Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

Molecular determinants of Akt-induced keratinocyte transformation.

The PI3K/PTEN/Akt signaling pathway has emerged in recent years as a main player in human cancers, increasing proliferation and decreasing apoptosis of transformed cells, and thus becoming a potential target for therapeutic intervention. Our previous data have demonstrated that Akt-mediated signaling is of a key relevance in the mouse skin carcinogenesis system, one of the best-known models of experimental carcinogenesis. Here, we investigated the involvement of several pathways as mediators of Akt-induced increased proliferation and tumorigenesis in keratinocytes. Tumors produced by subcutaneous injection of Akt-transformed keratinocytes showed increased Foxo3a phosphorylation, but no major alterations in p21(Cip1/WAF1), p27(Kip1) or mdm2 expression and/or localization. In contrast, we found increased expression and nuclear localization of DeltaNp63, beta-catenin and Lef1. Concomitantly, we also found increased expression of c-myc and CycD1, targets of the beta-catenin/Tcf pathway. Such increase is associated with increased phosphorylation and stabilization of c-myc protein as well as increased translation of c-myc and CycD1 due to mTOR activation. Using immunohistochemistry approaches in samples of oral dysplasias and human head and neck squamous cell carcinomas, we confirmed that increased Akt activation significantly correlates with increased DeltaNp63 and CycD expression, c-myc phosphorylation and nuclear accumulation of beta-catenin. Collectively, these results demonstrate that Akt is able to transform keratinocytes by specific mechanisms involving transcriptional and post-transcriptional processes.

Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.

BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

PURPOSE: To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS: Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS: Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION: Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.

Effects of preoperative chemotherapy on the morphology of resectable breast carcinoma.

We examined pathologic specimens from 43 patients with Stage T1-T3 lesions who were treated preoperatively with four cycles of doxorubicin/cyclophosphamide, followed by segmentectomy/mastectomy and axillary node dissection (the National Surgical Adjuvant Breast and Bowel Project B-18 protocol). Specimens from 46 patients treated post-operatively with the same regimen served as histologic controls. The initial diagnosis was made by core needle biopsy (28%) or by fine-needle aspiration (72%). Six changes were noted in 36 patients (84%), with complete regression in 10, but histologic evidence of regression and characteristic cytologic changes occurred in only one-half of the 43 patients, and there was poor correlation between histologic regression and clinical response; (2) an increased nuclear grade occurred in 32% of the cases; (3) unusually prominent intraductal and/or intralymphatic tumor was observed in 40%; (4) histologic evidence of tumor regression in axillary lymph nodes was noted in nine cases; (5) regressive changes also occurred in non-neoplastic breast tissue and in lymphoid populations of lymph nodes; and (6) difficulty was noted in evaluating residual atypical intraductal proliferations. These findings add a quantitative dimension to previously published descriptions and emphasize the need for pathologic staging in these patients. In addition, they provide histopathologic evidence of downstaging in axillary lymph nodes and of relative treatment resistance by intraductal and intralymphatic tumor.

Arterial injuries in orthopaedics: the posteromedial approach for vascular control about the knee.

Combined orthopaedic and vascular injuries are becoming more common owing to an increasing incidence of high-energy trauma and gunshot wounds. We present our experience using the posteromedial approach in treating eight orthopaedic patients with popliteal arterial injuries. All patients underwent popliteal exploration by a vascular surgeon through a posteromedial approach (releasing the pes anserinus and the medial gastrocnemius). The arterial injuries were reconstructed in five patients using a reverse saphenous vein graft and directly repaired in three patients. Two patients had delayed healing of their incisions as a result of the original injury. There were no neural injuries. The posteromedial approach is extensile and utilitarian, and it represents the exposure of choice for arterial injuries about the knee.

Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS: Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS: The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION: We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study.

PURPOSE: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. PATIENTS AND METHODS: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. RESULTS: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p = 0.45) and overall survival (p = 0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins > 1 cm, had superior survival compared to cases not meeting these requirements (p < 0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). CONCLUSION: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

Antibacterial activity and phytochemical analysis of Vochysia divergens (Vochysiaceae).

Vochysia divergens Pohl (Vochysiaceae) is a tree commonly found in wet soils of 'Pantanal' of Mato Grosso, Brazil, and used in folk medicine against infections and asthma. We have studied different extracts and some isolated compounds from this plant for antibacterial activity. From the extracts of the stem bark beta-sitosterol, betulinic acid and sericic acid were isolated. The minimal inhibitory concentration (MIC) for Staphylococcus aureus were: ethanolic extract (MIC = 1.5 mg/ml); ethyl acetate extract (MIC = 2.0 mg/ml); and sericic acid (MIC = 1.0 mg/ml). Escherichia coli was resistant until 5 mg/ml.

Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To compare chemohormonal therapy, chemotherapy alone, and hormonal therapy alone in postmenopausal patients with estrogen receptor (ER)-positive operable breast cancer and positive axillary nodes with respect to survival and disease-free survival (DFS). PATIENTS AND METHODS: Eight hundred ninety-two postmenopausal women with ER-positive, node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) from July 1979 to March 1989 and 74 by the Eastern Cooperative Oncology Group (ECOG) between June 1987 and March 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive the following: (1) tamoxifen 10 mg twice daily by mouth for 1 year; (2) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (IV) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 IV weekly for 1 year, vincristine .625 mg/m2 IV weekly for the first 10 weeks, and prednisone during weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (3) the combination of tamoxifen and CMFVP. RESULTS: The median follow-up duration is 6.5 years, with a maximum of 12.8 years. Treatment arms are not significantly different with respect to either survival or DFS (log-rank, 2 df, P = .82 and .23, respectively). The 5-year survival rate is 77% for the tamoxifen arm, 78% for CMFVP, and 75% for the combination. No significant differences were observed in node or receptor level subsets. Severe or worse toxicity was experienced by 56% of patients on CMFVP and 61% on CMFVP plus tamoxifen, compared with 5% on tamoxifen alone. CONCLUSION: CMFVP chemotherapy, either alone or in combination with tamoxifen, has not been shown to be superior to tamoxifen alone in the treatment of postmenopausal women with node-positive, ER-positive, operable breast cancer.

Effect of compounds from Mandevilla velutina on bradykinin-mediated contractile and relaxant responses of the isolated guinea pig trachea.

This study examines the action of three putative functional bradykinin (BK) antagonists isolated from Mandevilla velutina on BK and other agonist-induced contraction or relaxation responses in intact or in epithelium-denuded strips of tracheal muscle from guinea pigs. Compound MV 8612 (8 and 16 microM) and MV 8610 (12 and 24 microM) caused a graded rightward displacement of BK dose-response curves in the isolated guinea pig trachea (dose ratio 2- to 4-fold). Compound MV 8608 (28 microM) had a small effect on BK contractile responses. At high concentrations, compound MV 8612 (24 microM) caused a slight but significant depression of the BK-induced maximal responses. These pharmacological actions appear to be quite selective towards BK, since within the same concentration range these compounds failed to interfere with the sensitivities to prostaglandin F2 alpha, carbachol and histamine. However, these compounds significantly enhanced maximal responses to the latter two agonists, an action that was not influenced by indomethacin. In addition, MV 8612 and MV 8608 (16 and 56 microM) significantly potentiated BK-mediated epithelium-dependent relaxation responses in preparations precontracted with carbachol. These compounds also significantly potentiated isoprenaline but not theophylline-relaxant responses, an action that seems to occur independently of the generation of cyclooxygenase products of arachidonic acid pathway. These results further extend our previous studies and indicate that some of the M. velutina compounds exert a weak though selective antagonistic action against BK-induced contractile responses of the isolated epithelium-denuded guinea pig tracheal smooth muscle and potentiate BK-induced relaxations in tissues with intact epithelium precontracted with carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E1 enhances tumoricidal activity of 5-fluoro-2'-deoxyuridine in rats.

Addition of prostaglandin E1 (PGE1) to 5-fluoro-2'-deoxyuridine (FUDR) infused via the portal vein has been shown to diminish both the regional and the systemic toxicity of this chemotherapeutic agent. The effect of concomitant PGE1 infusion on tumor growth has not yet been determined. This study was designed to assess the effect of PGE1 in combination with FUDR on an established adenocarcinoma in the rat model. Fifty-gram Fischer rats underwent placement of a 3-mm3 fragment of colon carcinoma 4047 in the left thigh pad. After 6 weeks to allow for tumor growth, the animals were randomly assigned to receive a 7-day intravenous infusion of (1) saline, (2) PGE1 (0.1 microgram/kg/min), (3) FUDR (3 mg/kg/day), or (4) PGE1 + FUDR. At 10 days animals receiving PGE1 + FUDR had a significant decrease in tumor volume (mm3, log 10) (3.39 +/- 0.24 vs 3.85 +/- 0.12, P less than 0.05) compared with animals receiving FUDR alone. We conclude that PGE1 may be useful as an adjunctive cytotoxic agent.

Carcinoma of the pancreas: a retrospective review.

Eighty-five patients with adenocarcinoma of the pancreas were reviewed in order to evaluate the efficacy of our methods of diagnosis and treatment. The most useful diagnostic test was percutaneous transhepatic cholangiography (PTC) with a diagnostic rate of 96%. Pancreaticoduodenectomy (Whipple procedure) and total pancreatic resection were performed in 13 and 2 patients, respectively. The remaining 50 patients underwent various palliative drainage procedures. Twenty patients did not undergo operation for various reasons. The primary tumor was found in the head of the pancreas in 50 patients (59%), the body in 6 patients (7%), and in the tail in 8 patients (9%). Postoperative complications, including sepsis, bleeding, intra-abdominal abscesses, and anastomotic leaks, occurred in 37% of the patients. There were one operative and 9 postoperative deaths. The average survival for those patients undergoing surgical intervention was 6 months. There were no 5-year survivors.

Portal infusion of tumor necrosis factor increases mortality in rats.

