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Background: It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy., Aims: The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer., Patients: One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002., Methods: The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded., Results: Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage., Conclusions: Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.

Background: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation., Methods: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses., Results: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases., Conclusions: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

Background: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer., Methods: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT., Results: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months., Conclusions: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Purpose: Sentinel lymph node mapping using radiolabeled tracer and blue dye is widely accepted and applied for staging melanoma. Common practice involves injection of radiolabeled tracer on the morning of surgery. However, optimal timing of radiolabeled colloid injection with respect to surgery remains debated. Injection on the day before surgery would offer the advantages of increased scheduling flexibility and decreased radiation exposure to the patient and operating room staff. We hypothesized that a single injection of radiolabeled colloid given 24 hours before surgery would be sufficient and would possibly improve intraoperative sentinel lymph node identification., Patients and Methods: Ninety-five patients with newly diagnosed cutaneous melanoma underwent injection of radiolabeled colloid and lymphoscintigraphy 18 to 24 hours before surgery for sentinel lymph node mapping and biopsy. Sixty-three patients underwent repeat imaging immediately before surgery, and the images were compared with those obtained the previous day. Intraoperative mapping utilized a hand-held gamma probe and injection of blue dye to identify sentinel lymph nodes., Results: Two hundred fifty-one sentinel lymph nodes were identified by initial lymphoscintigraphy in 95 patients. Delayed imagingwithout reinjection of radiolabeled tracer compared with the initial lymphoscintigraphy demonstrated no change (71%), clarification of initial ambiguous patterns (10%), or newly identified nodes (19%). Two hundred sixty-one sentinel lymph nodes were resected, of which 79% stained blue. Microscopic metastases were present in 20 sentinel lymph nodes (8%) in 19 patients (20%). All positive nodes contained radioactivity and blue dye., Conclusions: A single injection of radiocolloid 24 hours before surgery combined with intraoperative blue dye injection identified all sentinel lymph nodes and did not miss any metastatic disease. In addition, delayed imaging may clarify initial ambiguous findings and identify additional nodes at risk for metastasis. This technique produces sentinel lymph node identification rates, harvest rates, and rates of positivity comparable to those reported with the use of injection of radiolabeled tracer on the day of surgery and greatly facilitates the technical and administrative aspects of sentinel lymph node mapping.

Objective: To examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma., Summary Background Data: Preoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates., Methods: A retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil +/- cisplatin and 4,500-5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival., Results: Median follow-up was 27 months, and mean age was 59 years (range 28-81). Mean tumor distance from the anal verge was 6 cm (range 1-15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival., Conclusions: Neoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Background: There is good prognostic correlation for the two microstaging systems, Breslow depth and Clark level, commonly used to stage melanomas. Many investigators have reported that Breslow depth is the superior microstaging method. Although Clark level has been dropped from most of the proposed American Joint Committee on Cancer (AJCC) melanoma staging system, the AJCC system still includes Clark Level IV as a criterion for upstaging thin melanomas. The authors sought to determine whether this is appropriate, based on melanoma patient data in the Duke Comprehensive Cancer Center database., Methods: Of the 8833 patients registered between January 1, 1970 and December 31, 1995, complete data on Breslow depth and Clark level was available for 4560 patients who were without nodal or metastatic disease at presentation. Ten-year survival was measured from the date of excision of the primary tumor until death from melanoma and analyzed using Kaplan-Meier and Cox proportional hazard methodologies., Results: When analyzed separately, both increased Breslow thickness and Clark level correlated with shorter survival times. During subgroup analysis, Breslow thickness remained a significant prognostic indicator of survival at Clark Levels III and IV. Conversely, at narrow levels of Breslow thickness (i.e., 0-0.75 mm, > 0.75 -1.0 mm, > 1.0-1.5 mm) survival times were indistinguishable between Clark Levels III and IV. For the broader Breslow thickness interval of 0-1.0 mm, a barely significant difference between Clark Levels III and IV could be obtained. However, for this thickness range, even greater differences in survival could be obtained by merely comparing Breslow subgroups (i.e., < or = 0.8 mm vs. > 0.8-1.0 mm, < or = 0.9 mm vs. > 0.9-1.0 mm)., Conclusion: The authors' data suggested that, after controlling for Breslow depth, Clark level was not a good prognostic indicator for survival. If the AJCC's objective is to design a classification system that will reliably predict the higher risk melanomas, then the system should be based on tumor thickness, which is clearly a better prognostic indicator, and should not be modified because of Clark level., (Copyright 2001 American Cancer Society.)

