Victor E. Pricolo

Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study

Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and glandular differentiation. Tight junction proteins also play critical roles in cellular proliferation and neoplastic pathways via their functions as couplers of the extracellular milieu to intracellular signaling pathways and the cytoskeleton. Neoplastic cells frequently exhibit structural and functional deficiencies in the tight junction. The purpose of this study was to determine the pattern of expression and prognostic value of four tight junction associated proteins, claudin-1, claudin-4, occludin and ZO-1 in a cohort of TNM stage II colon cancer using tissue microarray technology. In this study, we retrospectively analyzed, resected and otherwise untreated paraffin embedded specimens from 129 consecutive patients with TNM stage II colonic carcinomas for claudin-1, claudin-4, occludin and ZO-1 protein expression by immunohistochemistry. Seventy-five, 58, 56 and 44% of the tumors exhibited normal to elevated expression levels (+2 and +3 immunopositivity) of claudin-1, claudin-4, occludin and ZO-1 respectively. Low expression levels of claudin-1 and ZO-1 were directly associated with higher tumor grade (P=0.05 and 0.03 respectively). Multivariate analysis indicated that lymphovascular invasion (P=0.01) and low levels of claudin-1 (P=0.0001) expression were independent predictors of recurrence and that reduced claudin-1 expression (P=0.0001) was associated with poor survival. This study is the first to comprehensively examine the expression of several tight junction associated proteins in colonic neoplasms and to correlate their expression with disease progression. Loss of claudin-1 expression proved to be a strong predictor of disease recurrence and poor patient survival in stage II colon cancer.

Epidermal Growth Factor Receptor, c-MET, β-Catenin, and p53 Expression as Prognostic Indicators in Stage II Colon Cancer A Tissue Microarray Study

Purpose: Through the use of molecular markers, it may be possible to identify aggressive tumor phenotypes and tailor therapies to treat them. This approach would be particularly useful for stage II colon cancer. The purpose of this study was to define the prognostic value of epidermal growth factor receptor (EGFR), c-MET, β-catenin, and p53 protein expression in TNM stage II colon cancer using tissue microarray technology. Experimental Design: In this study, we retrospectively analyzed, resected, and otherwise untreated paraffin-embedded specimens from 134 consecutive patients with Tumor-Node-Metastasis stage II colonic carcinomas for EGFR, c-MET, β-catenin, and p53 protein expression by immunohistochemistry. Results: Thirty-five percent, 77, and 65% of tumors exhibited strong (+2 and +3 immunopositivity) expression of EGFR, c-MET, and β-catenin, respectively. Fifty-four percent exhibited nuclear staining for p53 in >10% of the tumor cells. Univariate analysis revealed that increased nuclear p53 expression (P = 0.001), strong membranous EGFR expression (P = 0.04), and lymphovascular invasion (P = 0.01) were significantly related to disease recurrence and that p53 (P = 0.02) and EGFR (P = 0.05) expression were associated with decreased survival. Increased nuclear p53 expression also correlated with the presence of distal metastasis (P = 0.027). No significant association was seen between c-MET expression and prognosis, whereas a strong trend was detected between loss of β-catenin (P = 0.065) expression and poor outcome. Multivariate analysis indicated that p53 (P = 0.04), EGFR (P = 0.05), and lymphovascular invasion (P = 0.03) were independent predictors of recurrence and that p53 (P = 0.02) and EGFR (P = 0.01) expression were both associated with poor survival. Conclusions: This retrospective tumor microarray study, restricted to Tumor-Node-Metastasis stage II colon cancer patients who did not undergo adjuvant therapy, supports the use of EGFR and p53 as biological markers, which may assist in predicting disease recurrence and survival.

Malignant potential in intestinal juvenile polyposis syndromes

AbstractBackground: Unlike familial polyposis coli, where the premalignant nature of adenomatous polyps is well established, the cancer risk in juvenile polyposis has generally been considered not increased. Methods: This study reviews all cases of juvenile polyposis reported in the English language to date to assess the occurrence and prognosis of carcinoma in the gastrointestinal tract. Results: A total of 218 patients met the inclusion criteria. Mean age at diagnosis was 18.5 years (range: 9 months to 67 years). No gender preference was identified. The most common presenting symptom was chronic anemia, followed by acute gastrointestinal bleeding, rectal prolapse of polyp, protein-losing enteropathy, and intussusception. A family history of juvenile polyposis could be established in ∼50% of patients, and associated congenital malformations were detected in 15%. Ninety-nine patients underwent 138 gastrointestinal operations: 121 colorectal, 12 gastric, and 5 small intestinal procedures. The development of a gastrointestinal carcinoma was reported in 36 cases (17%). Mean age at diagnosis of carcinoma was 35.5 years (range: 4–60 years). Most malignancies were located in the distal colon and rectum, with only one case of gastric and one case of duodenal carcinoma. Tumor stage at diagnosis was usually advanced, with poor survival figures. Conclusions: This study shows that juvenile polyposis syndromes carry a more significant risk of carcinoma than generally appreciated. Therefore, more intense endoscopic surveillance may be warranted, and definitive surgical options should often be considered in these syndromes.

