Robert D. Fry

Laparoscopic-assisted ileocolic resections in patients with Crohn's disease: are abscesses, phlegmons, or recurrent disease contraindications?

BACKGROUND Because of the inflammatory nature of Crohns disease, ileocolic resections are often difficult to perform, especially if an abscess, phlegmon, or recurrent disease at a previous ileocolic anastomosis is present. Our goal was to determine whether the above factors are contraindications to a successful laparoscopic-assisted ileocolic resection. METHODS Between 1992 and 1996, 46 laparoscopic-assisted ileocolic resections were attempted. Fourteen patients had an abscess or phlegmon treated with bowel rest before operation (group I), 10 patients had recurrent Crohns disease at the previous ileocolic anastomosis (group II), and 22 patients had no previous operation and no phlegmon or abscess associated with their disease (group III). These groups were compared with each other and with 70 consecutive open ileocolic resections for Crohns disease during the same time period (group IV). RESULTS Operative blood loss and time were greater in group IV than in groups I, II, and III (245 versus 151, 131, and 195 ml, respectively, and 202 versus 152, 144, and 139 minutes, respectively). Conversion to open procedure occurred in 5 patients (group I, 1 [7%]; group II, 2 [20%]; group III, 2 [9%]). Morbidity was highest in group IV (21% versus 0%, 10%, and 10%, respectively). Only one patient died (group IV, 1%). Length of hospital stay was longest in group IV (7.9 versus 4.8, 3.9, and 4.5 days, respectively). CONCLUSIONS The laparoscopic-assisted approach to Crohns disease is feasible and safe with good outcomes. Co-morbid preoperative findings such as abscess, phlegmon, or recurrent disease at the previous ileocolic anastomosis are not contraindications to a successful laparoscopic-assisted ileocolic resection in select patients.

Anal sphincter repair for obstetric injury: manometric evaluation of functional results.

Anal manometry before and after surgical repair on a homogeneous group of patients with anterior sphincter defect caused by obstetric injury defined the parameters affected by the repair to achieve anal continence. Between November 1985 and April 1989, 28 patients who underwent anterior anal sphincter reconstruction were studied using anal manometry and were graded for continence. Anal function was improved for 27 of 28 patients (96 percent) relative to their preoperative symptoms, and total control of solid and liquid stools was restored in 21 patients (75 percent). Anal manometry demonstrated that complete control of continence could be achieved if anal sphincter length, resting pressure, and squeeze pressure were restored to normal. Our results showed that sphincter length was improved in 20 patients (71 percent), resting pressure in 16 patients (57 percent), and squeeze pressure in 22 patients (79 percent). The most important factor in achieving normal function of the anal sphincter is restoration of a normal squeeze pressure.

Guanylyl Cyclase C Messenger RNA Is a Biomarker for Recurrent Stage II Colorectal Cancer

