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Abstract Background The purpose of this study is to assess the predictive accuracy of a multi-gene predictor of response to docetaxel, 5-fluorouracil, epirubicin and cyclophosphamide combination chemotherapy on gene expression data from patients who received these drugs as neoadjuvant treatment. Methods Tumor samples were obtained from patients with stage II-III breast cancer before starting neoadjuvant chemotherapy with four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX) on US Oncology clinical trial 02-103. Most patients with HER-2-positive cancer also received trastuzumab (H). The chemotherapy predictor (TFEC-MGP) was developed from publicly available gene expression data of 42 breast cancer cell-lines with corresponding in vitro chemotherapy sensitivity results for the four chemotherapy drugs. No predictor was developed for treatment with trastuzumab. The predictive performance of TFEC-MGP in distinguishing cases with pathologic complete response from those with residual disease was evaluated for the FEC/TX and FEC/TX plus H group separately. The area under the receiver-operating characteristic curve (AU-ROC) was used as the metric of predictive performance. Genomic predictions were performed blinded to clinical outcome. Results The AU-ROC was 0.70 (95% CI: 0.57-0.82) for the FEC/TX group (n=66) and 0.43 (95% CI: 0.20-0.66) for the FEC/TX plus H group (n=25). Among the patients treated with FEC/TX, the AU-ROC was 0.69 (95% CI: 0.52-0.86) for estrogen receptor (ER)-negative (n=28) and it was 0.59 (95% CI: 0.36-0.82) for ER-positive cancers (n=37). ER status was not reported for one patient. Conclusions Our results indicate that the cell line derived 291-probeset genomic predictor of response to FEC/TX combination chemotherapy shows good performance in a blinded validation study, particularly in ER-negative patients.

Abstract Background A localized hypoxic environment occurs during tumor growth necessitating an angiogenic response or tumor necrosis results. Novel cancer treatment strategies take advantage of tumor-induced vascularisation by combining standard chemotherapeutic agents with angiogenesis-inhibiting agents. This has extended the progression-free interval and prolonged survival in patients with various types of cancer. We postulated that the expression levels of angiogenesis-related proteins from various primary tumor cultures would be greater under hypoxic conditions than under normoxia. Methods Fifty cell sources, including both immortalized cell lines and primary carcinoma cells, were incubated under normoxic conditions for 48 hours. Then, cells were either transferred to a hypoxic environment (1% O2) or maintained at normoxic conditions for an additional 48 hours. Cell culture media from both conditions was collected and analyzed via an ELISA-based assay to determine expression levels of 11 angiogenesis-related factors: VEGF, PDGF-AA, PDGF-AA/BB, IL-8, bFGF/FGF-2, EGF, IP-10/CXCL10, Flt-3 ligand, TGF-β1, TGF-β2, and TGF-β3. Results A linear correlation between normoxic and hypoxic growth conditions exists for expression levels of eight of eleven angiogenesis-related proteins tested including: VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-β1, TGF-β2, EGF, and IP-10. For VEGF, the target of current therapies, this correlation between hypoxia and higher cytokine levels was greater in primary breast and lung carcinoma cells than in ovarian carcinoma cells or tumor cell lines. Of interest, patient cell isolates differed in the precise pattern of elevated cytokines. Conclusion As linear correlations exist between expression levels of angiogenic factors under normoxic and hypoxic conditions in vitro, we propose that explanted primary cells may be used to probe the in vivo hypoxic environment. Furthermore, differential expression levels for each sample across all proteins examined suggests it may be possible to build a predictor for angiogenesis-related anticancer agents, as each sample has a unique expression profile. Further studies should be performed to correlate in vitro protein expression levels of angiogenesis-related factors with in vivo patient response.

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer.

Background: Comparative data on D2-robotic gastrectomy (RG) vs D2-open gastrectomy (OG) are lacking in the Literature. Aim of this paper is to compare RG to OG with a focus on D2-lymphadenectomy., Study Design: Data of patients undergoing D2-OG or RG for gastric cancer were retrieved from the international IMIGASTRIC prospective database and compared., Results: A total of 1469 patients were selected for inclusion in the study. After 1:1 propensity score matching, a total of 580 patients were matched and included in the final analysis, 290 in each group, RG vs OG. RG had longer operation time (210 vs 330 min, p < 0.0001), reduced intraoperative blood loss (155 vs 119.7 ml, p < 0.0001), time to liquid diet (4.4 vs 3 days, p < 0.0001) and to peristalsis (2.4 vs 2 days, p < 0.0001), and length of postoperative stay (11 vs 8 days, p < 0.0001). Morbidity rate was higher in OG (24.1% vs 16.2%, p = 0.017)., Conclusion: RG significantly expedites recovery and reduces the risk of complications compared to OG. However, long-term survival is similar., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The laparoscopic approach in gastric cancer surgery is being increasingly adopted worldwide. However, studies focusing specifically on laparoscopic gastrectomy with D2 lymphadenectomy are still lacking in the literature. This retrospective study aimed to compare the short-term and long-term outcomes of laparoscopic versus open gastrectomy with D2 lymphadenectomy for gastric cancer., Methods: The protocol-based, international IMIGASTRIC (International study group on Minimally Invasive surgery for Gastric Cancer) registry was queried to retrieve data on patients undergoing laparoscopic or open gastrectomy with D2 lymphadenectomy for gastric cancer with curative intent from January 2000 to December 2014. Eleven predefined, demographical, clinical, and pathological variables were used to conduct a 1:1 propensity score matching (PSM) analysis to investigate intraoperative and recovery outcomes, complications, pathological findings, and survival data between the two groups. Predictive factors of long-term survival were also assessed., Results: A total of 3033 patients from 14 participating institutions were selected from the IMIGASTRIC database. After 1:1 PSM, a total of 1248 patients, 624 in the laparoscopic group and 624 in the open group, were matched and included in the final analysis. The total operative time (median 180 versus 240 min, p < 0.0001) and the length of the postoperative hospital stay (median 10 versus 14.8 days, p < 0.0001) were longer in the open group than in the laparoscopic group. The conversion to open rate was 1.9%. The proportion of patients with in-hospital complications was higher in the open group (21.3% versus 15.1%, p = 0.004). The median number of harvested lymph nodes was higher in the laparoscopic approach (median 32 versus 28, p < 0.0001), and the proportion of positive resection margins was higher ( p = 0.021) in the open group (5.9%) than in the laparoscopic group (3.2%). There was no significant difference between the groups in five-year overall survival rates (77.4% laparoscopic versus 75.2% open, p = 0.229)., Conclusion: The adoption of the laparoscopic approach for gastric resection with D2 lymphadenectomy shortened the length of hospital stay and reduced postoperative complications with respect to the open approach. The five-year overall survival rate after laparoscopy was comparable to that for patients who underwent open D2 resection. The types of surgical approaches are not independent predictive factors for five-year overall survival.

Purpose: To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC)., Methods: ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population., Results: Nine phase III randomized controlled trials met the inclusion criteria., Recommendations: Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Aim: To investigate the role of minimally invasive surgery for gastric cancer and determine surgical, clinical, and oncological outcomes., Methods: This is a propensity score-matched case-control study, comparing three treatment arms: robotic gastrectomy (RG), laparoscopic gastrectomy (LG), open gastrectomy (OG). Data collection started after sharing a specific study protocol. Data were recorded through a tailored and protected web-based system. Primary outcomes: harvested lymph nodes, estimated blood loss, hospital stay, complications rate. Among the secondary outcomes, there are: operative time, R0 resections, POD of mobilization, POD of starting liquid diet and soft solid diet. The analysis includes the evaluation of type and grade of postoperative complications. Detailed information of anastomotic leakages is also provided., Results: The present analysis was carried out of 1026 gastrectomies. To guarantee homogenous distribution of cases, patients in the RG, LG and OG groups were 1:1:2 matched using a propensity score analysis with a caliper = 0.2. The successful matching resulted in a total sample of 604 patients (RG = 151; LG = 151; OG = 302). The three groups showed no differences in all baseline patients characteristics, type of surgery ( P = 0.42) and stage of the disease ( P = 0.16). Intraoperative blood loss was significantly lower in the LG (95.93 ± 119.22) and RG (117.91 ± 68.11) groups compared to the OG (127.26 ± 79.50, P = 0.002). The mean number of retrieved lymph nodes was similar between the RG (27.78 ± 11.45), LG (24.58 ± 13.56) and OG (25.82 ± 12.07) approach. A benefit in favor of the minimally invasive approaches was found in the length of hospital stay ( P < 0.0001). A similar complications rate was found ( P = 0.13). The leakage rate was not different ( P = 0.78) between groups., Conclusion: Laparoscopic and robotic surgery can be safely performed and proposed as possible alternative to open surgery. The main highlighted benefit is a faster postoperative functional recovery., Competing Interests: Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

Introduction: Gastric cancer represents a great challenge for healthcare providers and requires a multidisciplinary treatment approach in which surgery plays a major role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and recently with the spread of robotic surgery, but a number of issues are currently being debated, including the limitations in performing an effective extended lymph node dissection, the real advantages of robotic systems, the role of laparoscopy for Advanced Gastric Cancer, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up., Methods and Analysis: A multi-institutional international database will be established to evaluate the role of robotic, laparoscopic and open approaches in gastric cancer, comprising of information regarding surgical, clinical and oncological features. A chart review will be conducted to enter data of participants with gastric cancer, previously treated at the participating institutions. The database is the first of its kind, through an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centres., Ethics and Dissemination: This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. A multicentre study with a large number of patients will permit further investigation of the safety and efficacy as well as the long-term outcomes of robotic, laparoscopic and open approaches for the management of gastric cancer., Trial Registration Number: NCT02325453; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Gastric cancer represents a great challenge for health care providers and requires a multidisciplinary approach in which surgery plays the main role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and more recently with the spread of robotic surgery, but a number of issues are currently being investigate, including the limitations in performing effective extended lymph node dissections and, in this context, the real advantages of using robotic systems, the possible role for advanced Gastric Cancer, the reproducibility of completely intracorporeal techniques and the oncological results achievable during follow-up., Method: Searches of MEDLINE, Embase and Cochrane Central Register of Controlled Trials were performed to identify articles published until April 2014 which reported outcomes of surgical treatment for gastric cancer and that used minimally invasive surgical technology. Articles that deal with endoscopic technology were excluded., Results: A total of 362 articles were evaluated. After the review process, data in 115 articles were analyzed., Conclusion: A multicenter study with a large number of patients is now needed to further investigate the safety and efficacy as well as long-term outcomes of robotic surgery, traditional laparoscopy and the open approach., (Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.)

Background: Race/ethnicity has long been suspected to affect survival in patients with gastric adenocarcinoma. However, the clinicohistopathological impact of race or ethnicity on early gastric cancer (EGC) is not known., Methods: From 2000 to 2013, 286 patients underwent gastrectomy and 104 patients had pathological confirmation of EGC. A retrospective analysis of pathological and clinical prognostic indicators was performed., Results: The study population consisted of 38 (37%) Asian Americans and 66 (63%) non-Asian Americans. Of these, 2 (5.3%) Asian Americans and 19 (28.8%) non-Asian Americans had pathological confirmation of lymph node metastasis (LNM) (p = 0.004). Univariate analysis comparing the clinicohistopathological characteristics in each group did not reveal significant difference regarding histotype, tumor size, grade, location, morphology, or lymphovascular invasion, except for the LNM rate and mean body mass index (23.2 versus 26.6, p < 0.001). Multivariate analysis showed that non-Asian race/ethnicity (odds ratio (OR), 9.09; 95% confidence interval (CI), 1.12-71.43; p = 0.038), younger age (OR, 1.11; 95% CI, 1.01-1.12; p = 0.046), and lymphovascular invasion (OR, 13.9; 95% CI, 2.40-79.99; p = 0.003) were significant predictors for LNM., Conclusions: This study demonstrated that Asian American race in EGC is associated with a significantly decreased rate of LNM in comparison to non-Asian Americans, despite similar histopathological characteristics of each group.

Genetic testing for the breast cancer susceptibility genes, BRCA1 and BRCA2, has been available for over a decade. Positive test results carry significant medical, psychological, and social implications. Knowledge of the public's awareness concerning BRCA testing, and perceived benefits and barriers to testing can help refine educational programs and identify subgroups needing additional support. Patients and their acquaintances with a breast complaint attending a surgical clinic or private office were asked to complete a questionnaire about their knowledge of breast cancer genes and their desire to be tested. Demographic information collected included ethnicity, education background, age, income, and personal and family history of breast cancer, knowledge of BRCA genes and testing, and their willingness to participate in genetic counseling. A total of 222 people completed the questionnaire that showed the majority of subjects in southeast Georgia believe breast cancer is inherited 26-50% of the time. Caucasians and those with advanced degrees are the most informed regarding awareness of BRCA genes (p < 0.05); the least informed groups include African Americans and those with no more than a college education. Participants with a family history of breast cancer were significantly more likely to know that genes had been identified that indicate an increased risk of breast cancer (p < 0.05). A history of breast cancer did not impact the degree of awareness (p > 0.05). Subjects aware of genetic testing are more willing to utilize counseling (p < 0.05). Perceptions of breast cancer inheritance, awareness of susceptibility genes, and availability of testing and counseling are not uniform among all population subgroups. In southeast Georgia, educational efforts should focus on the less educated and minority groups.

