Limitations of adjuvant radiotherapy for uterine sarcomas spread beyond the uterus

OBJECTIVE: The present review analyzes patients with advanced uterine sarcomas with the goal of identifying patients likely to benefit from larger volumes and higher dosages of radiotherapy. METHODS: A retrospective review was performed of medical records of all patients receiving adjuvant radiotherapy for advanced uterine sarcomas from 1978 to 1997 at the University of Minnesota. RESULTS: Nineteen women with advanced uterine sarcomas received adjuvant radiotherapy. Seven also received adjuvant chemotherapy. Three patients had FIGO stage IIIA, 1 stage IIIB, 5 stage IIIC, and 12 stage IVB. Patients with mixed mullerian tumors had overall and disease-free survivals of 31% at 1 year and 23% at 5 years. For leiomyosarcomas, overall survival was 67% at 1 year and 33% at 5 years, but relapse-free survival was 33% at 1 and 5 years. First sites of failure were three pelvic and abdominal, one abdominal only, one abdominal and distant, two pelvic and distant, one pelvic, abdominal, and distant, five distant only, and one unknown. No Grade 3 or 4 toxicity occurred. CONCLUSION: Ongoing technical advancements in radiotherapy offer more precise radiation delivery, particularly to the peritoneal cavity. Although abdominal failures are common in women with mixed mullerian tumors, translation of higher radiation dosage to cure is unproven, and the majority of failures have a distant component. Until effective systemic therapy is developed, the prognosis of uterine sarcomas with any spread beyond the uterus will remain poor.     

A prospective, randomized study analyzing sartorius transposition following inguinal-femoral lymphadenectomy

OBJECTIVES: Based on the reduced morbidity seen in our retrospective study, we undertook a prospective, randomized trial to determine whether transposition of the sartorius muscle improves post-operative morbidity in women with squamous cell carcinoma of the vulva undergoing inguinal-femoral lymphadenectomy. METHODS: Patients with squamous carcinoma of the vulva requiring inguinal-femoral lymphadenectomy were randomized to undergo sartorius transposition or not. All patients received perioperative antibiotics, DVT prophylaxis, and closed suction surgical site drainage. Outcomes assessed include wound cellulitis, wound breakdown, lymphocyst formation, lymphedema, and/or rehospitalization. Cohorts were compared using Fisher's exact test. Baseline characteristics were compared using Student's t test or Fischer's exact test as appropriate. Logistic regression was used to assess the impact of sartorius transposition, after adjusting for other factors. RESULTS: From June 1996 to December 2002, 61 patients underwent 99 inguinal-femoral lymphadenectomies, 28 with sartorius transposition, and 33 without. The mean (SD) age for controls and patients undergoing sartorius transposition was 63.5 (15.2) and 73.8 (13.7) years, respectively (P < 0.05). There were no statistically significant differences in BSA, tobacco use, co-morbid medical conditions, past surgical history, medication use, size of incision, duration of surgery, number of positive lymph nodes, pathologic stage, pathologic grade, pre- or postoperative hemoglobin, or length of hospitalization. There were no statistically significant differences in the incidence of wound cellulitis, wound breakdown, lymphedema, or rehospitalization. The incidence of lymphocyst formation was increased in the sartorius transposition group. After adjusting for age, however, the groups appeared similar. CONCLUSIONS: Sartorius transposition after inguinal-femoral lymphadenectomy does not reduce postoperative wound morbidity.     

Is early enteral feeding safe in patients who have suffered spinal cord injury?

OBJECTIVE: To examine whether enteral feeding is a safe technique to use in the acute stage of spinal cord injury. METHODS: We searched the departmental computerised patient database and clinical records for all patients with spinal cord injuries admitted to the Auckland Hospital Intensive Care Unit (ICU), known as the Department of Critical Care Medicine (DCCM), between January 1988 and December 2000. Patients were included in the study if they had suffered complete spinal cord transection resulting in either paraplegia or quadriplegia. Data was collected for the following variables: length of time to commence enteral feeding, type of enteral feeding, duration of enteral feeding and reasons for interrupting the feed. RESULTS: Thirty-three patients were found and were included in the study. Twenty-seven (82%) of the patients commenced enteral feeding in the DCCM, 25 by nasogastric (NG) and 2 by nasojejunal (NJ) tube. Feeding was commenced a median of 2 days after admission and the median length of enteral feeding was 7.7 days. The main feeding complications that resulted in interrupting the feed were high gastric aspirates. One patient commenced on enteral feeding developed medical complications that prevented continuation. Two patients on NG feeding converted to NJ feeding. CONCLUSION: No major complications associated with enteral feeding were seen in this study. This would indicate that enteral feeding can be safely administered in the acute stage of spinal cord injury provided complications are monitored for daily.     