Stage at diagnosis is the most important prognostic determinant for patients with colorectal cancer (1-6), and it dictates the role of adjuvant chemotherapy in this disease (7-10). Given the prognostic and therapeutic importance of staging, accurate histopathologic evaluation of lymph nodes to detect invasion by tumor cells is crucial. However, conventional microscopic lymph node examination has methodologic limitations (6, 11). It can be difficult to differentiate single or even small clumps of tumor cells from other types of cells, which limits sensitivity. The standard practice of examining only a limited number of tissue sections from each lymph node can omit from review more than 99% of each specimen and can introduce sampling error. These limitations are evident when the frequency of disease recurrence in patients with stage I and stage II disease is considered. By definition, such patients do not have extraintestinal disease at the time of curative resection. However, recurrence rates of 10% to 30% have been reported for lesions confined to the mucosa (stage I disease), and rates of 30% to 50% have been reported for lesions confined to the bowel wall (stage II disease) (12, 13). Alternate methods of detecting small numbers of tumor cells have been used for staging, including intensive review of serial tissue sections, immunohistochemical analysis to detect tumor-associated antigens, polymerase chain reaction (PCR) to detect tumor-specific mutations, and reverse transcriptase (RT) PCR to detect the expression of tumor-associated biomarkers (6, 11). In some studies of colorectal cancer, staging by these sensitive methods has been correlated with disease. However, the fact that serial sectioning is labor- and cost-intensive, the lack of uniform association between mutations and neoplastic transformation, and the nonspecificity of many biomarkers limit the applicability of these methods. An easily detected biomarker that is specifically expressed by all colorectal tumors would be useful for disease staging. Guanylyl cyclase C is expressed in normal intestinal mucosal cells, adenomatous polyps, and primary and metastatic colorectal tumors but not in extraintestinal tissues or tumors (14-17). Expression of guanylyl cyclase C has been detected by RT-PCR in all of the histologically confirmed colorectal tumors and colorectal cancer cell lines that have been examined (14-17). Therefore, guanylyl cyclase C may be a specific biomarker for metastasis of extraintestinal colorectal cancer (16, 17). We examined whether expression of guanylyl cyclase C messenger RNA (mRNA) in lymph nodes was associated with disease recurrence in patients with stage II colorectal cancer who had presumably been cured by surgical resection. Methods Patients and Tissues We examined the tumor registry database at Thomas Jefferson University (Philadelphia, Pennsylvania) for patients who had been treated for colorectal cancer between 1989 and 1995, an interval that permitted adequate follow-up (Figure). The initial search was designed to exclude patients who developed recurrent disease more than 3 years after the index surgery. In this way, we avoided inadvertent inclusion of patients who had metachronous rather than recurrent cancer. Our search yielded 445 patients with invasive colon or rectal cancer and no evidence of metastases (tumor, node, metastasis [TNM] classification, N0 M0) at surgery. Of these 445 patients, 260 had surgery at Thomas Jefferson University that yielded lymph nodes. Subsequently, 167 patients were excluded because they had stage I or less severe disease (T0-T2 N0 M0), because they developed recurrent disease locally or at unspecified sites, or because they received neoadjuvant chemotherapy or radiation therapy. Fifty-six patients with no evidence of recurrence were excluded because they had less than 6 years of follow-up. Of 18 patients who had had no evidence of disease for 6 or more years after surgery and were considered clinically cured, 16 had pathologic specimens available for further analysis; these patients formed the control group. Of 19 patients who developed metastases up to 3 years after surgery, 12 had pathologic specimens available for further analysis; these patients formed the case-patient group. The remaining 9 patients were excluded from analysis. Two controls (12.5% [patients 9 and 16]) and 1 case-patient (8.3% [patient 24]) received 5-fluorouracil-based adjuvant chemotherapy after surgery. Figure. Algorithm for selecting patient biopsy samples for analysis. Reverse Transcriptase Polymerase Chain Reaction In our study, lymph nodes were obtained for analysis under an institutional review board-approved protocol that maintained patient anonymity. Preliminary tests showed that mRNA isolated from single 10-m sections of individual lymph nodes yielded insufficient RNA for RT-PCR analysis. Consequently, at least five 10-m sections of representative lymph nodes for each patient were pooled and deparaffinized, and the total RNA was isolated (17). Reverse transcriptase polymerase chain reaction was performed by using the RNA PCR Kit, version 2 (Takara Shuzo Co., Ltd., Kyoto, Japan) (16, 17). We used only total RNA that yielded amplicons after -actin-specific RT-PCR was used (16, 17). Guanylyl cyclase C-specific RT-PCR and nested carcinoembryonic antigen-specific RT-PCR were performed as described elsewhere (16-18). Reactions from RT-PCR were separated by electrophoresis on 4% NuSieve 3:1 agarose (FMC Bioproducts, Rockland, Maine) and by amplification products visualized by ethidium bromide. We included positive control specimens, consisting of RNA isolated from human colorectal cancer cells that expressed guanylyl cyclase C and carcinoembryonic antigen (Caco2 cells [American Type Culture Collection, Rockville, Maryland]), and negative control specimens, consisting of RNA from lymph nodes without colorectal cancer and incubations in which no template was added. Amplicon identity was confirmed by sequencing (16, 17). Production of guanylyl cyclase C-specific amplicons was confirmed by Southern blot analysis, which used a 32P-labeled antisense probe that complemented a sequence found within the amplicon (19). Statistical Analysis Results are expressed as the mean SD, except for disease-free and overall survival, which are expressed as the median (range). We calculated P values by using the Fisher exact test. The odds ratios, with exact 95% CIs, were calculated by using the StatXact 4.0 statistical software package (Cytel Software Corp., Cambridge, Massachusetts). Role of the Funding Source Targeted Diagnostics and Therapeutics, Inc., which provided a portion of the grant support for this study, was not involved in the design of the study or in the collection and analysis of the data; it also had no role in the decision to submit the paper for publication. Results Characteristics of Patients Evaluated by Reverse Transcriptase Polymerase Chain Reaction Patients ranged in age from 37 to 85 years (mean, 68.1 9.5 years). Women and men were similar in age (range, 52 to 85 years [mean, 64.5 10.5 years] and 37 to 82 years [mean, 70.9 7.8 years], respectively). The ratio of men to women was 8:9 among controls and 5:7 among case-patients. One woman was African-American; all other patients were white. The ratio of cases of T3 to T4 disease was 3:13 among controls and 4:8 among case-patients. Patients were followed for 9 to 105 months (mean, 67.4 30.7 months). Controls were followed for 73 to 105 months (mean, 89.9 7.8 months), and case-patients were followed for 9 to 78 months (mean, 37.3 22.6 months). In the control group, 1 patient (6.3%) developed a new primary colonic lesion 96 months after initial diagnosis, 1 patient (6.3%) died of causes unrelated to colorectal cancer, and the remaining 14 patients (87.5%) were alive and free of disease 88 months after diagnosis (range, 73 to 97 months). In the case-patient group, 8 patients (66.7%) died of recurrent colorectal cancer after 13 months of disease-free survival (range, 3 to 35 months) and after 19 months of overall survival (range, 9 to 64 months). Four patients (33%) were alive with metastases after 12 months of disease-free survival (range, 2 to 36 months) and 52 months of overall survival (range, 17 to 78 months). Analysis by Reverse Transcriptase Polymerase Chain Reaction of RNA Expression in Lymph Nodes For all 28 patients, 524 lymph nodes (mean, 18.4 12.5 lymph nodes per patient) collected at surgery were reported to be free of tumor in the original histologic review. The number of lymph nodes obtained from each patient at the time of initial operative staging was similar in the control group (mean, 19.9 13.2 lymph nodes per patient) and the case-patient group (mean, 17.2 12.7 lymph nodes per person). Lymph nodes were omitted from RT-PCR analysis because they were not available from the pathology department (326 lymph nodes from 28 patients [62.2% of 524 lymph nodes obtained at surgery]). Of the 198 lymph nodes that were available for RT-PCR analysis, 19.7% (39 lymph nodes from 7 patients [7.4% of 524 lymph nodes obtained at surgery]) did not yield RNA. The number of lymph nodes available for RT-PCR analysis was similar in the control group (mean, 6.4 3.0 lymph nodes) and the case-patient group (mean, 8.1 6.3 lymph nodes). Twenty-one patients (75%) yielded 159 paraffin-embedded lymph nodes (mean, 7.6 5.2 lymph nodes per patient) that could be adequately evaluated by RT-PCR. In 5 case-patients (41.7%) and 2 controls (16.7%), -actin-specific amplicons (an indicator of intact RNA) were not detected in the total RNA from pooled sections of lymph nodes; these 7 patients were excluded from further analysis. Total RNA extracted from the pooled lymph node sections of the remaining 21 patients was analyzed by RT-PCR using guanylyl cyclase C-specific primers. Guanylyl cyclase C-specific amplicons were not detected in any reaction that used RNA from lymph nodes of control