Background: Development of a research agenda may help to inform researchers and research-granting agencies about the key research gaps in an area of research and clinical care. The authors sought to develop a list of research questions for which further research was likely to have a major impact on clinical care in the area of gastrointestinal and endoscopic surgery., Methods: A formal group process was used to conduct an iterative, anonymous Web-based survey of an expert panel including the general membership of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). In round 1, research questions were solicited, which were categorized, collapsed, and rewritten in a common format. In round 2, the expert panel rated all the questions using a priority scale ranging from 1 (lowest) to 5 (highest). In round 3, the panel re-rated the 40 questions with the highest mean priority score in round 2., Results: A total of 241 respondents to round 1 submitted 382 questions, which were reduced by a review panel to 106 unique questions encompassing 33 topics in gastrointestinal and endoscopic surgery. In the two successive rounds, respectively, 397 and 385 respondents ranked the questions by priority, then re-ranked the 40 questions with the highest mean priority score. High-priority questions related to antireflux surgery, the oncologic and immune effects of minimally invasive surgery, and morbid obesity. The question with the highest mean priority ranking was: "What is the best treatment (antireflux surgery, endoluminal therapy, or medication) for GERD?" The second highest-ranked question was: "Does minimally invasive surgery improve oncologic outcomes as compared with open surgery?" Other questions covered a broad range of research areas including clinical research, basic science research, education and evaluation, outcomes measurement, and health technology assessment., Conclusions: An iterative, anonymous group survey process was used to develop a research agenda for gastrointestinal and endoscopic surgery consisting of the 40 most important research questions in the field. This research agenda can be used by researchers and research-granting agencies to focus research activity in the areas most likely to have an impact on clinical care, and to appraise the relevance of scientific contributions.

A 75 year-old woman presented to the authors' institution with abdominal pain and early satiety. An adrenal mass was found on CT scanning. Laparoscopic adrenalectomy was performed, and the patient was found to have a retroperitoneal bronchogenic cyst adherent to the adrenal gland. The workup of an adrenal mass is discussed as well as the pathophysiology of bronchogenic cysts.

Minimally invasive esophageal surgery has the potential to improve mortality, hospital stay, and functional outcomes when compared with open methods. Although technically complex, combined laparoscopic and thoracoscopic esophageal resection is feasible. A case series of 20 patients who underwent minimally invasive total esophagectomy is presented. This study was a review of a prospective database. The purpose was to evaluate early results with laparoscopic total esophagectomy for benign and malignant disease. Between January 2003 and November 2005, 20 patients underwent minimally invasive esophageal surgery. All operations were performed by the same two surgeons. Age, gender, indications for surgery, pathologic stage, operative time, blood loss, transfusion requirements, intensive care unit length of stay, hospital length of stay, postoperative complications, and mortality were recorded. Diet progression, dysphagia, and need for stricture management were also recorded. Of the 20 minimally invasive total esophagectomies performed, 18 (90%) were completed successfully. The average age of the patients was 53 years. Indications for surgery were malignancy (n = 13), carcinoma in situ in the setting of Barrett's esophagus (n = 2), and benign stricture (n = 3). The average operating time was 467 minutes (range 346-580 min). Median blood loss was 350 mL (range 150-500 mL). The median intensive care unit stay was 2 days, and the median hospital length of stay was 12 days. Pathology revealed that 7 per cent of patients had stage I disease, 27 per cent of patients had stage II disease, and 53 per cent of patients had stage III disease. There was a single mortality (5%), a cervical leak in two patients (10%), a gastric tip necrosis in one patient (5%), and tracheoesophageal fistula in one patient (5%). Major complications occurred in eight patients (40%) and minor complications in nine (50%). Thirteen (72%) patients were discharged on enteral tube feeds to supplement caloric intake. The application of minimally invasive techniques in the arena of esophageal surgery continues to evolve. This approach has the potential to improve mortality, hospital stay, and other outcomes when compared with open methods. Although technically complex, laparoscopic total esophagectomy is feasible.

We report a rare case of microscopic pulmonary tumor embolism from breast cancer in a young woman with no prior medical history. The patient presented with progressive dyspnea and questionable abnormalities of the left breast and axilla on physical examination. Results of an axillary lymph node biopsy and subsequent radiologic studies raised the possibility of either microscopic pulmonary tumor emboli or lymphangitic spread of cancer as a cause of the dyspnea. The patient died due to advanced breast cancer confirmed at autopsy despite chemotherapy.

Background: We have observed a putative immunocytolytic factor secreted by several pancreatic adenocarcinoma cell lines that mediates a potent cytolytic effect on lymphocytes. We sought to investigate its mechanism of action and determine if it is Fas ligand (FasL)-mediated., Materials and Methods: Coincubation assays with murine splenocytes and supernatants from various species of pancreatic adenocarcinoma cell lines were performed. The mechanism of lymphocytic cell death was evaluated by the TUNEL assay. Pancreatic adenocarcinoma supernatant was coincubated with Fas-sensitive Jurkat cells and Western blotting for FasL was performed., Results: A marked reduction in the viability (%/control) of target splenocytes was observed after incubation with the conditioned media from hamster PAN-1 (14.7%), PC 1.0 (21.7%), Taka-1 p70 (12.4%), Taka-1 p79 (7.6%), murine PANCO2 (16.1%), and human Capan-1 (14.0%) pancreatic adenocarcinoma cell lines. FACS analysis demonstrated significant lymphoid apoptosis at 16 h. The cytolytic effect appeared to be specific for lymphocytes and was not observed with the conditioned media of other tumor cells or normal pancreatic ductal cells. Pancreatic adenocarcinoma supernatant had no killing effect on Jurkat cells compared with control supernatant of TC-248 cells (87% vs 15%) and immunoblotting did not demonstrate soluble FasL., Conclusions: These findings demonstrate that pancreatic adenocarcinoma cells secrete a potent cytolytic factor that induces apoptosis of lymphocytes and is not FasL-mediated., (Copyright 2000 Academic Press.)