Regional lymph node metastasis is a powerful predictor of decreased overall survival from malignant melanoma. However, the therapeutic value of elective node dissections and the role of adjuvant therapy for node-positive disease have been highly controversial. Sentinel lymph node biopsy has reshaped the debate by allowing for staging of the regional lymph nodes with less morbidity and greater accuracy. This review summarizes the current consensus on the management of node-positive melanoma in the era of sentinel lymph node biopsy.

Objective: To describe a large series of patients with carcinoid tumors in terms of presenting symptoms, hormonal data, stage at diagnosis, pathologic features, and survival., Summary Background Data: Published series have described significant prognostic features of carcinoid tumors as site of origin, age, sex, stage at diagnosis, presence of high hormone levels, and increased T stage. Of these, stage at diagnosis and T stage seem to emerge most often as independent predictors of survival in multivariate analyses. Of carcinoid tumors, those arising from a midgut location have higher levels of serotonin and serotonin breakdown products, as well as more frequent metastatic disease at presentation, than those arising from either foregut or hindgut locations., Methods: A prospective database of carcinoid patients seen at Duke University Medical Center was kept from 1970 to the present. Retrospective medical record review was performed on this database to record presenting symptoms, hormonal data, pathologic features, and survival. Statistical methods included analysis of variance, Kaplan-Meier analysis, and Mantel-Cox proportional hazard survival analysis, with P <.05 considered significant for all tests., Results: Carcinoids arising in different locations had different presentations: rectal carcinoids presented significantly more often with gastrointestinal bleeding, and midgut carcinoids presented significantly more often with flushing, diarrhea, and the carcinoid syndrome. Patients with midgut tumors had significantly higher levels of serotonin and serotonin breakdown products, corresponding to higher metastatic tumor burdens. Although age, stage, region of origin, and urinary level of 5-hydroxyindoleacetic acid predicted survival by univariate analysis, only the latter three were independent predictors of survival by multivariate analysis. Of the patients with metastatic disease at diagnosis, those with midgut tumors had better survival than those with foregut or hindgut tumors., Conclusions: Although region of origin is certainly an important factor in determination of prognosis, stage of disease at presentation is more predictive of survival. Pancreatic and midgut carcinoids are metastatic at diagnosis more often than those arising in other locations, leading to a worse overall prognosis. Among patients with distant metastases, patients with midgut primary tumors have improved survival despite increased hormone production compared with patients with tumors arising in other primary sites.

Background: Several recent studies have demonstrated the low yield of anatomically based computed tomography scans in evaluating Stage III (American Joint Committee on Cancer) patients with malignant melanoma. The purpose of this study was to investigate the efficacy and clinical utility of functionally based positron emission tomography (PET) scans in the same patient population., Methods: A prospective evaluation of 106 whole body PET scans obtained after injection of 2-fluorine-18, 2-fluoro-2-deoxy-D-glucose (FDG) was performed in 95 patients with clinically evident Stage III lymph node and/or in-transit melanoma. Areas of abnormality on FDG PET scanning were identified visually as foci of increased metabolic activity compared with background, and all positive foci were assessed pathologically., Results: In this patient population, there were 234 areas that were evaluated pathologically of which 165 were confirmed histologically to be melanoma. PET scanning identified 144 of the 165 areas of melanoma for a sensitivity of 87.3%. The 21 areas of melanoma that were missed included 10 microscopic foci, 9 foci less than 1 cm, and 2 foci greater than 1 cm. There were 39 areas of increased PET activity that were not associated with malignancy for a 78.6% predictive value of a positive test. Of the 39 false-positive areas (false-positive rate of 56.5%), 13 could be attributed to recent surgery, 3 to arthritis, 3 to infection, 2 to superficial phlebitis, 1 to a benign skin nevus, and 1 to a colonic polyp. Pathologic evaluation of the remaining false-positive areas failed to reveal a definitive etiology for their increased activity on PET scan. With the application of pertinent clinical information, the predictive value of a positive PET scan could be improved to 90. 6%. The specificity of PET scanning in this study was only 43.5% because very few prophylactic lymph node dissections were performed. Thirty-six of the total 183 abnormal areas (19.7%) on PET scanning proved to be unsuspected areas of metastatic disease. These findings led to a change in the planned clinical management in patients after 16 of the 106 PET scans (15.1%)., Conclusions: FDG PET scanning can be helpful in managing patients with Stage III melanoma in whom further surgery is contemplated. Although false-positive areas are not uncommon, PET scans did change the management of patients 15% of the time. PET's inability to identify microscopic disease suggests that it is of limited use in evaluating patients with Stage I-II disease.

Background: Frozen section evaluation has been reported to be inaccurate in detecting foci of adenocarcinoma within adenomas of the ampulla of Vater, leading many authors to advocate pancreaticoduodenectomy as the method of treatment for these neoplasms. The authors hypothesized that (1) ampullary resection is less morbid than pancreaticoduodenectomy, and (2) frozen section evaluation following ampullary resection is accurate and allows for a selective application of pancreaticoduodenectomy to those with carcinoma or benign lesions too large to be locally resected., Methods: A retrospective review of a single-surgeon experience was conducted. Thirty-eight patients who underwent ampullary resection and pancreaticoduodenectomy (39 procedures) for benign and malignant ampullary neoplasms were identified. Our technique of step-frozen section analysis is described., Results: Twenty-one ampullary resections were performed for preoperative diagnoses of benign (16) and malignant (5) ampullary neoplasms. Frozen section evaluation accurately predicted the final histology in all patients undergoing ampullary resection. Ampullary resection (vs pancreaticoduodenectomy) was associated with a statistically lower operative time (169 minutes vs 268 minutes), estimated blood loss (192 mL vs 727 mL), mean length of stay (10 days vs 25 days), and overall morbidity (29% vs 78%)., Conclusions: Frozen section evaluation of ampullary neoplasms is accurate. Because ampullary resection is less morbid than pancreaticoduodenectomy and frozen section evaluation is accurate, ampullary resection with frozen section evaluation is our current approach to the treatment of small benign ampullary neoplasms.

Background: Gastrointestinal foregut carcinoids make up a small percentage (3% to 6%) of all reported carcinoids. Because these tumors are so uncommon, comparisons between the subtypes have been difficult. The goal of this study was to compare the hormonal and clinical characteristics of gastric, duodenal, and pancreatic carcinoids., Methods: A prospective database of approximately 750 carcinoid patients seen by one author over 25 years was reviewed, and the 104 patients with gastric (33), duodenal (17), or pancreatic (54) carcinoids were selected as the subgroup for analysis. These patients were compared with regard to hormone levels, clinical course, treatment, and survival., Results: Duodenal carcinoids exhibited significantly lower serotoninergic hormone levels than did the gastric and pancreatic carcinoids (urine 5-hydroxyindoleacetic acid [mg/24 h], 5 +/- 1 vs 16 +/- 5 and 47 +/- 12, respectively, P = .03). Pancreatic carcinoids presented with more advanced stage (distant metastases 87% vs 42% and 20% for gastric and duodenal, respectively) and had worse outcomes than patients with gastric and duodenal tumors with 10-year survivals of 10%, 59%, and 58%, respectively (P = .003)., Conclusions: Pancreatic carcinoids produce higher levels of serotoninergic hormones and have a significantly higher stage and worse outcome than other foregut carcinoids. This study demonstrates that the organ of origin is an important determinant of hormonal activity and clinical course for patients with foregut carcinoids.

The diagnosis and management of follicular carcinoma of the thyroid gland remains a controversial topic. Fine needle aspiration, although very sensitive with other types of thyroid cancer, has limited accuracy with follicular lesions. The role of suppression combined with observation has yet to gain widespread acceptance. The extent of surgical excision of follicular carcinoma also raises several competing views. The goal of this review is to address these issues and present an algorithm for the management of follicular neoplasms of the thyroid.

