More is less: systemic treatment for local control in soft tissue sarcoma.
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Publications and source records attributed to M F Brennan.
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BACKGROUND: Limb salvage after primary site failure of extremity soft tissue sarcoma is a challenging problem. Amputation may be the most effective treatment option in selected patients with local recurrence. We compared the outcome of patients treated with amputation versus limb-sparing surgery (LSS) for locally recurrent extremity sarcoma. METHODS: From 1982 to 2000, 1178 patients with localized primary extremity sarcoma underwent LSS. Of these, 204 (17%) developed local recurrence. Eighteen (9%) required major amputation and the remainder underwent LSS, of which 34 were selected for matched-pair analysis according to established prognostic variables. Rates of recurrence or death were estimated by the Kaplan-Meier method. Following adjustment for prognostic variables, a Mantel-Haenszel test was used to compare the outcome between the two treatment groups. RESULTS: Patients in each group were well matched. All patients had high-grade tumors deep to the fascia. Median time to local recurrence was similar for both groups. Median follow-up was 95 months. Amputation was associated with a significant improvement in local control of disease (94% vs. 74%; P = .04). We observed no difference in disease-free (P = .48), disease-specific (P = .74), or overall survival (P = .93) between the two groups. Median postrecurrence survival was 20 months and 5-year OS was 36% for the entire study group. CONCLUSIONS: Limb-sparing treatment achieves local control in the majority of recurrent extremity sarcomas for which amputation is infrequently indicated. Amputation improves local disease control but not survival under these circumstances.
BACKGROUND: We have developed a method to identify, filter, review, and distribute the published level I evidence for solid tumor oncology. METHODS: A standardized MEDLINE search identified prospective randomized controlled trials (PRCTs) in solid tumor oncology. Only PRCTs with therapeutic end points were included. All references were reviewed by a surgical oncology fellow in consultation with experts in the field. The full citations were imported into a comprehensive database. Data on statistical methods according to the Consolidated Standard of Reporting Trials statement were tabulated along with reviewer's comments. A designation of Ia was given to articles that were well designed and significant contributions to their field. The database powers a dynamic, easily searchable Web site on our intranet and is available in personal digital assistant (PDA) format. RESULTS: By using standard search criteria, only .03% of the 11 million articles listed in MEDLINE are PRCTs concerning therapy for solid organ malignancies. Approximately 14% of reviewed articles were given a designation of Ia. Having comprehensive data readily available with intranet access or PDAs during conferences enhances their educational value and specificity. CONCLUSIONS: We have developed an exciting tool that uses a highly trained filter to screen and record the medical data available to the clinician. This information has been made available and portable by using the Internet and PDAs.
Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).
BACKGROUND: Sott tissue sarcomas (STS) of the groin may present a difficult problem because or misdiagnosis as groin hernia and proximity to major neurovascular structures. We evaluated our management and survival in a large cohort of patients. STUDY DESIGN: Patients treated between July 1, 1982 and July 1, 1998 with primary or recurrent STS of the groin were included. Groin sarcomas were defined as those tumors within 5 cm of the inguinal crease. Patient, tumor, clinical, and survival data were analyzed using a log rank test and Cox regression. RESULTS: We treated and followed 88 patients with STS of the groin. The median age was 52 years (range 16 to 86 years) and 55 patients (63%) were male. Disease-specific survival was 72% at 5 years. Tumors tended to be larger than 5 cm (52%), deep (72%), and high-grade (60%). Unfavorable prognostic factors for disease-specific survival were high grade (p < 0.001), neurovascular invasion (p < 0.001), positive margin (p < 0.01), deep depth (p < 0.01), and selection for adjuvant therapy (p < 0.005). Multivariate analysis indicated age greater than 50 years (p < 0.05), high grade (p < 0.001), neurovascular invasion (p < 0.001), and positive microscopic margins (p < 0.001). Fourteen patients (16%) were diagnosed with STS at hernia operation then went on to a definitive operation with no impact on survival. Seventeen patients (19%) had involvement of a major vessel or nerve, and 5 of these ultimately required amputations, 3 for local recurrence. CONCLUSIONS: High grade, neurovascular invasion, and positive microscopic margins are associated with poor outcomes. The biology of these tumors is similar to other extremity STS, and similar principles of management apply. Even with neurovascular involvement, most patients with primary groin STS do not require amputation.