Background: Breast cancer survival is improving because mammography is leading to diagnosis at earlier stages of the disease. Because young women with breast cancer rarely undergo mammography before diagnosis, outcomes for breast cancer in young women may not be improving. In addition to advanced stage, young age at diagnosis is associated with biologically more aggressive cancers with higher rates of local and distant recurrence., Study Design: Risk factors, clinical presentations, pathologic findings, tumor characteristics, extent of disease, treatment, and outcomes for 101 women under age 36 treated for breast cancer between 1989 and 1997 were compared with 631 patients 36 years and older treated by us during the same interval. Stage IV patients were excluded., Results: Patients younger than 36 years were more likely to present with a palpable mass (87% versus 55%, p < 0.001) and were less likely to undergo spot localization breast biopsy for mammographic findings (40% versus 6%, p < 0.001). Patients younger than 36 years had larger tumors (median 2.0 cm versus 1.5 cm, p < 0.001), more nodal involvement (50% versus 37%, p = 0.022), more nodes involved (median 1.0 versus 0, p = 0.010), and were more likely to be diagnosed with stage II or III cancer (60% versus 43%, overall p < 0.001). Young patients' cancers were more poorly differentiated (80% versus 44%, overall p < 0.001), estrogen receptor-negative (52% versus 31%, p < 0.001), aneuploid (70% versus 49%, p = 0.013), and had higher S-phase fractions (59% versus 29%, p = 0.001). Patients less than 36 years were treated more often with mastectomy (59% versus 22%, p < 0.001) and adjuvant chemotherapy (80% versus 54%, p < 0.001) and less often with tamoxifen (36% versus 58%, p = 0.001). Cumulative 5-year local and distant disease-free survival were significantly worse for patients younger than 36 years (p = 0.011 and p = 0.044, respectively). The higher rate of local recurrence in patients less than 36 years was from an excess number of local recurrences in patients treated with breast conservation. After consideration for nodal involvement, chemotherapy, and tamoxifen using the Cox proportional hazards model, no other variable, including age, was significantly related to local disease-free outcomes. After consideration for tumor size and nodal involvement, no other variable was significantly related to distant disease failure rates., Conclusions: Patients diagnosed with breast cancer before age 36 differ from older patients in numerous respects. They present more often with a palpable mass rather than a mammographic finding and their cancers are more advanced with features that are more aggressive. Despite aggressive treatment, most commonly with mastectomy and chemotherapy, local and distant failure rates are higher than for patients 36 and older. The higher rate of local recurrence in patients less than 36 years reflects an excess number of local recurrences in patients treated with breast conservation.

An intrahepatic tumor model for metastatic breast cancer was generated in syngeneic mice by direct inoculation of JC cells, a murine mammary adenocarcinoma cell line. Intratumoral administration of a recombinant adenoviral vector expressing the murine Interleukin-12 (ADV-mIL-12) resulted in significant reduction in the tumor volume compared to control vector. Tumor regression was also evident on histopathologic analysis of the liver, where inflammatory changes as opposed to nuclear atypia predominated after IL-12 vector treatment. There was a significant prolongation in the long term survival of IL-12 treated animals, with complete tumor rejection in 40% of the animals. In vivo depletion studies using specific monoclonal antibodies against the various lymphocyte subsets showed a significant reduction in long term survival after natural killer (NK) cell depletion. This suggests that the NK cell is a critical effector in the antitumor effect mediated by IL-12. These results strongly support the potential role of gene mediated cytokine therapy for the treatment of metastatic breast cancer.

We observed a putative immunocytolytic factor secreted in the supernatant of several pancreatic adenocarcinoma cell lines that induces apoptosis in lymphocytes. A marked reduction in the viability of the target splenocytes was evident after coincubation with the supernatants from various pancreatic adenocarcinoma cell lines (human, hamster, and murine). The immunocytolytic effect was not evident with the conditioned media of normal pancreatic duct epithelial cells or other nonpancreatic tumor cells. Biologic activity of the supernatants was determined to be heat sensitive and reside in a 30- to 50-kDa range. Immune and functional assays have excluded known immunosuppressive factors.

Background: The availability of a commercial test for the breast cancer susceptibility genes, BRCA1 and BRCA2, has generated interest in both the medical community and the general public., Methods: Patients and family members were approached in the waiting room and asked to fill out an anonymous questionnaire about their awareness of breast cancer genes and breast cancer gene testing, and their desire to be tested. chi2 analysis was used to analyze frequencies between groups., Results: A total of 354 women completed a questionnaire concerning the breast cancer genes BRCA1 and BRCA2. The very young, the very old, and African-Americans were the least informed in terms of awareness of the genes and the availability of testing for the breast cancer susceptibility genes. Jewish people, people with a college education or beyond, people earning more than $30,000 a year, and Caucasians were more aware of the genes and of testing for these genes. Interest in being tested was similar in all groups, except for participants over 60 and those who had only an elementary-school education., Conclusions: Information concerning the breast cancer susceptibility genes has not reached the general public uniformly. A concerted effort is needed if this information is to be passed on to those people at risk.

Conclusions: In this series, the overall reoperative rate following pancreatic surgery is 9%. Complications following pancreatectomy that require reoperation fall into four categories: hemorrhage, infectious, delayed gastric emptying, and anastomotic leak. A delay in the management of these types of complications can be fatal., Background: Despite the improvement in the morbidity and mortality rates associated with pancreatic resection, complication still arise that require surgical intervention. This study reviews the pancreatic surgical experience at a major medical center to determine the overall reoperative complication rate., Study Design: From 1985 to 1995, 107 patients underwent pancreatic resection. There were 50 pancreaticoduodenectomies, 20 total pancreatectomies, and 37 distal pancreatectomies for 102 periampullary or pancreatic cancers and five for chronic pancreatitis. The operative mortality rate was 6.5% and the morbidity rate was 43%. Ten patients (9%) developed complications that required reoperation., Results: Re-exploration was performed in five patients for hemorrhage. Four patients had bleeding intra-abdominally and one had a suture line bleed. One patient developed a wound infection and fascial necrosis which necessitated reoperation. Three patients were explored for sepsis and one was found to have a pancreatic leak. One patient had persistent gastric outlet obstruction and he required conversion of the gastrojejunostomy to a Roux-en-y anastomosis. The mortality rate for re-exploration was 3/10 (30%).