Gracilis Muscle Transposition for Iatrogenic Rectourethral Fistula

ObjectiveTo assess the utility of gracilis muscle transposition in the treatment of iatrogenic rectourethral fistula. Summary Background DataIatrogenic rectourethral fistula poses a rare but challenging complication of treatment for prostate cancer. A variety of procedures have been described to treat this condition, none of which has gained acceptance as the procedure of choice. The aim of this study was to review the authors’ experience with gracilis muscle transposition in the treatment of iatrogenic rectourethral fistula. MethodsA retrospective chart review of all patients who underwent gracilis muscle transposition for iatrogenic rectourethral fistula was performed, and follow-up was established by telephone interview. Successful repair was defined as absence of a fistula after reversal of fecal and urinary diversions. ResultsEleven men, mean age of 62 years, underwent 12 gracilis muscle transpositions for rectourethral fistula between 1996 and 2001. Six patients had a history of pelvic radiotherapy, and five patients had previous failed attempts to repair the fistula. In nine patients, the fistula healed following gracilis muscle transposition. One patient developed a rectocutaneous fistula that healed with fibrin glue injection, and one developed perineal sepsis requiring debridement of the transposed gracilis. This patient underwent a second gracilis transposition, which uneventfully healed. Overall, all of the patients had closure of their diverting stomas and maintained healed rectourethral fistulas. There were no intraoperative complications, and the only long-term complication of this procedure was mild medial thigh numbness in two patients. ConclusionsGracilis muscle transposition is an effective surgical treatment for iatrogenic rectourethral fistula. It is associated with low morbidity and a high success rate.

Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

PURPOSE To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. METHODS AND MATERIALS Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. RESULTS The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). CONCLUSIONS Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.

Prognostic value of TP53 and K-ras-2 mutational analysis in stage III carcinoma of the colon

Background Genetic mutations involving onccgenes and tumor-suppressor genes occur in carcinogenesis, and may affect biologic behavior of neoplasms. In this study, we analyzed the prognostic value of mutational analysis in Colon carcinoma. Patients and methods Archival pathology specimens from 70 consecutive patients, resected for stage III colon carcinoma, were analyzed for point mutations by amplification and direct sequencing of exons from the K- ras -2 and the TP53 genes (topographic genotyping). Mutations were compared with adverse histopathologic features (poor differentiation, vascular and lymphatic invasion, mucin production) as prognostic markers. Results Five-year survival was 75% in patients with nonmutated lesions, significantly lower (21%) with TP53 mutations ( P = 0.01), and intermediate with K- ras -2 only (45%) or both K- ras -2 and TP53 mutations (36%). A TP53 mutation carried the highest relative risk of death (2.39; 95% confidence interval, 1.29 to 4.42; P = 0.006). There was an additive effect on the risk of death between TP53 mutations and adverse histopathologic features. Conclusions The information derived from mutational analysis is creating new prognostic variables that may play a role in the choice of therapy for colorectal carcinoma.

Portal Venous Gas Detected by Computed Tomography: Is Surgery Imperative?

Background: Portal vein gas (PVG) has historically been associated with mortality rates of 75% or higher and mandatory abdominal exploration. The following study reassesses the clinical significance of gas in the portal venous system detected by computed tomography (CT) and reevaluates the need for surgical intervention in that setting. Methods: We performed a retrospective chart review of 26 patients presenting with gas in the portal venous system as imaged by CT between August 1, 1993 and April 8, 2001. Characteristics assessed included age, sex, clinical presentation and course, additional CT findings, diagnosis, surgical versus non-surgical management, surgical findings, pathologic correlation, and mortality. Results: Of the 26 patients who had gas in the portal venous system by CT, 11 underwent surgery to determine underlying pathology. Of those who underwent surgery, 8 survived to be discharged while 3 died (73% surgical survival). The survivors presented with gastrointestinal related signs/symptoms and were found at the time of surgery to have adhesions, non-surgically treated inflammation, unclear pathology, or resectable lesions. Those who died all demonstrated marked bowel ischemia intraoperatively. Among patients who did not undergo surgery, 9 survived and 6 died (60% nonsurgical survival). Those who survived presented either asymptomatically or with pathology including acute pancreatitis, recent hypotensive episode, uncomplicated diverticulitis, unresectable colon cancer, or infectious etiology. Those who died were poor surgical candidates or status postvascular procedure. The overall survival in patients with portal venous gas by CT was 65%. Conclusion: Portal venous gas on CT is associated with a wide range of pathologies that do not necessarily warrant surgical management. Clinical presentation should be correlated with the presence of PVG and other associated CT findings prior to deciding whether surgery should be performed.