Complete surgical resection is the most effective modality for the treatment of retroperitoneal sarcomas. Previous studies of all types of retroperitoneal sarcomas have not shown a survival benefit of incomplete resection over no resection. Because death often occurs as a result of local progression in retroperitoneal liposarcomas (RPLS), it is possible that incomplete resection may be beneficial in this histologic type. In this study we have sought to determine the clinical outcomes in patients with incompletely resected and unresected RPLS with the aim of defining patients who may benefit from palliative resection. From a prospective clinical database 55 patients with incompletely resected (n = 43) or unresected (n = 12) RPLS were identified between 1982 and 1999. Statistical analyses were performed using the log-rank test and Kaplan-Meier estimates with disease-specific survival as the primary end point. Variables studied included age, gender, recurrent versus primary disease, tumor grade, and tumor size. The patient population consisted of 34 men and 21 women with a mean age of 61 +/- 14 (SD) years. The median time to death was 10 months (range 1 to 83 months) with a median followup of 12 months (range 1 to 60 months) for survivors. Partial resection was an independent factor for increased survival as compared with exploration or biopsy only (median survival 26 versus 4 months, p < 0.0001). Of patients who received incomplete resections, locally recurrent presentation (n = 19) versus primary disease (n = 24) was a negative prognostic variable (median survival 17 versus 46 months, p = 0.009). Successful palliation of symptoms was achieved in 24 of 32 patients (75%) with preoperative symptoms. In select patients with unresectable RPLS, incomplete surgical resection can provide prolongation in survival and successful symptom palliation. Most likely to benefit are those patients presenting with primary tumors, suggesting that surgical resection should be attempted in the majority of patients.
BACKGROUND: Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex. METHODS: From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews. RESULTS: Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%). CONCLUSIONS: Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.
In the past, colloid (mucinous noncystic) carcinoma (CC) of the pancreas had been included under the category of ordinary ductal adenocarcinoma, a tumor with a dismal prognosis, or was frequently misdiagnosed as mucinous cystadenocarcinoma. The clinicopathologic features of CC have not yet been well characterized, because most cases on record have been parts of studies on either mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasms (IPMN), with which colloid carcinomas are frequently associated. To determine the clinicopathologic characteristics of CC, 17 pancreatic tumors composed predominantly (>80%) of CC (defined as nodular extracellular mucin lakes with scanty malignant epithelial cells) and in which the invasive carcinoma measured larger than 1 cm were studied. Ten of these were originally classified as mucinous ductal adenocarcinoma and four as mucinous cystadenocarcinoma. The mean age of the patients was 61 years; 9 were men and 8 were women. The mean size of the CC was 5.3 cm (range, 1.2-16 cm). In more than half of the patients, CC represented the invasive component of an IPMN (in nine cases) or MCN (in one case). The tumors were composed of well-defined pools of mucin with sparse malignant cells in various patterns of distribution. Signet-ring cells floating in the mucin (but not as individual cells infiltrating stroma, a characteristic finding of signet-ring cell adenocarcinomas) were commonly identified and were prominent in five cases. Perineurial invasion was noted in six cases and regional lymph node metastases in eight. Mutation in codon 12 of the k-ras gene was detected in only 4 of 12 cases studied and p53 mutation in 2 of 9. Immunohistochemical and histochemical mucin stains suggested luminalization of the basal aspects of the cells. Five-year survival was 57%. At an overall mean follow up of 57 months, 10 patients were alive with no evidence of disease (median, 79 mos), including four with lymph node metastasis, three others with perineurial invasion, and another with vascular invasion. Four patients died of disease (18, 18, 25, and 26 mos), and three died of thromboembolism (with persistent disease) at 2, 5, 10 months. All seven patients who died with or of tumor had undergone incisional biopsy of the tumor either before the operation or intraoperatively, whereas none of the patients who were alive had incisional biopsy. When compared with 82 cases of resectable ordinary ductal adenocarcinoma on whom follow-up and staging information was complete, it was found that the patients with CC present with larger tumors (p = 0.03) but lower stage (p = 0.01). The prognosis of CC is significantly better: 2-year and 5-year survival are 70% versus 28% and 57% versus 12%, respectively (p = 0.001). In conclusion, pancreatic CC may occur with or without an identifiable IPMN and MCN component, and should be distinguished from mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, and signet-ring cell adenocarcinoma. CC of the pancreas is associated with a significantly better prognosis than ordinary ductal adenocarcinoma. In addition to its distinctive morphologic and clinical characteristics, CC of the pancreas also appears to have a low incidence of mutation in codon 12 of the k-ras gene. In cases with a clinical suspicion of colloid carcinoma, the possibility that an incisional biopsy may contribute to thromboembolic complications or even dissemination of the tumor may need to be considered. The luminalization of the basal aspects of the tumor cells may be the cause of stromal mucin accumulation that characterizes colloid carcinoma and may act as a containing factor.
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OBJECTIVE: To test the hypothesis that routine intraperitoneal drainage is not required after pancreatic resection. SUMMARY BACKGROUND DATA: The use of surgically placed intraperitoneal drains has been considered routine after pancreatic resection. Recent studies have suggested that for other major upper abdominal resections, routine postoperative drainage is not required and may be associated with an increased complication rate. METHODS: After informed consent, eligible patients with peripancreatic tumors were randomized during surgery either to have no drains placed or to have closed suction drainage placed in a standardized fashion after pancreatic resection. Clinical, pathologic, and surgical details were recorded. RESULTS: One hundred seventy-nine patients were enrolled in the study, 90 women and 89 men. Mean age was 65.4 years (range 23-87). The pancreas was the tumor site in 142 (79%) patients, with the ampulla (n = 24), duodenum (n = 10), and distal common bile duct (n = 3) accounting for the remainder. A pancreaticoduodenectomy was performed in 139 patients and a distal pancreatectomy in 40 cases. Eighty-eight patients were randomized to have drains placed. Demographic, surgical, and pathologic details were similar between both groups. The overall 30-day death rate was 2% (n = 4). A postoperative complication occurred during the initial admission in 107 patients (59%). There was no significant difference in the number or type of complications between groups. In the drained group, 11 patients (12.5%) developed a pancreatic fistula. Patients with a drain were more likely to develop a significant intraabdominal abscess, collection, or fistula. CONCLUSION: This randomized prospective clinical trial failed to show a reduction in the number of deaths or complications with the addition of surgical intraperitoneal closed suction drainage after pancreatic resection. The data suggest that the presence of drains failed to reduce either the need for interventional radiologic drainage or surgical exploration for intraabdominal sepsis. Based on these results, closed suction drainage should not be considered mandatory or standard after pancreatic resection.
OBJECTIVE: To evaluate the outcome of patients with liver metastases from sarcoma who underwent hepatic resection at a single institution and were followed up prospectively. SUMMARY BACKGROUND DATA: The value of hepatic resection for metastatic sarcoma is unknown. METHODS: There were 331 patients with liver metastases from sarcoma who were admitted to Memorial Hospital from 1982 to 2000, and 56 of them underwent resection of all gross hepatic disease. Patient, tumor, and treatment variables were analyzed to assess outcome. RESULTS: Of the 56 patients who underwent complete resection, 34 (61%) had gastrointestinal stromal tumors or gastrointestinal leiomyosarcomas. Half of the patients required an hepatic lobectomy or extended lobectomy. There were no perioperative deaths in the completely resected group, although 3 of the 75 patients who underwent exploration (4%) died. The postoperative 1-, 3-, and 5-year actuarial survival rates were 88%, 50%, and 30%, respectively, with a median of 39 months. In contrast, the 5-year survival rate of patients who did not undergo complete resection was 4%. On multivariate analysis, a time interval from the primary tumor to the development of liver metastasis greater than 2 years was a significant predictor of survival after hepatectomy. CONCLUSIONS: Complete resection of liver metastases from sarcoma in selected patients is associated with prolonged survival. Hepatectomy should be considered when complete gross resection is possible, especially when the time to the development of liver metastasis exceeds 2 years.
OBJECTIVE: Surgery plays an important role in achieving local tumor control and cure for primary and metastatic tumors of the spine. As has been established with regard to sarcomas at extraspinal sites, these goals may best be achieved by en bloc resection with negative histological margins. Unfortunately, sarcomas of the spine often present with tumor patterns that are amenable only to intralesional resection, if neurological preservation is a priority. This study is a retrospective analysis of the long-term outcomes of patients who had operations for sarcomas of the spine using modern surgical approaches, intralesional resections, and spinal instrumentation. METHODS: Between 1985 and 1997, 59 patients had spinal operations for sarcoma involving the extrasacral spine. Data regarding tumor histology, grade, surgical indications, patterns of spinal tumor involvement, and neurological and functional outcomes were reviewed at presentation and at tumor recurrence. RESULTS: Thirty-five patients underwent a single operation, and 24 patients required reoperation for locally recurrent tumors. At presentation, only nine patients (15%) had tumors that were amenable to marginal or wide resections. Functional outcomes after initial spinal surgery and after operations performed at first tumor recurrence showed that 95% of patients had maintained or regained ambulation. Intradural extension of tumor was seen in 5 of 12 patients who had three or more operations for locally recurrent disease. The median survival from first spine operation was 18 months, and the median event-free interval between the first and second spine operations was 13 months. CONCLUSION: Surgery for sarcoma of the spine is useful for maintaining or improving neurological and functional outcomes, but local tumor recurrences are common. Because of the anatomy of the tumor at presentation and concern for neurological preservation, few patients are candidates for marginal or wide resections.