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

Background: Thoracoabdominal esophagogastrectomy is associated with a number of potential life-threatening complications., Patients: We describe a patient with intraoperative hypotension in which a number of therapeutic maneuvers eventually led to the diagnosis of cardiac tamponade., Results: Once the diagnosis of tamponade was made, it was successfully treated by the release of intrapericardial blood., Conclusions: Although rare, tamponade should be considered as a cause of hemodynamic instability whenever intraoperative manipulation of the heart has occurred.

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, IIIA, and IIIB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.

The most common malignancy concurrent with pregnancy is breast cancer. Since an increasing number of women are electing to postpone pregnancy to their late thirties and forties, the incidence of breast cancer concurrent with pregnancy is increasing. This article critically reviews the incidence, unique diagnostic and therapeutic considerations, the natural history and ultimate prognosis of breast carcinoma associated with pregnancy and lactation.

Introduction: Small bowel neoplasms account for only a small percentage of gastrointestinal tumors, but their prognosis is one of the worst., Purpose: This study examines the histopathology, treatment, recurrence, and overall survival of a group of patients with primary small bowel tumors., Methods: From 1970 to 1991, a retrospective review identified 73 patients with primary small bowel tumors. Four histologic groups were identified: 1) group 1, adenocarcinoma, 29 patients; group 2, lymphoma, 18 patients; group 3, sarcoma, 8 patients; and group 4, carcinoid, 18 patients. There were 44 men and 29 women. The median age was 57 years (range, 26 to 90). Median follow-up was 15 months. Survival analysis was by the Mantel-Cox and Breslow methods., Results: The most common, by type, was group 1, duodenum; group 2, jejunum; group 3, jejunum; and group 4, ileum. The preoperative diagnosis was made in only 14 patients. The median survival for adenocarcinomas and lymphomas was 13 months, 18 months for sarcomas, and 36 months for carcinoids. Curative resection could be achieved in 48 (65%) of 73 patients, and the median survival was significantly longer for this group (26 months vs. 11 months, p < 0.05). Of the 48 curative resections, 20 patients (42%) recurred: group 1, 8/19 (42%); group 2, 4/12 (33%); group 3, 4/13 (31%); group 4, 4/4 (100%). The median time to recurrence was 17 months, and the median survival after recurrence was 20 months. Adjuvant chemotherapy-radiation therapy did not alter survival in any group., Conclusions: The preoperative diagnosis of small bowel tumors rarely is made because symptoms are vague and nonspecific. Surgical resection for cure results in improved survival. Recurrence is common and survival after recurrence is poor. Other treatment methods have no role in the management of these patients.

Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.

Background: Risk factors for carcinoma of the breast may also have prognostic influence. Because benign breast disease is a risk factor for carcinoma of the breast, we compared the outcomes of patients with carcinoma of the breast with a history of benign breast disease to patients with carcinoma of the breast without a history of benign breast disease., Study Design: Patients with benign breast disease and subsequent carcinoma of the breast were matched by age and ethnicity to patients with carcinoma of the breast with no prior history of benign breast disease. Risk factors, pathologic findings, and disease-free survival rates were compared., Results: Patients with previous benign breast disease had a significantly greater family history of carcinoma of the breast (35 percent compared with 22 percent, p = 0.015) and used postmenopausal hormones significantly more frequently (16 percent compared with 5 percent; p < 0.001) than women without benign breast disease. In patients with benign breast disease, their subsequent carcinomas were smaller (T1, 53 percent compared with 43 percent), with significantly fewer nodes involved (1.8 compared with 2.7, p = 0.031), and were significantly more likely to contain an infiltrating lobular component (9 percent compared with 3 percent, p = 0.023). Significantly fewer patients with previous benign breast disease had metastatic disease (18 percent compared with 31 percent; p = 0.001). The ten-year cumulative disease-free survival rate for patients with benign breast disease was 68 percent compared with 59 percent for women without a history of benign breast disease., Conclusions: This study indicates that women with benign breast disease who have carcinoma of the breast develop may have a better outcome than women without a history of benign breast disease.

Conclusions: Spiral CT allows for a noninvasive evaluation of the mesenteric arterial and venous vessels. This test can be performed quicker, with less expense, and with a reduced radiation and contrast load than angiography. Comparison studies of angiography and spiral CT are needed in patients with pancreatic cancer to determine the best method of evaluating possible vessel involvement., Background: Preoperative imaging of patients with pancreatic cancer is crucial in determining resectability and planning management. Computed tomography (CT) remains the diagnostic procedure of choice for the evaluation of the primary tumor and angiography is the gold standard to evaluate vessel encasement. This case evaluates the usefulness of spiral computed tomography in determining vessel encasement., Methods: A 53-yr-old female presented with vague abdominal complaints and evaluation revealed a mass in the pancreas. CT suggested portal vein involvement and collateralization was noted in the upper abdomen. Spiral CT revealed normal arterial anatomy and near complete obstruction of the portal vein at the superior mesenteric vein (SMV) splenic vein (SV) confluence., Results: Operative findings confirmed the involvement of the portal vein at the confluence of the SMV and SV. Pancreatico-duodenectomy with portal vein resection and primary anastomosis was performed. The patient's postoperative course was uneventful and she was discharged home on the 13th postoperative day.

Background: Breast cancer has a strong genetic component, and at least two breast cancer genes exist. But these genes probably play little role in most breast cancers. Other factors, such as environmental estrogens and diet, may cause the genetic changes involved in the genesis of sporadic breast cancer. A method of observing genetic changes indirectly might be to measure tumor markers known to be associated with breast cancer., Methods: We measured, by biochemical extraction and partition, lipid-associated sialic acid in plasma (LASA-P), a circulating tumor marker, in a group of 239 women with benign or malignant breast tumors., Results: The concentration of LASA-P was elevated in women with both benign and malignant tumors and no family history of breast cancer (p = 0.046, one-way ANOVA). Because LASA-P levels rise with age and number of pregnancies, we analyzed our data using multiple linear regression. Benign versus malignant character of the tumor, family history of breast cancer, number of pregnancies, and age were the independent variables. Family history of breast cancer had a significant effect on LASA-P levels (p = 0.0146) independent of the effects of age (p = 0.011), number of pregnancies (0.012), and whether the tumor was benign or malignant (p = 0.31)., Conclusions: We hypothesize that elevated LASA-P in women with breast tumors and no family history of breast cancer is a result of the genetic changes occurring in nonfamilial breast cancer. These genetic changes, possibly related to environmental estrogens or other environmental factors, are distinct from the changes due to mutations of BRCA1 or other familial breast cancer genes. Moreover, the elevation of LASA-P suggests that the surface membranes of breast cancer may differ in composition. Further study may lead to exact characterization of the genetic and cell membrane changes associated with familial and nonfamilial breast tumors, and perhaps to better methods of breast cancer prevention and treatment.

