strictures.
Serial balloon and bougie dilations and SEPS placement.
The interval between endoscopic interventions and the number of endoscopic interventions before and after SEPS placement.
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).
The small number of patients.
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.
[Show abstract][Hide abstract] ABSTRACT: Esophageal adenocarcinoma has demonstrated a rapid increase in incidence over the last 10 years. This increase mirrors a dramatic rise in that of Barrett esophagus, which is associated with esophageal adenocarcinoma in at least 95% of cases. In an attempt to understand the pathogenesis of esophageal adenocarcinoma, attention has turned to the antiapoptotic and oncogenic pathways. Here we demonstrated that Akt was frequently activated in Barrett esophagus-related adenocarcinoma. Remarkably, the levels of Akt activation were associated with tumor progression. After institutional review board ethics approval, 60 archival tissue specimens of esophageal adenocarcinoma arising on a background of Barrett esophagus were selected for immunohistochemical staining with phosphorylated Akt (p-Akt) antibody. The slides were scored by 2 independent observers. Approximately 80% of high-grade dysplasia and esophageal adenocarcinoma cases demonstrated strong to moderate Akt activity. Sixty-two percent of Barrett mucosa revealed low Akt activity, the remaining cases being p-Akt negative. None of the low-grade dysplasia cases exhibited strong p-Akt staining, whereas only weak p-Akt activity is seen in a portion of metaplastic Barrett mucosa, Akt is highly activated in high-grade dysplasia and esophageal adenocarcinoma arising from Barrett esophagus. These findings suggest a role of p-Akt in the progression of Barrett esophagus to esophageal adenocarcinoma and provide the rationale for using p-Akt inhibitor API-2/triciribine, which is currently in clinical trial, in the treatment of esophageal adenocarcinoma.
Human Pathlogy 11/2007; 38(10):1526-31. DOI:10.1016/j.humpath.2007.03.003 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Solid-pseudopapillary tumors of the pancreas are a rare pancreatic neoplasm that carries a 95 per cent 5-year survival rate. However, despite the excellent overall prognosis, aggressive variants been described that likely represent malignant degeneration in an otherwise indolent tumor. Therefore, surgical resection is indicated in all instances. We report a case in a young Hispanic woman, including appropriate work-up and operative intervention.
The American surgeon 04/2007; 73(3):290-3. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between cytomegalovirus infection and inflammatory bowel disease challenges both the clinician and the pathologist to establish the correct diagnosis and to prescribe the most appropriate form of therapy. To understand this association the authors report three patients who presented with signs and symptoms mimicking reactivated inflammatory bowel disease who responded poorly to aggressive treatment of inflammatory bowel disease. Microscopic examination, in all three cases revealed numerous nuclear and cytoplasmic viral inclusions, as demonstrated by cytomegalovirus immunohistochemistry, as well as histologic findings consistent with inflammatory bowel disease (ulcerative colitis and/or Crohn's disease). Because the clinical pathologic features of cytomegalovirus colitis and inflammatory bowel disease often overlap, and because of the possible coexistence of cytomegalovirus colitis with idiopathic colitis, the possibility of cytomegalovirus infection should be always considered, so that the most appropriate therapy can be instituted for these patients.
The American surgeon 02/2007; 73(1):58-61. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Cancer control: journal of the Moffitt Cancer Center 02/2006; 13(1):52-60. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Benign tumors of the esophagus are a rare but diverse group of lesions. Although non-malignant in biology, their presence can cause significant morbidity, including dysphagia, bleeding, gastrointestinal obstruction, and even asphyxiation. Diagnosis is frequently made using radiographic and endoscopic means, even in the absence of definitive biopsy. If discovered early, endoscopic or minimally invasive techniques may be used to excise these lesions, with essentially 100% cure rates. However, if discovered late, open excision or even esophagectomy may be required. Angiolipoma represents perhaps one of the rarest of the benign entities to affect the esophagus, with only a few cases reported in the current literature. We present the case of an 85-year-old man who developed complete esophageal obstruction due to a large, pedunculated angiolipoma, requiring open surgical excision.
Diseases of the Esophagus 02/2006; 19(3):203-7. DOI:10.1111/j.1442-2050.2006.00567.x · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We tested the hypothesis that rectal tumors are most responsive to neoadjuvant therapy if they possess p53 and/or caspase 8 activity.
Fifty patients diagnosed with biopsy-proven rectal cancer underwent neoadjuvant chemoradiation therapy consisting of 5-fluorouracil (300 mg/m(2) daily) and radiation (4,500 cGy). Endorectal ultrasonography was performed before and after neoadjuvant therapy along with digital rectal examination and/or sigmoidoscopy for staging purposes and to evaluate response to therapy. All patients underwent resection with specimens submitted for gross and microscopic review. Pretreatment biopsy specimens were subjected to immunohistochemical staining for mutated p53 and caspase 8 bioactivity.
The study population consisted of 32 men and 18 women. There were 17 complete responses (CRs; 34%), 17 partial responses (PRs; 34%), and 16 cases of no response (NR; 32%). There were 10 stage I tumors (20%), 22 stage II tumors (44%), and 18 stage III tumors (36%) in the cohort at the time of initial diagnosis. p53 protein staining (ie, mutated p53) was positive in 31 tumors (62%; CR, n = 8; PR, n = 11; NR, n = 12); caspase 8 positivity was apparent in 30 specimens (60%; CR, n = 13; PR, n = 13; NR, n = 4). In terms of pretreatment predictions, we scored 3 separate levels of response (CR, 3; PR, 2; NR, 1) and compared them with the expected responses (ie, p53 positivity and caspase 8 negativity should yield NR, whereas all other combinations should yield responses). Wilcoxon 2-sample tests yielded a 1-sided P value of 0.007.
The present study highlights a possible mechanism for tumor response to neoadjuvant manipulation, namely that dual mechanisms for apoptotic cell death are working in concert to cause tumor regression; one is p53 transcription-dependent, and the other is p53 transcription-independent.
Clinical Colorectal Cancer 08/2005; 5(2):114-8. DOI:10.3816/CCC.2005.n.023 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adenocarcinoma arises in Barrett's 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 Barrett's epithelium.
Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barrett's epithelia from which three of the cancers had arisen. Pooled samples from the Barrett's epithelia of six patients without cancer or dysplasia served as a reference.
Barrett's epithelia from which cancer had arisen differed from the reference Barrett's 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 Barrett's epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barrett's 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 Barrett's epithelium differed from cancers that had arisen from a Barrett's epithelium by having an even greater number of these overexpressed genes.
Histologic progression from Barrett's 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 Barrett's epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.
Clinical Cancer Research 05/2005; 11(7):2478-85. DOI:10.1158/1078-0432.CCR-04-1280 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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%).
Journal of Gastrointestinal Surgery 03/2004; 8(3):227-31; discussion 231-2. DOI:10.1016/j.gassur.2003.11.024 · 2.39 Impact Factor