Trends in selenium status of South Australians

OBJECTIVE: To assess trends in selenium status in South Australians from 1977 to 2002. DESIGN: Six cross-sectional surveys. PARTICIPANTS: 117 participants in 1977, 30 in 1979, 96 and 103 (separate surveys) in 1987, 200 in 1988, and 288 volunteer blood donors in 2002. A total of 834 healthy Australian adults (mean age, 42 years [range, 17-71 years]; 445 were male). MAIN OUTCOME MEASURES: Plasma and whole blood selenium concentrations. RESULTS: The 2002 survey yielded a mean plasma selenium concentration of 103 micro g/L (SE, 0.65), which reached the estimated nutritional adequacy level of 100 micro g/L plasma selenium. Mean whole blood selenium declined 20% from the 1977 and 1979 surveys (mean whole blood selenium concentration, 153 micro g/L) to the 1987, 1988 and 2002 surveys (mean whole blood selenium concentration, 122 micro g/L). Plasma selenium was higher in men (P = 0.01), and increased with age in both men and women (P = 0.008). CONCLUSIONS: In healthy South Australian adults sampled from 1977 to 2002, whole blood and plasma selenium concentrations were above those reported for most other countries and in most previous Australian studies, notwithstanding an apparent decline in selenium status from the late 1970s to the late 1980s.     

Substance use and sexual risk: a participant- and episode-level analysis among a cohort of men who have sex with men

Prior reports associating substance use with sexual risk behavior have generally used summary measures and have not adjusted for participants' background levels of substance use. In this 1999-2001 US study (the EXPLORE study), the authors determined whether substance use during sex was independently associated with sexual risk during recent sexual episodes, as reported by 4,295 human immunodeficiency virus-negative men who have sex with men. The main outcome measure was serodiscordant unprotected anal sex (SDUA). The influence of participant-level characteristics was examined by using repeated-measures logistic models. In assessing the influence of episode-level predictors on SDUA, the influence of participant-level characteristics, including 6-month substance use, was removed by using conditional logistic regression, in effect making each participant his own control. The authors also adjusted for partner characteristics. Eleven percent of participants reported heavy alcohol use, 37% used poppers, 19% sniffed cocaine, and 13% used amphetamines. In the participant-level analysis, use of poppers, amphetamines, and sniffed cocaine as well as heavy alcohol use in the prior 6 months were independently associated with SDUA. In the conditional analysis, consumption of > or = 6 alcoholic drinks or use of poppers, amphetamines, or sniffed cocaine just before or during sex was independently associated with SDUA. The authors concluded that programs aimed at preventing human immunodeficiency virus transmission should emphasize the influence of substance use during sex on increased risk behavior.     

Phase I/II study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours

DHA-paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA-paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA-paclitaxel 660 mg m(-2) and carboplatin AUC 5 with DHA-paclitaxel 880 mg m(-2). Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33-71). All patients had advanced cancer refractory to standard treatment, performance status 0-2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60-506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHA-paclitaxel 660 mg m(-2) given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m(-2), given every 28 days, are warranted in chemo-naive patients.     

A gene expression signature associated with metastatic outcome in human leiomyosarcomas

Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.     

Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group

Previous studies have shown that activating mutations of c-KIT/PDGFRA, potential therapeutic targets for imatinib mesylate, are implicated in the pathophysiology of gastrointestinal stromal tumours (GISTs). In this study, GISTs from 37 patients enrolled in an European Organisation for Research and Treatment of Cancer (EORTC) phase I/II clinical study of imatinib were examined for mutations of c-KIT/PDGFRA in order to explore whether the mutational status of the tumour predicts the clinical response to therapy. Mutations were screened by denaturing high-pressure liquid chromatography (DHPLC) and characterised by bi-directional DNA sequencing. Activating mutations of c-KIT or PDGFRA were found in 29 (78%) and 2 (6%) GISTs, respectively. Most c-KIT mutations involved exon 11 (n=24; 83%), all but one being an in-frame deletion; no isolated point mutations were found. The other c-KIT mutations included exon 9 AY 502-503 duplication (n=4; 14%) and exon 13 Lys-->Glu(642) missense mutation (n=1; 3%). Two tumours with no detectable c-KIT mutations demonstrated PDGFRA Asp-->Glu(842) amino acid substitutions. Patients with GISTs harbouring exon 11 mutations were more likely to achieve a partial response (PR) on imatinib therapy (83%) than all of the others (23%). The overall survival and progression-free survival rates for the entire group at 106 weeks were 78.3% and 46.9%, respectively. Based on a Kaplan-Meier analysis, patients with GISTs harbouring c-KIT mutations had longer median survival times and were less likely to progress than the other patients. These findings indicate that the mutational status of the c-KIT/PDGFRA oncoproteins could be useful to predict the clinical response of patients imatinib therapy.