Background: Carcinoids are rare neuroendocrine tumors typically arising in the gastrointestinal tract. A significant percentage of these tumors present as metastatic disease of unknown primary site. The aim of this study was to better define the functional and clinical characteristics of carcinoids of unknown primary (CUP) site., Methods: This study examines the hormonal activity, clinical characteristics, and survival of 434 patients with carcinoids originating in the foregut, midgut, hindgut, or unknown location. The 143 patients with CUP were compared with the other groups with regard to presenting characteristics, diagnostic tests and therapeutic modalities used, hormonal activity, and survival., Results: The hormone levels (urinary 5-hydroxyindoleacetic acid and serotonin, serum and platelet serotonin) of CUP were not significantly different from midgut carcinoids with metastatic disease. Although survival with CUP was shorter than with carcinoids with identified primaries (10-year survivals of 22% vs 62%, 50%, and 48% for foregut, midgut, and hindgut, respectively), the survival curve for CUP was quite similar to that of patients with midgut carcinoids with distant disease (10-year survival of 22% vs 28%)., Conclusions: CUP are similar to midgut carcinoids presenting with metastatic disease with regard to hormone production and survival. Like other carcinoids, CUP can be an indolent disease process with gradual progression over decades.

Background: Melanomas arising from the mucous membranes lining the respiratory, digestive, and genitourinary tracts are rare. Women are more commonly affected than are men, mainly because there is no male counterpart for vulvovaginal lesions. The mainstay of therapy is surgery, with little current use of adjuvant modalities in primary therapy. These lesions usually are advanced at initial presentation; consequently, the prognosis is poor, with 5-year survivals well below 50% in most series., Methods: One hundred and nineteen patients with primary mucosal melanoma were reviewed. They represented 1.1% of the 10,393 melanoma patients seen at Duke University between 1970 and 1995. All data were obtained from the patients' clinic charts and computerized databases., Results: There were 43 tumors arising from the head and neck region, 46 from the urogenital tract, and 30 from the anorectum. A female predominance was observed, with a female-to-male ratio of 2.7:1. All but five of the patients underwent resection with curative intent. Regional or distant metastases, or both, were encountered in 36 patients at the time of presentation. In patients with head and neck and urogenital tumors, local recurrences accounted for most of the treatment failures, whereas systemic recurrences were more common with tumors arising in the anorectum. The age and gender of the patient, anatomic site of origin of the tumor, clinical stage at initial presentation, and ulceration of the primary all clearly affected prognosis. Overall, the probabilities of being alive 1, 5, and 10 years after diagnosis were 80%, 29%, and 15%, respectively., Conclusions: Widely accepted classification systems are needed so that results from separate institutions can be compared adequately. Multi-institutional trials could help in delineating standardized therapeutic protocols and in establishing the potential roles of emerging modalities in the treatment of this subtype of melanoma.

Lymphocytes from HIV-1-seropositive and -seronegative individuals were examined to determine whether HIV-1 infection interfered with the ability to generate a lymphokine-activated killer (LAK) cell response. Following a 3-day ex vivo incubation in the presence of 1000 U/ml of recombinant interleukin-2, lymphocytes from seropositive individuals exhibited a LAK cell response which was equivalent to or greater than that of seronegative controls as measured against Daudi cell targets. LAK cells from seropositive and seronegative donors showed no specific cytolytic activity against gp120-coated or HIV-1-infected targets. However, in the presence of patient sera, significant levels of virus-specific LAK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) were observed. The level of this specific LAK cell-mediated ADCC was greater than that mediated under similar conditions by freshly isolated peripheral blood mononuclear cells. The greatest improvement in ADCC over baseline activity was seen with lymphocytes from AIDS patients after the 3-day ex vivo activation, suggesting that this patient population might benefit the most from adaptive LAK cell therapy., (Copyright 1998 Academic Press.)

Laparoscopic evaluation of patients with suspected periampullary malignancies has been utilized more frequently in recent years. Its exact role with regard to staging and surgical bypass for palliation have yet to be clearly defined. To better define the role of laparoscopy in the evaluation and palliation of periampullary malignancy, a retrospective review of the Duke experience was carried out. Fifty-three patients with suspected pancreatic or periampullary malignancies were referred for surgical evaluation at Duke University Medical Center between 1993 and 1995. All patients underwent CT scanning and lesions were classified as resectable or unresectable based on previously established criteria. Patients either underwent laparoscopic evaluation (n = 30; 11 with laparoscopic palliation) or proceeded directly to celiotomy (n = 23). Charts were reviewed for postoperative course including complications, length of stay, and hospital costs. Although laparoscopy had a sensitivity of 93.3% for metastatic disease, CT scans accurately staged 86.8% of patients missing only one patient with peritoneal/hepatic disease. Based on these results, laparoscopy may not be beneficial for every patient with a suspected pancreatic malignancy. Retrospectively an attempt was made to determine which patients benefited from laparoscopy and which patients are best served by proceeding directly to open exploration. From these data we devised an algorithm that outlines an efficient and cost-effective approach for this patient population.