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PURPOSE: A specific TLS-CHOP fusion gene resulting from the t(12;16) is present in at least 95% of myxoid liposarcomas (MLS). Three common forms of the TLS-CHOP fusion have been described, differing by the presence or absence of TLS exons 6-8 in the fusion product. Type 5-2 (also known as type II) consists of TLS exons 1-5 fused to CHOP exon 2; type 7-2 (also known as type I) also includes TLS exons 6 and 7 in the fusion, whereas type 8-2 (also known as type III) fuses TLS exons 1-8 to CHOP exon 2. We sought to determine the impact of TLS-CHOP fusion transcript structure on clinical outcome in a group of well-characterized MLS cases. We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations. METHODS: We analyzed TLS-CHOP fusion transcripts by reverse-transcription PCR using RNA extracted from frozen tissue in 82 MLS confirmed previously to harbor a CHOP rearrangement either by Southern blotting or by cytogenetic detection of the t(12;16). Parameters analyzed included age, location, size, percentage of round cell (RC) component, areas of increased cellularity, necrosis, and surgical margins. In 71 (87%) cases, adequate tumor tissue was available for immunohistochemical analysis of P53 status, using DO7 antibody. The Kaplan-Meier method, log-rank, and Cox regression tests were used for survival analyses. RESULTS: Most MLS were >10 cm (73%), arising in the thigh (70%), and localized at presentation (89%). RC component was <5% in 47 (57%) cases and > or =5% in 35 (43%). The TLS-CHOP fusion transcript was type 5-2 in 55 (67%), type 7-2 in 16 cases (20%), and type 8-2 in 8 (10%). One tumor had a unique variant fusion, between exon 6 TLS and exon 2 CHOP. Two other cases (2%) showed an EWS-CHOP fusion transcript. Overexpression of P53 (defined as > or =10% nuclear staining) was detected in 12 (17%) cases. High histological grade (defined as > or =5% RC; P < 0.01), presence of necrosis (> or =5% of tumor mass; P < 0.05), and overexpression of P53 (P < 0.001) correlated with reduced metastatic disease-free survival in localized tumors. The presence of negative surgical margins (P < 0.01) and extremity location (P = 0.02) were found to be significant in predicting local recurrence in the entire group as well as localized cases by univariate and multivariate analysis. Although there was no significant correlation between TLS-CHOP transcript type and histological grade or disease-specific survival, an association was found between the P53 status and type 5-2 fusion (P < 0.01). CONCLUSION: In contrast to some other translocation-associated sarcomas, the molecular variability of TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in MLS. Instead, high histological grade (> or =5% RC), presence of necrosis, and P53 overexpression are predictors of unfavorable outcome in localized MLS.
BACKGROUND: Analyses of surgical results for gastric carcinoma often lead to the conclusion that gastric carcinoma occurring in Japan is different from that diagnosed in the U.S. METHODS: To elucidate factors that might explain the differences in surgical results between the two countries, the authors compared data from a cancer center and a university hospital in Japan and a specialist cancer hospital in the U.S (Memorial Sloan-Kettering Cancer Center [MSKCC]). RESULTS: The mean age and body mass index were significantly greater in patients in the U.S. The N category appeared to be determined less accurately at MSKCC compared with the Japanese centers. The occurrence of early gastric carcinoma was not confined to Japanese patients because 20% of U.S. patients who underwent surgery were determined to have early stage disease. However, mucosal (in situ) carcinoma was detected rarely, and the proportion of advanced stage disease was greater in the U.S. Lesions in the upper gastric body, including the gastroesophageal junction, occurred in > 50% of cases at MSKCC but in only 20% of cases at the Japanese centers (P < 0.001). D2 lymph node dissection was possible with low morbidity and minimum mortality (31% and 3%, respectively, at MSKCC). The 5-year survival rates, stratified by tumor location and T category, revealed more similar results between Japan and the U.S. than had been reported previously. The marked difference between Japanese and American institutions only was observed for T1 and T2 tumors occurring in the lower gastric body and for T3 tumors occurring in the middle and upper third of the stomach. CONCLUSIONS: Based on the findings of the current study, it would appear that the more favorable outcome noted for gastric carcinoma patients in Japan primarily is explained by the differences in tumor location, a greater frequency of early stage disease, and more accurate staging compared with gastric carcinoma patients in the U.S. Results of gastric carcinoma treatment comparable to those obtained in Japan can be obtained in Western centers.