Tumor necrosis factor (TNF) is a protein found in the serum of mice presensitized with BCG following injection of endotoxin. Although TNF has been shown to cause hemorrhagic necrosis of certain tumors, the marked toxicity of recombinant human TNF has limited the clinical usefulness of this compound. This experiment was designed to determine whether hepatic metabolism would reduce the systemic toxicity of TNF delivered by the portal circulation. Twenty male Fischer rats received a continuous infusion of recombinant human TNF (100 micrograms/kg/day), 10 through a portal venous branch, and 10 through a branch of the inferior vena cava. Control animals received an infusion of carrier solution by the same route. After 7 days the animals were sacrificed and their organs weighed and sectioned. Mortality in the portal TNF group was 100%. The animals followed the clinical pattern seen with lethal TNF injection. Histologic sections revealed significant gastric and small intestinal mucosal injury, pulmonary edema, and acute tubular necrosis. Animals receiving TNF systemically lost more weight per day of infusion than controls, but followed a relatively benign course. Systemically infused animals had evidence of mild pulmonary edema, and a periportal mononuclear infiltrate in the liver, but no obvious renal or gastrointestinal injury. In a second experiment the effect of escalating doses of portal TNF infusion on liver enzymes was assessed. TNF was infused intraportally at 10, 50, or 100 micrograms/kg/day for 3 days. Control animals received a carrier solution. Mortality was dose-related with 100% mortality in animals receiving 100 micrograms/kg/day, and 40% mortality in the 50 micrograms/kg/day group.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunocytochemical analysis of estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance.

An estrogen receptor-immunocytochemical assay (ER-ICA) was performed on frozen sections of 130 samples of human breast carcinoma. A standard dextran-coated charcoal assay (DCCA) was performed on the same samples. Concordance of results between the tests was 91%. The sensitivity and specificity of the ER-ICA, compared with the DCCA, were 92% and 89%, respectively. We describe the ER-ICA technique and review the literature regarding the use of the ER-ICA in evaluating breast cancer with respect to the agreement of results with the DCCA, the nature of discordant results, the ability to predict the clinical response to hormone therapy, and the ability to predict disease-free survival. The combined experience of many studies has shown that the ER-ICA is a highly specific and sensitive method for measuring the level of ERs in breast tumors with a high level of agreement with the DCCA. Early experience has suggested that the ER-ICA can predict the response to hormone therapy and disease-free survival, as well as or better than the DCCA. The evaluation of receptor heterogeneity, made possible by the ER-ICA, may enhance our ability to discriminate ER-positive tumors with a relatively high risk of recurrence.

Demonstration of anti-bradykinin compounds in callus cultures of Mandevilla velutina

Calluses from stems and leaves of Mandevilla velutina were grown in culture for 30,45 and 60 days. Thin-layer chromatography of ethyl acetate extracts of calluses from stems of M. velutina revealed the presence of 6 compounds. Two of them had RF values identical to those of the anti-bradykinin (BK) compounds MV8609 and MV8610 previously isolated from the natural plant. The ethyl acetate extract (20 to 80 microng/ml) from stem callus culture antagonized in a concentration-dependent and reversible manner contractions caused by BK (0.1-100 nM) in the isolated rat uterus. The extracts obtained from calluses cultured for 30,45 and 60 days were about 79-, 63-and 31-fold more potent, respectively, in antagonizing BK than the crude extract obtained from the rhizome of the plant

Needle aspiration biopsy of palpable breast masses.

One hundred fifteen patients underwent needle aspiration biopsy of palpable breast masses prior to open biopsy. Aspirates were obtained by surgical residents, prepared by a cytotechnologist present at the procedure, and evaluated by a single pathologist. Cytologic findings were interpreted as positive or highly suspicious for malignancy, normal or benign, or insufficient. All patients underwent open biopsy. Patients with positive or highly suspicious cytologic findings who preferred partial mastectomy and radiotherapy were offered a segmental mastectomy. No patient was offered total mastectomy based on cytologic findings alone. There were two false-positive and two false-negative results, for a 92 percent sensitivity and 97 percent specificity. The value of needle aspiration biopsy lies in its ability to identify patients at high risk for malignancy. Total mastectomy cannot be recommended based on cytologic findings alone. The setting of a surgical residency program does not adversely affect the reliability of the technique.

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Blockade of the bradykinin-evoked diphasic response of isolated rat duodenum by the crude extract of and compounds obtained from Mandevilla velutina

The influence of an aqueous/ethanolic extract of M. velutina (CE) and of two compound (MV 8608 and MV 8612) purified from the plant on BK-, Ad- and K+ -induced responses of the rat duodenum was analyzed in vitro. In preparations precontracted with Ca2+, the CE (1 and 2 mg/ml) markedly inhibited BK -induced relaxation in a dose-dependent manner but was less effective against Ad-induced relaxation. The CE (0.5 mg/ml) also antagonized BK -induced relaxation and contraction of strips bathed in normal medium. The two compounds from M. velutina (10 and 20 microng/ml) also promoted a dose-dependent blockade of both responses to BK, only slightly depressing the response to K+