Locoregional recurrence and survival after curative resection of adenocarcinoma of the colon

BACKGROUND There is wide variability in reported locoregional recurrence rates after curative resection of adenocarcinoma of the intraperitoneal colon, and there is no universally accepted surgical technique regarding length of the resected specimen or extent of lymphadenectomy. The aim of this study was to determine the disease-free survival, locoregional failure, and perioperative morbidity of patients undergoing curative resection of colon adenocarcinoma. STUDY DESIGN The records of 316 consecutive patients undergoing curative resection for primary adenocarcinoma of the intraperitoneal colon between 1990 and 1995 were reviewed. Locoregional recurrence was defined as disease at the anastomosis or in the adjacent mesentery, peritoneum, retroperitoneum, or carcinomatosis. The product-limit method (Kaplan-Meier) was used to analyze survival and tumor recurrence. RESULTS The study population comprised 167 men and 149 women, mean age 70+/-12 years (range 22 to 95 years). Median followup was 63+/-25 months. Five-year disease-free survival was 84% overall. Disease-free survival paralleled tumor stage: stage I, 99% (n = 73); stage II, 87% (n = 151); stage III, 72% (n = 92). The predominant pattern of tumor recurrence was distant failure only. Overall locoregional recurrence (locoregional and locoregional plus distant) at 5 years was 4%. Locoregional recurrence paralleled tumor stage: stage I, 0%; stage II, 2%; stage III, 10%. Of the 12 patients who suffered locoregional recurrence, 9 (75%) had T4 primary tumors, N2 nodal disease, or both. Major and minor complications occurred in 93 patients (29%) including: anastomotic leak or intraabdominal abscess (n = 4, 1%); hemorrhage (n = 8, 3%); cardiac complications (n= 17, 5%); pulmonary embolism (n=4, 10%); death (n=2, 1%). Multivariate analysis (Cox proportional hazards) revealed that the only independent predictor of disease-free survival and locoregional control was tumor stage. CONCLUSION Longterm survival and locoregional control can be achieved for patients with colon cancer, with low morbidity. In the absence of adjacent organ invasion and N2 nodal disease, locoregional recurrence should be a rare event. Just as for rectal cancer, the technical aspects of colectomy for colon cancer deserve renewed attention.

Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0,N0 pathology

PURPOSE: The postradiation preoperative staging results of 25 patients with rectal cancer who were found to have Stage T0,N0 lesions after surgery were examined. Our aim was to assess the ability of preoperative staging following radiation therapy to predict the absence of disease. METHODS: From 1983 to 1994, 25 patients treated with preoperative radiation therapy for biopsy-proven rectal cancer were found to have no pathologic evidence of disease in the resected specimen (T0,N0). The preoperative postradiation disease staging results of these patients were compared with the postoperative pathologic findings. Each patient received 4,500 to 5,580 cGy during a five-week to six-week period, and four patients had preoperative chemotherapy. Surgical resection was performed six to eight weeks after completion of radiation therapy. All 25 patients were staged by digital rectal examination before surgery. In addition, 13 patients were assessed using computed tomography, 6 by endorectal ultrasound, and 1 by magnetic resonance imaging. RESULTS: Most irradiated lesions were overstaged by radiologic assessment and physical examination. No technique could reliably distinguish between postradiation fibrosis and residual cancer. The negative predictive value for digital rectal examination was 24 percent. Computed tomography accurately staged 23 percent of lesions, and endorectal ultrasound predicted 17 percent of lesions correctly. The single patient evaluated by magnetic resonance imaging was overstaged and thought to have a T2 lesion. CONCLUSIONS: Our ability to assess local eradication of rectal cancer following radiation therapy remains poor. Conventional imaging and clinical examination techniques are unable to safely predict which patients do not require surgical excision following curative radiation therapy for rectal cancer.

Changing epidemiology of anorectal melanoma.

PURPOSE: We reviewed 117 cases of anorectal melanoma to better define epidemiologic and survival characteristics of this rare neoplasm. METHODS: The National Cancer Institute Surveillance, Epidemiology, and End Results database covering the period 1973 through 1992 was used. This represents 9.5 percent of the United States population. Melanoma arising in the anorectum was identified using International Classification of Diseases for Oncology codes. Two-tailed Studentst-test, chi-squared, and Wilcoxons tests were used for comparisons of means, proportions, and actuarial survival rates, respectively. RESULTS: One hundred seventeen cases of anorectal melanoma were identified, representing 0.048 percent of all colorectal malignancies in the database. The male-to-female ratio was 1:1.72. The mean age was 66±16 years. Mean age by gender, however, was lower for males (57 years) then for females (71 years;P<0.001). The age difference represents an increased incidence of anorectal melanoma in males younger than the age of 45 years. Furthermore, the incidence of anorectal melanoma in young males ages between 25 to 44 years tripled in the San Francisco area when compared with all other locations (14.4vs. 4.8 per 10 million population;P=0.06). Males have a survival advantage over females (62.8 percentvs. 51.4 percent 1-year and 40.6 percentvs. 27.7 percent 2-year;P<0.01). CONCLUSIONS: The overall incidence of anorectal melanoma continues to rise and survival rates remain poor. A new trend toward bimodal age distribution was observed. There is indirect evidence that implicates human immunodeficiency virus infection as a risk factor. Survival rate is better in young patients aged 25 to 44 years.