Background: The HER2 gene, located on the long arm of chromosome 17, codes for a protein with the characteristics of a growth factor receptor. In a preliminary study, we reported that high levels of tumor HER2 (erbB-2/neu) protein are associated with a family history of breast cancer (that is, one or more female blood relatives with breast cancer)., Methods: We have now collected a larger number of subjects (94) and performed a multivariate analysis of the independent variables family history of breast cancer, tumor estrogen receptor, age, and tumor DNA index. Family history of breast cancer was assessed by questioning the patient, in many cases by telephone., Results: HER2 levels were significantly higher in women with a family history of breast cancer (p = 0.015, two-tailed t-test). The 27 women with family history were predominantly postmenopausal, mean age 61 +/- 2.3 (mean +/- SEM), versus a mean age of 56 +/- 1.7 for the 67 women with no family history. Of the 27 women with a family history of breast cancer, 13 had a first-degree relative (mother or sister) with the disease. The remaining 14 women had other relatives (grandmothers, aunts, cousins, or a niece) with breast cancer. The results of multiple linear regression analysis, with HER2 as the dependent variable, showed that family history of breast cancer was significantly associated with elevated HER2 levels in the tumors (p = 0.0038), after controlling for the effects of age, tumor estrogen receptor, and DNA index., Conclusions: The association of family history of breast cancer and elevated tumor HER2 protein suggests that postmenopausal familial breast cancer may be associated with altered HER2 expression.

Background: Many invasive breast cancers are accompanied by a variety of noninvasive components. Histological distinctions have been made between these components, but to understand their importance, it is essential to examine their molecular biology., Methods: Proliferative indices, oncoproteins, and steroid receptor expression were compared for invasive breast cancers containing comedo-type ductal carcinoma in situ (n = 35), noncomedo-type ductal carcinoma in situ (n = 34), and pure invasive cancers (n = 49). Ploidy, S-phase fraction, Ki-67 staining, estrogen receptor (ER), progesterone receptor (PR), and the expression of HER-2/neu and epidermal growth factor receptor (EGFR) were evaluated in these tumors., Results: The comedo-invasive subgroup differed significantly from the noncomedo-invasive subgroup, demonstrating significantly higher mean ploidy (1.6 vs. 1.3; p = 0.0156), S-phase fraction (7.9% vs. 4.3%; p = 0.0066), Ki-67 staining (20.3% vs. 12.0%; p = 0.0058), and HER-2/neu values (2,247 fm/mg vs. 1,014 fm/mg; p = 0.0412) and lower ER (76 fm/mg vs. 339 fm/mg; p = 0.006) and PR values (99 fm/mg vs. 265 fm/mg; p = 0.0608). A higher percentage of comedo-invasive carcinomas demonstrated aneuploidy 71%; p = 0.0158), elevated levels of S-phase fraction (75%; p = 0.0016) and Ki-67 staining (55%; p = 0.0512), overexpression of HER-2/neu oncogene (47%; p = 0.0011), and were ER negative (35%; p = 0.0148), PR negative (47%; p = 0.0073) when compared to noncomedo-invasive carcinomas. Comedo-invasive and noncomedo-invasive tumors were comparable for nodal status and tumor size, but differences were noted for tumor differentiation and percentage of tumors that were > 1 cm. Comedo-invasive tumors were predominantly poorly differentiated (60 vs. 32%) and were > 1 cm (94 vs. 77%, p < 0.05)., Results: Comedo-invasive cancers were comparable to pure invasive cancers for ploidy, S-phase fraction, Ki-67 staining, and ER, PR, and EGFR expression. However, comedo-invasive carcinomas had greater HER-2/neu overexpression when compared to pure invasive tumors (47 vs. 19%; p = 0.0359)., Conclusions: These results are consistent with the hypothesis that comedo carcinoma is a more aggressive type of ductal carcinoma in situ and may have independent prognostic value when seen in association with infiltrating ductal carcinoma. In invasive tumors, comedo carcinomas are associated with poor prognostic factors, including higher ploidy, S-phase fractions, Ki-67 staining, negative ER and PR status, poorer differentiation, larger tumors, and presence of HER-2/neu oncogene overexpression.

Background: Prognostic factors are used routinely in the management of breast cancer. However, their potential for identifying precursor malignant lesions has not been assessed., Methods: We have examined 285 breast biopsy specimens (140 benign, 145 malignant) for DNA ploidy, S-phase fraction, Ki-67 nuclear antigen proliferative indices, and HER-2/neu and epidermal growth factor receptor oncoproteins., Results: When proliferative indices were compared between the benign and malignant groups, differences were noted for DNA ploidy, S-phase fraction, and cell cycling index (p < 0.0005). When the benign nonproliferative specimens were compared with the atypical/proliferative benign specimens, proliferative indices failed to show any differences. When the specific subset of proliferative/atypical benign breast tissue was compared with the malignant specimens, DNA index, S-phase fraction, and cell cycling index showed significant differences. The mean for epidermal growth factor receptor was greater in the non-proliferative group but not statistically significant (p < 0.1). HER-2/neu oncoprotein failed to show any differences between the benign and malignant groups. Within the atypical benign group, Ki-67 correlated strongly with S-phase fraction and HER-2/neu (p < 0.01)., Conclusions: We have demonstrated that proliferative indices can differentiate between benign and malignant breast tissues but not among specific subgroups. In addition, epidermal growth factor may differentiate between nonproliferative and proliferative/atypical benign biopsy results. Oncoprotein determination, ploidy, and DNA proliferative indices may be useful in defining malignant and benign breast disease but are not useful in distinguishing between benign and malignant breast disease with an increased likelihood for malignant transformation.

New laparoscopic instrumentation coupled with standard surgical techniques allows one to perform procedures previously thought impossible via the laparoscope. This report reviews the natural history, the indications for resection, and the technique of laparoscopic resection of hepatic hemangiomata. Two women, 24 and 62 years of age, were first seen with abdominal pain. A diagnosis of hemangioma was made in each case, and both lesions were removed laparoscopically. Operative blood loss was 200 cc in each case, and neither patient required transfusion. Diets were started on the first postoperative day (POD), and the patients were discharged on the second and fourth PODs without narcotic analgesia. If the size and location of the tumor are favorable, laparoscopic resection of liver hemangiomata can be performed safely. Blood loss comparable to that of open procedures and a quicker recovery support an endosurgical approach to resection of liver hemangiomata in selected cases.