Modern Management of Rectal Cancer

The management of rectal cancer has undergone significant evolution in the past decade. The standardization of operative surgical techniques, the demonstrated efficacy of adjuvant radiation therapy as well as chemotherapy, along with improvement in diagnostic imaging aimed at preoperative staging of the disease, have significantly improved the overall results of treatment for rectal carcinoma. No other area in the gastrointestinal tract requires such careful planning and individualization of treatment options, which are needed to achieve satisfactory oncological as well as functional results. The ability to preserve anal sphincteric function and to avoid genitourinary complications, without compromising the goals of a curative resection, can now be offered to the vast majority of patients who present with rectal carcinoma. The diagnostic and therapeutic armamentarium available to the clinician approaching a case of rectal cancer has never been so rich. The recent literature abounds with information regarding the reliability of new imaging modalities to diagnose primary as well as recurring rectal cancer, the efficacy of adjuvant treatments both in the preoperative and in the postoperative setting, and the feasibility of anal sphincter-saving procedures, ranging from transanal local excisions to coloanal anastomoses. The colorectal surgeon who is managing rectal cancer must maintain a leading role in the proper planning and delivery of the various treatment modalities, taking into account patient characteristics, as well as tumor variables.

Trendelenburg versus Pasg Application—hemodynamic Response in Man

Diminished venous return is the primary determinant of reduced cardiac output in hemorrhagic hypoperfusion. In this study the hemodynamic response of two therapies commonly employed to increase venous return in hemorrhagic hypoperfusion--pneumatic antishock garment (PASG) application and Trendelenburg (TREND) positioning--were compared in normovolemic man. Five patients had PASG pressure of 20 mm Hg compared with 10 degrees Trendelenburg, eight patients had 20 and 40 mm Hg PASG application compared with 10 degrees Trendelenburg. PASG application at both 20 and 40 mm Hg resulted in a significant increase in CVP (11.1 +/- 1.9 baseline to 16.0 +/- 2.7 PASG 40; p less than 0.01) left atrial pressure (LAP) (10.1 +/- 1.3 baseline to 14.4 +/- 1.8 PASG 20; p less than 0.01) pulmonary capillary wedge pressure (PCWP) (11.6 +/- 2.0 baseline to 16.8 +/- 3.4 PASG 40; p less than 0.01) and esophageal pressure (Pes) (5.0 +/- 0.8 baseline to 8.6 +/- 0.9 PASG 40; p less than 0.01). However, transmural right and left atrial pressure (RATP, LATP) and cardiac index (CI) were unchanged. Ten degrees of Trendelenburg resulted in no increase in CVP, PCWP, RATP, or LATP, but CI (2.67 +/- 0.07 baseline to 2.82 +/- 0.1 TREND; p less than 0.01) was significantly increased. Systemic vascular resistance index (570 +/- 46 TREND vs. 668 +/- 53 PASG 40; p less than 0.01) was significantly less in Trendelenburg compared to PASG at 40 mm Hg. The data demonstrate that elevation in CVP, LAP, and PCWP following PASG application is secondary to an increase in intrathoracic pressure (as measured by Pes).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Magnetic Resonance Enterography in the Management of Crohn Disease

OBJECTIVE To assess the impact of magnetic resonance enterography (MRE) on therapeutic decision making for patients with Crohn disease. DESIGN Retrospective study. SETTING Tertiary care medical center. PATIENT One hundred twenty patients who had either a history of or high suspicion for Crohn disease with onset of new symptoms underwent MRE over 18 months at our institution. All patients with Crohn disease were classified according to the Montreal system. INTERVENTIONS Magnetic resonance enterography and medical vs surgical therapy. MAIN OUTCOME MEASURE Changes in management after MRE findings. RESULTS Magnetic resonance enterography demonstrated active Crohn disease in 57.5% of patients, chronic changes of Crohn disease without active inflammation (eg, stricture, fistula, or abscess) in 12.5% of cases, and no evidence of Crohn disease in 30% of cases. After MRE, 37 (31%) had no change in medical therapy, 64 (53%) had additional medical management for active inflammation, and 19 (16%) underwent an operation for complicated Crohn disease or medical intractability. In all surgical patients, the intraoperative findings were consistent with the MRE diagnosis. The mean (SD) MRE score was 1.6 (0.5) for patients who had no change in their treatment plans, 5.8 (1) for patients who underwent surgery, and 8 (0.4) for patients who had their drug regimen changed (P < .001). The MRE score independently correlated with need for intervention (P = .001). CONCLUSIONS Magnetic resonance enterography shows promising ability to characterize the presence of active Crohn disease as well as chronic complications (eg, differentiate between stricture due to edema vs fibrotic scarring). Magnetic resonance enterography is fast becoming a useful adjunct in the management algorithm of patients with Crohn disease.