Objective: In this study, the impact of preoperative chemotherapy and radiation on the histopathology of a subgroup of patients with rectal adenocarcinoma was examined. As well, survival, disease-free survival and pelvic recurrence rates were examined, and compared with a concurrent control group., Summary Background Data: The optimal treatment of large rectal carcinomas remains controversial; current therapy usually involves abdominoperineal resection plus postoperative chemoradiation; the combination can be associated with significant postoperative morbidity. In spite of these measures, local recurrences and distant metastases continue as serious problems., Methods: Fluorouracil, cisplatin, and 4500 cGy were administered preoperatively over a 5-week period, before definitive surgical resection in 43 patients. In this group of patients, all 43 had biopsy-proven lesions > 3 cm (median diameter), involving the entire rectal wall (as determined by sigmoidoscopy and computed tomography scan), with no evidence of extrapelvic disease. The patients ranged from 31 to 81 years of age (median 61 years), with a male:female ratio of 3:1. A concurrent control group consisting of 56 patients (median: 62 years, male:female ration of 3:2) with T2 and T3 lesions was used to compare survival, disease-free survival, and pelvic recurrence rates., Results: The preoperative chemoradiation therapy was well tolerated, with no major complications. All patients underwent repeat sigmoidoscopy before surgery; none of the lesions progressed while patients underwent therapy, and 22 (51%) were determined to have complete clinical response. At the time of resection, 21 patients (49%) had gross disease, 9 (22%) patients had only residual microscopic disease, and 11 (27%) had sterile specimens. Of the 30 patients with evidence of residual disease, 4 had positive lymph nodes. In follow-up, 39 of the 43 remain alive (median follow-up = 25 months), and only 1 of the 11 patients with complete histologic response developed recurrent disease. Six of the 32 patients with residual disease (2 with positive nodes) have developed metastatic disease in follow-up (median time to diagnosis 10 months, range 3-15 months). Three of these patients with metastases have died (median survival after diagnosis of metastases = 36 months). Local recurrence was seen in only 2 of 43 patients (< 5%). Cox-Mantel analysis of Kaplan-Meier distributions demonstrated increased survival (p = 0.017), increased disease-free survival (p = 0.046), and decreased pelvic recurrence (p = 0.031) for protocol versus control patients., Conclusions: This therapeutic regimen has provided enhanced local control and decreased metastases. Furthermore, the marked degree of tumor downstaging, as seen by a 27% incidence of sterile pathologic specimens and a low rate of positive lymph nodes in this group with initially advanced lesions, strongly suggest that less radical surgery and sphincter preservation may be used with increasing frequency.

To determine whether IL-1 alpha and/or IL-1 beta protein is expressed by human melanoma tumor in vivo, we first analyzed nine human melanoma cell lines and optimized the in situ detection of these proteins. Three of the melanoma cell lines stained positively for both IL-1 alpha and IL-1 beta using immunohistochemistry (IHC). THe specificity of IHC was confirmed by the ability of purified recombinant IL-1 alpha and IL-1 beta protein to abolish the staining after being adsorbed by their respective antibodies before use in IHC. The three positively staining cell lines were also the only lines to demonstrate IL-1 production by western blot analysis as well as IL-1 secretion by ELISA. Next we examined 29 surgically obtained melanoma tumor specimens (6 primary and 23 metastases) that had been formalin fixed and paraffin embedded. Using the same anti-IL-1 antibodies, 5 of 23 metastatic tumors stained positively. None of the 6 primary lesions stained for either IL-1 alpha or IL-1 beta. Comparison of staining pattern performed on serially sectioned tissue using preimmune serum and antibodies against S-100 protein, melanoma-associated antigen (HMB-45), and CD68 (kappa P1), which recognizes monocyte-macrophage cell lineage, demonstrates for the first time that IL-1 protein is produced by human melanoma tumor cells in vivo. These findings provide the basis for examination of what may be a previously unrecognized biologically distinct subset of patients.