Background: Poor survival among African American patients with breast cancer has been attributed to low socioeconomic status and lack of access to health care. However, Hispanics of equivalent socioeconomic status and health care access exhibit much higher survival rates, almost comparable to whites. This suggests that biologic differences play a role in differences in breast cancer survival in addition to socioeconomic and health care access factors., Methods: The authors studied clinical and molecular differences between patients with breast cancer of different ethnicity to determine biologic explanations for the observed differences in survival. Consecutive patients scheduled for breast biopsies were identified preoperatively and were interviewed. Blood was withdrawn for serum marker measurements, and tumor specimens collected at frozen section diagnosis were analyzed by flow cytometry, hormone receptor concentration, tumor grade, and Ki-67 nuclear antigen, HER-2/neu, and epidermal growth factor oncoprotein expression., Results: Age, age at menarche, number of lymph nodes with metastasis, estrogen and progesterone receptor levels, ploidy status, S-phase, Ki-67, HER-2/neu expression, tumor grade, epidermal growth factor receptor expression, lipid-associated sialic acid (LASA), and carcinoembryonic antigen level were not significantly related to ethnicity. African Americans presented at a significantly more advanced stage and with significantly larger tumors. They were significantly heavier and had a significantly higher mean Quetelet's index and a significantly higher number of pregnancies and number of live births. Whites and Hispanics were significantly older at menopause., Conclusions: The molecular indices associated with breast cancer prognosis do not differ significantly among whites, African Americans, and Hispanics, suggesting that the reported differences in survival among these groups are not due to biologic differences in breast cancer among ethnic groups.

Background: Since the risk of carcinoma of the breast is increased in women with a family history of the disease, new primary carcinomas of the breast may be increased after treatment. Women with several relatives with carcinoma of the breast are thought to be at higher risk of having a second primary carcinoma of the breast develop and mastectomy is more frequently recommended., Study Design: The computerized registry of the Mount Sinai Medical Center Breast Service was used to identify 1,337 patients with complete information concerning family history. Three hundred fifty-nine patients with a family history of carcinoma of the breast were compared with women with no family history., Results: Compared with patients with no family history of carcinoma of the breast, patients with a family history of carcinoma of the breast were significantly younger (54.0 versus 55.8 years of age, p < 0.01), were significantly more likely to have used oral contraceptives (26 versus 13 percent, p < 0.001), had significantly more ductal carcinoma in situ (10 versus 4 percent, p < 0.01), and were significantly more often treated with breast conservation (42 versus 31 percent, p < 0.001). Simultaneous contralateral carcinoma of the breast was diagnosed more frequently in patients with a family history (3 versus 1 percent, p < 0.025), but metachronous contralateral carcinomas were not increased. In comparing the two groups, there were no significant differences in proportion premenopausal, parity, use of postmenopausal hormones, tumor size, tumor differentiation, nodal involvement, TNM stage, estrogen receptor status, or use of adjuvant radiation, chemotherapy, or tamoxifen. Complete five-year follow-up evaluation for 748 patients, 179 with a family history, found no differences in local, distant, or disease-free survival rates for mastectomy or breast conservation in relation to family history. Outcome for patients with first-degree affected relatives and those with more than one affected relative was the same as those with no family history., Conclusions: These results indicate that women with a family history of carcinoma of the breast should be treated no differently than women with no family history.

Autolymphocyte therapy (ALT) is adoptive cellular therapy of cancer using ex vivo activation of autologous peripheral blood lymphocytes (PBL). Memory T cells are the principal effector population in ALT, with in vivo activity in patients with metastatic renal cell carcinoma (RCC) and melanoma, and ex vivo cytotoxicity against autologous tumor targets. However, the noncytolytic lymphocyte portion of ex vivo-activated memory T cells (ALT cells) may also contribute as antitumor effectors. Pretreatment of murine and human tumor cells ex vivo with chemotherapeutic agents can enhance their susceptibility to antitumor lymphocytes ex vivo and in vivo. To determine whether cis-diamminedichloroplatinum(II) (DDP) could enhance ex vivo antitumor effects of ALT cells by immunomodulation, human breast and colorectal carcinoma target cells were derived from both primary and metastatic surgical specimens and incubated in complete medium (CM) with DDP or in CM alone (control group). Viability of each group was confirmed by trypan blue-dye exclusion test. ALT cells were prepared from autologous PBL at surgery. Primary and metastatic tumor cells from each group were used as targets for ALT cells and levels of interferon-gamma (IFN-gamma) release were measured as a determination of antitumor effect and recognition. Primary tumor target cells incubated in DDP showed enhanced antitumor effects and recognition by autologous ALT cells, as measured by the IFN-gamma assay compared to non-DDP-treated controls. Metastatic autologous tumor target cells demonstrated less IFN-gamma release than did the primary targets, although this was enhanced by pre-treating metastatic tumor targets with DDP. ALT cells demonstrated minimal IFN-gamma release when incubated with allogeneic tumor targets. These data suggest that autotumor recognition of metastatic tumor targets is comparable to that of primary lesions following ex vivo pretreatment of metastatic cells with nonlethal doses of certain chemotherapeutic agents. DDP may somehow alter the physical properties of target cells, rendering them susceptible to immune-mediated attack and the combination of ALT and DDP may lead to increased therapeutic efficacy in patients with metastatic breast and colon cancer.