PURPOSE: Adjuvant radiotherapy (RT) has been shown to improve local control in patients with soft tissue sarcoma of the extremities (STS). The specific impact of adjuvant radiation on patients with positive margins, however, has not been clearly defined. The purpose of this study was to determine if adjuvant RT improves local control in patients with high-grade STS who had positive margins of resection. METHODS AND MATERIALS: Between 8/82 and 2/97, 110 adult patients with primary high-grade STS of an extremity underwent limb sparing surgery and were found to have a histologically positive microscopic surgical margin. Ninety-one (83%) received RT and 19 (17%) had no RT. The two groups were balanced with regard to size, site, location, and tumor depth. Adjuvant RT was delivered with brachytherapy (BRT) alone in 34 patients, external beam radiotherapy (EBRT) alone in 33 patients, or BRT+EBRT in 24 patients. The BRT dose was 45 Gy when used alone and 15-20 Gy when used as a boost. The EBRT dose was 60-70 Gy when used alone and 45-50 Gy when given with BRT. The median follow-up time was 41 months (range, 3-186 months). RESULTS: The overall 5 year local control rate was 71%. This rate was significantly higher in the RT group compared to the no RT group (74% vs. 56%, respectively) (p = 0.01). On univariate analysis, lower extremity site and proximal location were also found to be predictors of improved local control (p = 0.03 and 0.03, respectively). However, only proximal location and the use of RT retained their significance as predictors of improved local control on multivariate analysis (p = 0.003 and 0.01, respectively). The overall 5-year distant relapse-free survival, disease-free survival, and overall survival rates were 54%, 44%, and 53%, respectively. No statistical differences were found in these survival rates between RT and no RT groups. CONCLUSION: Based on this study, adjuvant radiotherapy seems to improve local control in patients with high-grade STS of the extremity with positive margins. However, local recurrence still occurs in a substantial proportion of patients, mandating further need for improvement.
PURPOSE: We have previously shown that adjuvant brachytherapy (BRT) improves local control in soft tissue sarcoma (STS) of the extremity and superficial trunk. A detailed assessment of the morbidity of this approach has not been examined. The purpose of this study was to evaluate the toxicity associated with adjuvant BRT in terms of wound complications, bone fracture, and peripheral nerve damage. METHODS AND MATERIALS: Between July 1982 and June 1992, 164 adult patients with STS of the extremity or superficial trunk were randomized intraoperatively to receive or not to receive BRT after complete resection. BRT was delivered with (192)Ir to a total dose of 42-45 Gy. The BRT and no-BRT arms were balanced with regard to age, sex, presentation (primary vs. recurrent), site, grade, size, and depth. Morbidity was assessed in terms of significant wound complication, bone fracture, and peripheral nerve damage (grade > or = 3). The significant wound complications were defined as those wound problems requiring operative revision for coverage or threatened limb loss, persistent seroma requiring repeated aspirations and/or drainage, wound separation > 2 cm, hematoma > 25 ml, and/or purulent wound discharge. The median follow-up was 100 months. RESULTS: The significant wound complication rate was 24% in the BRT group and 14% in the no-BRT group, (p = 0.13). The rate of wound reoperation, however, was significantly higher in the BRT arm (10% vs. 0%; p = 0. 006). Examination of other covariables that may have contributed to wound reoperation revealed the width of the excised skin (WES) to be a significant factor [1% (WES < or = 4 cm) vs. 10% (WES > 4 cm), p = 0. 02]. Bone fracture only occurred in patients receiving BRT (n = 3, 4%), although this was not statistically significant (p = 0.2). The rate of peripheral nerve damage, however, was similar in both arms (7% vs. 7%). CONCLUSION: The overall morbidity associated with adjuvant BRT was not significantly higher than that with surgery alone. However, BRT and WES > 4 cm were associated with significantly higher wound reoperation rate. This has significant implications for strategies designed to maximize wound coverage in patients who receive BRT.