Laparoscopic-assisted and minilaparotomy approaches to colorectal diseases are similar in early outcome

OBJECTIVE: The purpose of this study was to compare laparoscopy with minilaparotomy approaches to colorectal diseases. METHOD: Outcomes after minilaparotomy and laparoscopy were prospectively compared for a 12-month period. RESULTS: Minilaparotomy was performed in 35 patients to achieve right colectomy (14), left colectomy (8), total colectomy (2), low anterior resection (6), abdominoperineal resection (2), colostomy (1), and ileal resection (1). Laparoscopic techniques were used in 52 patients to perform right colectomy (20), left colectomy (11), low anterior resection (5), abdominoperineal resection (7), total colectomy (3), ileal resection (1), colostomy (3), transverse colectomy (1), and colostomy closure (1). Mean operative times were 69 minutes for minilaparotomy (range, 33–180) and 173 minutes for laparoscopy (range, 60–300). Mean incision lengths were 12 (range, 8–18) cm and 8 (range, 0–25) cm; mean time to bowel movement was four (range, 1–7) days and 3-9 (range, 0–8) days; mean day of discharge was 6.9 (range, 3–15) days, and 6 (range, 1–15) days postoperatively, respectively. Laparoscopy procedures were completed in 39 of 52 patients (75 percent); mean time to bowel movement was 3-5 (range, 0–6) days, and mean day of discharge was 5.3 (range, 1–14) days (P=<0.005). CONCLUSION: The use of a small incision, whether by minilaparotomy or by laparoscopy, results in similar early return of function and discharge.

Accuracy of transrectal ultrasound in predicting pathologic stage of rectal cancer before and after preoperative radiation therapy

Transrectal ultrasound (TRUS) and CT scan staging of rectal cancers before, and TRUS staging after, 45 Gy of irradiation were compared with the pathologic stage of the resected specimen in 19 patients. Accuracy of TRUS before and after irradiation, and of CT scan before irradiation, was 32 percent, 63 percent, and 53 percent, respectively. CT scan before and TRUS after irradiation predicted lymph node involvement in 79 percent and 68 percent of cases, respectively. Positive predictive value for lymph node involvement before irradiation was 60 percent for CT scan and 37.5 percent for TRUS; after irradiation, it was 50 percent for TRUS. Negative predictive value was 100 percent for CT scan and TRUS before radiation and 88 percent for TRUS after irradiation. Preoperative radiation therapy makes TRUS and CT scan less effective as staging techniques. The absence of lymph nodes on TRUS and CT scan before and after irradiation is reliable.

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.

Surgeon specialty is associated with outcome in rectal cancer treatment.

AbstractPURPOSE: The aim of this study was to determine the effect of surgeon specialty on disease-free survival and local control in patients with adenocarcinoma of the rectum. Patients underwent curative treatment with neoadjuvant external beam radiotherapy and proctectomy by colorectal surgeons and noncolorectal surgeons. METHODS: The records of 384 consecutive patients treated by colorectal surgeons (n = 251) and noncolorectal surgeons (n = 133) from 1977 to 1995 were reviewed independently by physicians in the Division of Radiation Oncology. Local recurrence was defined as pelvic recurrence occurring in the presence or absence of distant metastatic disease. RESULTS: The study population comprised 213 males, mean age 64 (range, 19–97) years. Preoperative radiotherapy was delivered as 4,500 cGy in 25 fractions six to eight weeks before surgery (n = 293) or 2,000 cGy in 5 fractions immediately before surgery (n = 91). Concurrent preoperative chemotherapy was given to 14 patients, postoperative chemotherapy to 55. Overall actuarial disease-free survival and local control rates were 74 and 90 percent, respectively, at five years. Actuarial disease-free survival and local control rates at five years were 77 and 93 percent for colorectal surgeons vs. 68 and 84 percent for noncolorectal surgeons (P ≤ 0.005 for both, Tarone-Ware). Multivariate analysis revealed that pathologic stage and background of the surgeon were the only independent predictors of disease-free survival (both P ≤ 0.006, Cox proportional hazards) and that pathologic stage, background of the surgeon, and proximal location of the tumor were independent predictors of local control (all P ≤ 0.02, Cox proportional hazards). Radiation dose and use of chemotherapy were not significant factors. Sphincter preservation was more common by colorectal surgeons (131/251, 52 percent) than noncolorectal surgeons (40/133, 30 percent; P = 0.00004, Fisher’s exact test, two-tailed). CONCLUSION: Good outcome for patients with adenocarcinoma of the rectum who undergo neoadjuvant external beam radiotherapy and proctectomy is associated with subspecialty training in colon and rectal surgery.