Laboratory investigation of "biorhythms".

Three subjects were tested on an information processing task on a daily basis for a period of 70 d. Performance measurement included reaction time, movement time, and information processing rate. The data set obtained was subjected to Fast Fourier Transforms (FFT) in an attempt to identify periodicities in performance. Twelve significant harmonics were identified and nine were found to be within 1 d of at least one of the cycles hypothesized by the theory of "biorhythms." The probability of this occurring by chance is remote (p less than 0.05), assuming a uniform distribution of significant amplitude. The results were interpreted as suggesting the possibility of a biorhythmic influence in the performance of the task.     

Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.

PURPOSE: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. PATIENTS AND METHODS: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

Role of radiology in the treatment of malignant hilar biliary strictures 2: 10 years of single‐institution experience with percutaneous treatment

We reviewed the results of percutaneous intervention of hilar biliary malignancy over a 10‐year period at a single institution: the Royal Melbourne Hospital. Ninety‐nine patients (100 treated in total) were included. Information was retrieved by retrospective examination of patient notes and radiology, combined with interviews with family and relevant physicians. Sixty‐nine patients were treated with insertion of semipermanent stents, 19 had external drain tubes, and 25 received percutaneous access for Iridium brachytherapy. Adequate drainage was achieved in 87% of the patients stented, and percutaneous access was successful in 96% of patients planned for brachytherapy. Of those patients undergoing endoprosthesis insertion, early complications occurred in 39% and late complications in 23%. Average survival for the entire patient population was 227.3 days, with a median of 167 days. Longer survival times (213 vs 142 days) and lower complication rates (44 vs 64%) are observed with metal stents in comparison with plastic stents. Percutaneous intervention is an important treatment option in hilar biliary malignancy, particularly in patients unfit for surgery. Reasonable survival with good palliation is the most common outcome, and most patients do not require further intervention.     

Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.     

Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography.

PURPOSE: Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS: Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS: Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION: In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.     

Markers of coagulation and angiogenesis in cancer-associated venous thromboembolism.

PURPOSE: We sought to determine whether venous thromboembolism in cancer patients is associated with aberrant plasma levels of hemostatic and angiogenic factors. PATIENTS AND METHODS: Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVT; DVT + cancer group, n = 32), those without DVT (cancer control group, n = 36), and patients with acute DVT but no cancer (DVT control group, n = 58). Plasma assays of activation and inhibition of coagulation and fibrinolysis, as well as angiogenesis activation, were then performed. RESULTS: Median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P =.0001 and P =.003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P <.0001 and P =.011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P <.0001, respectively). Median levels of tissue-type plasminogen activator were also significantly higher, while protein C activity was lower in the DVT + cancer group than in the DVT control group (14.6 ng/mL v 9.50 ng/mL, respectively, P =.0005; 0.89 U/mL v 1.11 U/mL, respectively, P =.0008). CONCLUSION: These data not only support prior observations of coagulation activation in patients with malignancy, but also provide new evidence for enhanced coagulation activation in the setting of acute venous thromboembolism in cancer. Future prospective studies are warranted to determine whether these and other potential markers of hypercoagulability may help to identify cancer patients at highest risk for venous thromboembolism.     

Do Multiple Measurements Employing Different Ultrasonic Techniques Improve the Accuracy of Amniotic Fluid Volume Assessment?

Summary: This investigation was undertaken to determine if the accuracy of the ultrasound assessment of abnormal amniotic fluid volume (oligohydramnios or poly-hydramnios) is improved by employing multiple sonographic amniotic fluid measurements. Four ultrasound techniques consisting of the subjective assessment (ultrasonic visualization without measurement), largest vertical pocket, amniotic fluid index and 2-diameter pocket technique were performed followed by amniocentesis and dye-dilution confirmation of amniotic fluid volume in 66 singleton pregnancies. The ultrasound accuracy to detect abnormal amniotic fluid volume ranged from 61% with the largest vertical pocket to 70% with the 2-diameter pocket procedure used separately. Receiver operator characteristic curves demonstrated that combining the 4 ultrasonic measurements did not improve the accuracy of identifying amniotic fluid volumes.     

Patient satisfaction with health care providers in South Africa: the influences of race and socioeconomic status.

OBJECTIVE: The first democratic government elected in South Africa in 1994 inherited huge inequalities in health status and health provision across all sections of the population. This study set out to assess, 4 years later, the influence of race and socioeconomic status (SES) on perceived quality of care from health care providers. DESIGN: A 1998 countrywide survey of 3820 households assessed many aspects of health care delivery, including levels of satisfaction with health care providers among different segments of South African society. RESULTS: Fifty-one percent (n = 1953) of the respondents had attended a primary care facility in the year preceding the interview and were retained in the analysis. Both race and SES were significant predictors of levels of satisfaction with the services of the health care provider, after adjusting for gender, age, and type of facility visited. White and high SES respondents were about 1.5 times more likely to report excellent service compared with Black and low SES respondents, respectively. CONCLUSION: In South Africa, race and SES are not synonymous and can no longer be considered reliable proxy indicators of one another. Each has distinct and significant but different degrees of association with client satisfaction. Any assessment of equity-driven health policy in South Africa should consider the impacts of both race and SES on client satisfaction as one of the indicators of success.     

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer.

We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non-small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.