Scott D. Goldstein

Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma

AbstractPURPOSE: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity. METHODS: Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45–54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28–56 days) and Group B (10-week to 14-week interval; 67–97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Student’s t-test were calculated. RESULTS: Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant. CONCLUSIONS: Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.

Use of guanylyl cyclase C for detecting micrometastases in lymph nodes of patients with colon cancer

INTRODUCTION: Guanylyl cyclase C appears to be expressed only in colorectal cancer cells in extraintestinal tissues. Thus, guanylyl cyclase C may be useful as a marker to detect colorectal cancer micrometastases not detectable by histopathology in lymph nodes of patients. METHODS: Twelve patients with colon adenocarcinoma, Dukes Stages A through C2, and one patient with a tubulovillous adenoma were included in this study. Forty-two lymph nodes were collected from fresh surgical specimens, and each was examined by histopathology and reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers. Histopathology identified colon cancer cells in 6 of 16 lymph nodes from five Dukes Stage C patients but not in lymph nodes from the patient with a tubulovillous adenoma, the Dukes Stage A patient, or six Dukes Stage B patients. Reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers was performed on all 42 lymph nodes. RESULTS: Guanylyl cyclase C messenger RNA was not detected by reverse transcription followed by polymerase chain reaction in lymph nodes from the patient with the tubulovillous adenoma or the patient with Dukes Stage A colon carcinoma. Seven lymph nodes from Dukes Stage C patients revealed guanylyl cyclase C messenger RNA including six lymph nodes containing histopathologically confirmed metastases. Of significance, guanylyl cyclase C messenger RNA was detected in 6 of 21 lymph nodes from Dukes Stage B patients. Indeed, clinical staging of two patients could be upgraded from B to C using reverse transcription followed by polymerase chain reaction and guanylyl cyclase C-specific primers. CONCLUSION: Reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers might be useful to more accurately assess micrometastases in lymph nodes of colorectal cancer patients undergoing disease staging.

Colonic Crypt Changes during Adenoma Development in Familial Adenomatous Polyposis : Immunohistochemical Evidence for Expansion of the Crypt Base Cell Population

Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.

Escherichia coli heat-stable enterotoxin receptors : a novel marker for colorectal tumors

PURPOSE: Receptors forEscherichia coliheat-stable toxin (ST) are selectively expressed in membranes of intestinal mucosa cells and colon carcinoma cellsin vitro,suggesting their use as a marker for colorectal tumorsin vivo.The present studies examined the expression and function of ST receptors in normal human tissues and primary and metastatic colorectal tumors obtained from patients at surgery. METHODS: Surgical specimens were obtained as follows: from normal colon; from primary adenocarcinomas from all anatomic divisions of the colon and rectum; from gallbladder, kidney, liver, lung, lymph node, ovary, peritoneum, stomach; and from colon carcinomas metastatic to liver, lung, lymph node, ovary, and peritoneum. Membranes prepared from these specimens were assessed for the presence and functional characteristics of ST receptors. RESULTS: ST bound specifically to membranes from each division of normal colon and rectum and all primary and metastatic colorectal tumors examined. The affinity and density of ST receptors were similar in tumors of different grades and from various metastatic sites. ST-receptor interaction was coupled to activation of guanylyl cyclase in all normal samples of colon and rectum and all primary and metastatic colorectal tumors examined. In contrast, neither ST binding nor ST activation of guanylyl cyclase was detected in any extraintestinal tissues examined. CONCLUSIONS: Functional ST receptors are expressed in normal colonic tissue and primary and metastatic colorectal tumors but not by extraintestinal tissues in humans. Expression of ST receptors does not vary as a function of the metastatic site or grade of these tumors. Receptors expressed by colorectal tumors retain their characteristic function, with binding of ST coupled to activation of guanylyl cyclase. These studies support the suggestion that ST receptors represent a specific marker for human colorectal tumors that may have use as a target for directing diagnostics and therapeutics to these tumorsin vivo.

Sphincter preservation for cancer of the distal rectum using high dose preoperative radiation

Sphincter preservation surgery for cancer of the distal rectum is recognized as being associated with a high incidence of local recurrence. High dose preoperative radiation with new surgical techniques is described as an attempt to widen the scope of sphincter preservation in patients who by conventional management would have an abdomino-perineal resection and permanent colostomy and to reduce the incidence of local recurrence. Since 1976, 121 patients with cancers of the rectum have selectively been treated with high dose preoperative radiation (4000 cGy to 6000 cGy) followed by combined abdominotranssacral resection (56); transanal abdominotransanal resection (28); anterior resection (21), or a full thickness wide local excision (16). This report details the results of 43 patients observed for a minimum of 2 years whose tumors were located from 0-6 cm of the dentate line. All patients received the full course of preoperative radiation, a minimum dose of 4000-4500 cGy in approximately 4 1/2 weeks that was delivered using 180-250 cGy per fraction. Patients with tumor fixation were given an additional boost of 1000-1500 cGy preoperatively. Surgery was carried out 4-6 weeks following the completion of radiation. There was no perioperative mortality. Anastomotic failure occurred in 3 patients and was reconstituted in two. Sphincter function was maintained in all but 6 patients (86%), 2 of these had a subsequent abdominoperineal resection, and 3 a diverting colostomy. Seven of 43 (16%) patients with tumors below 6 cm developed a local recurrence, and 6 of the 7 recurrences occurred in patients with fixed tumors, especially those located from 0-3 cm from the dentate line. Eleven patients are dead of disease. The 5-year actuarial survival rate for this group is 72%. Results indicate that high dose preoperative radiation can significantly extend the scope of sphincter preservation to selected cancers of the disal rectum with excellent survival without increasing the risk of pelvic perineal recurrence.

Anastomotic recurrences after low anterior resection

A retrospective study was done comparing the rates of local recurrence in cancer of the rectum treated by low anterior resection using the stapling device or hand-sewn. It was found that there was no increase in recurrences when the stapler was used, even though lower lesions were treated.

Survivin-Induced Aurora-B Kinase Activation: A Mechanism by Which APC Mutations Contribute to Increased Mitoses during Colon Cancer Development

APC mutations initiate most colorectal cancers (CRCs), but cellular mechanisms linking this to CRC pathology are unclear. We reported that wild-type APC in the colon down-regulates the anti-apoptotic protein survivin, and APC mutation up-regulates it, explaining why most CRCs display survivin overexpression and apoptosis inhibition. However, it does not explain another hallmark of CRC pathology--increased mitotic figures and cell proliferation. Because survivin activates aurora-B kinase (ABK) in vitro, catalyzing mitosis, we hypothesized that in normal colonic crypts, APC controls ABK activity, while in neoplastic APC-mutant crypts, ABK activity is up-regulated, increasing mitosis. We quantitatively mapped intracryptal distributions of survivin, ABK, and markers of activated downstream signaling and mitosis (INCENP, phospho-histone-H3, phospho-centromere-protein-A). In normal crypts, gradients for these markers, ABK:survivin:INCENP complexes, and ABK activity were highest in the lower crypt (inverse to the APC gradient). In neoplastic crypts that harbor APC mutations, proliferating (Ki-67+) cells and cells expressing survivin, ABK, and phospho-histone-H3 were distributed farther up the crypt. Hence, as cells migrate up neoplastic crypts, transitions between cell phenotypes (eg, from stem to proliferating) appear delayed. In CRC cell lines, increasing wild-type APC, inhibiting TCF-4, or decreasing survivin expression down-regulated ABK activity. Thus, APC mutation-induced up-regulation of the survivin/ABK cascade can explain delayed crypt cell maturation, expansion of proliferative cell populations (including mitotic figures), and promotion of colon tumorigenesis.

Reducing colorectal surgical site infections: a novel, resident-driven, quality initiative

BACKGROUND Surgical site infections (SSIs) cause significant patient morbidity and increase costs. This work prospectively examines our institutional effort to reduce SSIs through a resident-driven quality initiative. METHODS A general surgery resident-championed, evidenced-based care bundle for patients undergoing colorectal surgery at a single academic institution was developed using attending mentorship. National Surgical Quality Improvement Program definitions for SSIs were used. Data were collected prospectively and bundle compliance was monitored using a checklist. The primary outcome compared SSIs before and after implementation. RESULTS In the 2 years preceding standardization, 489 colorectal surgery cases were performed. SSIs occurred in 68 patients (13.9% SSI rate). Following implementation of the bundle, 212 cases were performed with 10 SSIs (4.7% SSI rate, P < .01). Multivariate logistic regression analysis found a decrease in superficial and overall SSIs (odds ratio .17, 95% confidence interval .05 to .59; odds ratio .31, 95% confidence interval .14 to .68). CONCLUSIONS These data demonstrate that resident-driven initiatives to improve quality of care can be a swift and effective way to enact change. We observed significantly decreased SSIs with a renewed focus on evidence-based, standardized patient care.

A Phase I study of AD5-GUCY2C-PADRE in stage I and II colon cancer patients

Meeting abstracts Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed

Adenocarcinoma of the Prostate Presenting as an Obstructing Rectal Mass

With more than 230,000 new diagnoses and 30,000 deaths each year in the United States, adenocarcinoma of the prostate (“prostate cancer”) is the most common cancer occurring in men [1]. In the era of prostate specific antigen (PSA) screening, most cases of prostate cancer present at an asymptomatic stage with organ-confined disease. The majority of patients (83.1%) present with disease confined to the capsule (AJCC Stages I–II). Only 6.4% have advanced disease (AJCC Stage IV) at the time of diagnosis [2]. When symptomatic, the most common symptoms are urinary urgency, nocturia, and hesitancy. Prostate cancer may also present at an advanced stage with a symptom such as bone pain from bone metastases. Rectal involvement, by direct invasion or metastasis, occurs in 1.5% to 11% of those with prostate cancer [3–6]. In a male with a rectal mass, it is important to consider prostate cancer in the differential diagnosis. We describe a