Screening mammography improves carcinoma of the breast survival through early detection and treatment of nonpalpable, often noninvasive, carcinomas. Consideration of the roentgenologic characteristics of mammographic masses and calcifications in combination with risk factors of patients may improve the yield of spot localization breast biopsy. Risk factors solicited by questionnaire were correlated with the roentgenologic appearance and histopathologic factors of 482 specimens from spot localization breast biopsies (39 percent malignant). Masses with irregular contour (p < 0.001) and high density (p < 0.005) were associated with malignant tumors. Packed, coarse and round calcifications were associated with benignity (p < 0.001), whereas scattered, fine and mixed calcifications were associated with malignant tumors (p < 0.05). Malignant masses with smooth contour were significantly more likely to be associated with noninvasive histology. Patients found to have malignant tumors were significantly older than patients with benign lesions (58 versus 52 years, p < 0.001). Stepwise logistic regression was used to evaluate the relative usefulness of demographics and roentgenologic features in predicting benign and malignant pathology among masses and calcifications. Age and irregular contour were independent significant predictors of malignancy for masses. Age, round, coarse, packed or scattered calcifications were significant independent predictors of benignity among calcifications. The radiologist correctly predicted malignant pathology in 60 percent of the patients and benign pathology in 78 percent. Parity, age at menarche, age at first pregnancy, age at menopause, history of benign breast disease, history of carcinoma of the breast, family history of carcinoma of the breast, birth control pill exposure and smoking were not significantly associated with the diagnosis of malignant tumor. These results suggest that risk factors for carcinoma of the breast are insignificant for nonpalpable lesions because patients referred for needle localization are already selected for high risk. Roentgenologic patterns of masses are useful for predicting which lesions are invasive.

Ninety-five patients with bilateral carcinoma of the breast treated with mastectomy (60 patients), conservation of the breast (17 patients), or both (18 patients), were studied. Cumulative five year local control rates for the 138 mastectomies was 94 percent and for the 52 breast conservations, 90 percent. Distant metastases appeared in one-third of the patients but one-half of them occurred beyond 60 months. Cumulative five year distant disease-free survival rate measured from treatment for the second carcinoma was 74 percent. Second carcinomas were diagnosed at significantly earlier stage than first carcinomas--28 percent of first carcinomas were stage I compared with 43 percent of second carcinomas (p < 0.05). Distant recurrence-free survival rates for metachronous carcinomas were better then for synchronous carcinomas, but this difference can be attributed to earlier overall staging of metachronous carcinomas. The interval between the diagnosis of first and second carcinomas had a profound effect on outcome for second carcinomas--cumulative five year distant recurrence-free survival rate of patients with second carcinomas diagnosed within five years was 58 percent compared with 95 percent for patients diagnosed more than five years after the first carcinoma.

The risk and prognosis of patients with carcinoma of the breast exposed to postmenopausal hormones are controversial. Carcinoma of the breast from 35 postmenopausal women who had taken hormones were compared with carcinomas from age and histologic matched postmenopausal women who had never taken hormones. Hormone users averaged 1.1 fewer pregnancies (p < 0.005) and 1.4 fewer live births (p < 0.0005). In addition, the carcinomas had significantly lower S-phase fractions (5.36 versus 6.77, p > 0.01) and less nodal involvement (1.2 versus 1.9, p < 0.0005). Estrogen and progesterone receptor content, ploidy and deoxyribonucleic acid index were comparable in both groups. These results indicate that hormone users present with slower growing tumors of earlier stage than nonusers, possibly resulting in improved prognosis.

We have examined the histopathological factors affecting the degree of local spread, regional lymph node (RLN) metastases, and overall survival (O.S.) in a group of 39 cases of resected carcinoma of the exocrine pancreas. Although the mean O.S. for the group was 14.3 months, resected patients without RLN involvement had a mean survival of 24 months. In contrast the mean O.S. rate was 8 months for patients with RLNs involved. Size, tumor location, and histological grade were compared to RLN involvement and O.S. The mean size of primary tumor did not differ significantly between patients with or without RLN's (r.1 versus 4.6 cms). However, 7 or 8 T1 tumors were < 4 cm and 35% of tumors < 4 cm were T1 lesions. In contrast, only 1 of 17 tumors (6%) > 4 cm was T1. Histological grade was correlated with nodal status and O.S. There was a significant difference between histological grade and the presence of metastatic lymph nodes (G1, 37% positive, G2-4.50% positive). Patients with well differentiated tumors had a mean survival of 21 months compared to a mean survival of 10 months for less differentiated tumors (p < 0.05). This difference was even more significant when stratified for nodal status. The patients with well differentiated tumors and no RLN involvement had a mean survival of 32.5 months compared to 8.6 months for well differentiated tumors with RLN involvement. In summary, we have shown that size, histological grade, and local spread predict for nodal status. However, specific patient subsets (G1, node negative) may exhibit an excellent survival when curative pancreas resection is successful.

A series of 100 patients with locally advanced carcinoma of the breast was analyzed for chest wall recurrence alone after primary treatment. Five patients were found to have had chest wall recurrence alone and were treated with en bloc chest wall resection. This group of patients was analyzed for the pathophysiology of recurrence including characteristics of the primary tumor, location of the chest wall recurrence, and overall local salvage and survival after chest wall recurrence. In this series, local recurrence after radical chest wall resection was 20%. The incidence of systemic recurrence after chest wall resection was 60%. The mean survival for the entire group was 17 months after chest wall recurrence and radical resection. The main surgical objectives, including relief from painful, inflammatory, and bleeding complications, were achieved in all patients after chest wall resection. Although patients with isolated chest wall recurrence included a highly selected group, chest wall resection with myocutaneous reconstruction may provide long-term disease-free survival for these patients.

We have been interested in the possible direct effects of luteinizing hormone releasing hormone (LHRH) and somatostatin (SS) analogs on the growth of human mammary tumor cells. Four recently synthesized peptide hormones including the LHRH agonists D-Trp6-LHRH and zoladex, LHRH antagonists SB30 and SB75, and the somatostatin analog RC 160 were analyzed for their effects on DNA synthesis of MCF-7 breast cancer cells in culture. At 48 hr, D-Trp6-LHRH and SB30 did not show significant effects (dose range, 10(-12)-10(-6) M). However, the combination of these two peptides at 10(-10) M produced significant inhibition of 3[H]thymidine incorporation (50% control). At 72 hr in the absence of estradiol-stimulated growth, D-Trp6-LHRH showed inhibition at 10(-12) and 10(-10) M (P less than 0.005 and 0.001). At higher concentrations, no significant inhibition was noted. In contrast to D-Trp6, SB30 (antagonist) showed no inhibition but significant stimulation of DNA synthesis at 10(-6) and 10(-4) M. In the presence of added estradiol (10(-9) M), complete reversal of D-Trp6-LHRH analog inhibition is noted. In contrast, there is persistent stimulation by SB30 (P less than 0.001). At 96 hr, D-Trp6-LHRH continued to show maximal inhibition of 70% in the absence of estradiol. SB30 stimulated DNA synthesis 100% at 10(-6) M. At 72 hr, the SS analog RC 160 demonstrated significant inhibition (53%) that was similar to D-Trp6 and SB75 peptides.(ABSTRACT TRUNCATED AT 250 WORDS)