New treatments for breast cancer: Breakthroughs for patient care or just steps in the right direction?

Three areas of clinical research in breast cancer treatment led to news breaking presentations at the American Society of Clinical Oncology (ASCO) meeting, 1998, in Los Angeles. All three subjects represent important advances in cancer medicine. Prevention: Two related drugs, tamoxifen and raloxifene, were found in placebo controlled trials to significantly reduce the incidence of breast cancer for women at increased risk of developing the disease. Patterns of relapse showed that the reduced rate of breast cancer was exclusively observed for tumors expressing estrogen receptors, while the rate of tumors classified as estrogen-receptor negative was similar for the treatment and the control groups. This may indicate that the observed reduction in breast cancer incidence is due to a treatment effect on occult disease rather than its prevention. We certainly have no adequate information on mortality prevention. Adjuvant therapies: Taxol given every three weeks for four courses following an adjuvant treatment with four courses of doxorubicin and cyclophosphamide (AC) combination was found to be superior to not adding treatment after the four courses of AC in a trial involving 3170 patients. At 22 months of median follow-up, the quoted P-values were P = 0.0077 for disease-free survival and P = 0.039 for overall survival, but these did not cross the prospectively defined interim analysis boundaries for statistical significance at the 0.05 level. The difference was observed early during follow-up, and was exclusively seen in the 40% of patients who had ER-negative primaries and, therefore, did not receive tamoxifen following chemotherapy. One may thus argue that the early difference observed was primarily due to differences in the duration of the treatment regimens in the two groups and the early entry into the trial of patients with particularly aggressive neoplasia (e.g., ER-negative primaries) who would have benefited from a longer duration treatment. Treatment of advanced disease: The use of monoclonal antibodies to c-erb-B2 was found to induce responses in metastatic breast cancer. Patients with tumors expressing c-erb-B2 responded to weekly infusions of this biological agent. It was particularly impressive that the response rate for patients receiving infusion of the monoclonal antibodies together with the cytotoxics was superior to that with chemotherapy alone in a randomized trial. It is important to note that only patients with tumors overexpressing c-erbB-2 (the overall incidence is about 20%) were tested. It must still be demonstrated that the effect of these monoclonal antibodies is indeed confined to cells overexpressing c-erbB-2. Treatment related cardiac tox-icity remains a problem, and the effects of treatment in various subsets of patients need to be defined before starting investigations in the adjuvant setting, which is a clear further objective of this specific research. The significant findings from clinical research opened several new questions, which must be answered before allowing them to be employed in routine patient car

Chronic Rejection and Extrahepatic Biliary Tract Obstruction 8 Years After Orthotopic Liver Transplantation Using the Gallbladder-Conduit Technique

A case of delayed biliary obstruction and cholangitis, occurring in the setting of chronic allograft rejection, 8 years after liver transplantation using the gallbladder-conduit, is presented. Extrahepatic biliary obstruction may be seen in the late follow-up of liver grafting and rejection phenomena may play a significant role in the development of such obstruction

Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS

A Systematic Review of the Perforated Duodenal Diverticula: Lessons Learned from the Last Decade

Background: The perforated duodenal diverticulum remains a rare clinical entity, the optimal management of which has not been well established. Historically, primary surgery has been the preferred treatment modality. This was called into question during the last decade, with the successful application of non-operative therapy in selected patients. The aim of this systematic review is to identify cases of perforated duodenal diverticula published over the past decade and to assess any subsequent evolution in treatment. Methods: A systematic review of English and non-English articles reporting on perforated duodenal diverticula using MEDLINE (2008-2020) was performed. Only cases of perforated duodenal diverticula in adults (> 18 years) that reported on diagnosis and treatment were included. Results: Some 328 studies were identified, of which 31 articles met the inclusion criteria. These studies included a total of 47 patients with perforated duodenal diverticula. This series suggests a trend towards conservative management with 34% (16/47) of patients managed non-operatively. In 31% (5/16) patients initially managed conservatively, a step-up approach to surgical intervention was required. Conclusion: Conservative treatment of perforated duodenal diverticula appears to be an acceptable and safe treatment strategy in stable patients without signs of peritonitis under careful observation. For patients who fail to respond to conservative treatment, a step-up approach to percutaneous drainage or surgery can be applied. If surgery is required, competence in techniques ranging from simple diverticulectomy to Roux-en-Y gastric diversion or even Whipple's procedure may be required depending on tissue friability and diverticular collar size. Keywords: Duodenal diverticulum; Duodenum; Management; Perforation

Phylobioactive hotspots in plant resources used to treat Chagas disease

Globally, more than six million people are infected with Trypanosoma cruzi, the causative protozoan parasite of the vector-borne Chagas disease (CD). We conducted a cross-sectional ethnopharmacological field study in Bolivia among different ethnic groups where CD is hyperendemic. A total of 775 extracts of botanical drugs used in Bolivia in the context of CD and botanical drugs from unrelated indications from the Mediterranean De Materia Medica compiled by Dioscorides two thousand years ago were profiled in a multidimensional assay uncovering different antichagasic natural product classes. Intriguingly, the phylobioactive anthraquinone hotspot matched the antichagasic activity of Senna chloroclada, the taxon with the strongest ethnomedical consensus for treating CD among the Izoceño-Guaraní. Testing common 9,10-anthracenedione derivatives in T. cruzi cellular infection assays demarcates hydroxyanthraquinone as a potential antichagasic lead scaffold. Our study systematically uncovers in vitro antichagasic phylogenetic hotspots in the plant kingdom as a potential resource for drug discovery based on ethnopharmacological hypotheses

Bioactivity-guided isolation of trypanocidal coumarins and dihydro-pyranochromones from selected Apiaceae plant species.

Bioactivity-guided isolation of natural products from plant matrices is widely used in drug discovery. Here, this strategy was applied to identify trypanocidal coumarins effective against the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease (American trypanosomiasis). Previously, phylogenetic relationships of trypanocidal activity revealed a coumarin-associated antichagasic hotspot in the Apiaceae. In continuation, a total of 35 ethyl acetate extracts of different Apiaceae species were profiled for selective cytotoxicity against T. cruzi epimastigotes over host CHO-K1 and RAW264.7 cells at 10 μg/mL. A flow cytometry-based T. cruzi trypomastigote cellular infection assay was employed to measure toxicity against the intracellular amastigote stage. Among the tested extracts, Seseli andronakii aerial parts, Portenschlagiella ramosissima and Angelica archangelica subsp. litoralis roots exhibited selective trypanocidal activity and were subjected to bioactivity-guided fractionation and isolation by countercurrent chromatography. The khellactone ester isosamidin isolated from the aerial parts of S. andronakii emerged as a selective trypanocidal molecule (selectivity index ∼9) and inhibited amastigote replication in CHO-K1 cells, though it was significantly less potent than benznidazole. The khellactone ester praeruptorin B and the linear dihydropyranochromones 3'-O-acetylhamaudol and ledebouriellol isolated from the roots of P. ramosissima were more potent and efficiently inhibited the intracellular amastigote replication at < 10 μM. The furanocoumarins imperatorin, isoimperatorin and phellopterin from A. archangelica inhibited T. cruzi replication in host cells only in combination, indicative of superadditive effects, while alloimperatorin was more active in fractions. Our study reports preliminary structure-activity relationships of trypanocidal coumarins and shows that pyranocoumarins and dihydropyranochromones are potential chemical scaffolds for antichagasic drug discovery

Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?

Background: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly. Methods: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. Results: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. Conclusions: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this populatio

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

Background: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. Patients and methods: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. Results: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. Conclusion: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherap