Experience from Asian centers in a named-patient-use program for afatinib in patients with advanced non-small-cell lung cancer who had progressed following prior therapies, including patients with uncommon EGFR mutations.

BACKGROUND: This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib. METHODS: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory. RESULTS: 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months. CONCLUSIONS: Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations.

Patterns of surgical treatment for women diagnosed with early breast cancer in Queensland.

BACKGROUND: Australian women with early breast cancer should be given the choice between breast-conserving surgery (BCS) or mastectomy. This is the first Australian study to report on patterns of surgical care specifically for early breast cancer at a population level. METHODS: Two population-based routine data collections were linked to obtain surgical treatment information for breast cancer cases diagnosed in 2004 in Queensland, from which we identified 1274 cases of early female breast cancer. Logistic regression was used to assess the likelihood of female breast cancer patients having mastectomy, BCS, and axillary node dissection, after adjusting for patient and hospital demographics, tumor size, and comorbidities. RESULTS: Three-quarters (77%) of women had BCS, 29% had a mastectomy, and 86% had dissection of the axillary lymph nodes. The likelihood of women having mastectomy was higher among women living in rural areas, those treated in public hospitals, and women who had comorbidities of anemia or heart failure. In contrast, BCS was more likely for women treated in private hospitals or hospitals with high surgical caseload. Heart failure decreased the likelihood of BCS. Having an axillary node dissection was more likely among younger women and those treated in high caseload hospitals. CONCLUSION: The observed differentials in surgical treatment for early breast cancer patients suggest that access issues may have contributed to the decision-making process. Understanding the reasons why women with early breast cancer choose a certain treatment strategy should be a focus of future research.

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program.

INTRODUCTION: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup. METHODS: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC. RESULTS: Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six). CONCLUSIONS: This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.

Diagnostic management of pulmonary embolism using clinical assessment, plasma D-dimer assay, complete lower limb venous ultrasound and helical computed tomography of pulmonary arteries. A multicentre clinical outcome study.

The objective of the study was to assess the clinical validity of a non-invasive diagnostic strategy for acute pulmonary embolism using clinical assessment combined with both ELISA D-dimer and complete lower limb ultrasound (US) examination of proximal and distal veins, before single-detector helical computed tomography (CT) of pulmonary arteries. We expected the strategy to have a high diagnostic exclusion power and to safely decrease the number of CT scans. This prospective, multicenter outcome study included 274 consecutive outpatients. All underwent a priori clinical probability, D-dimer and bilateral complete lower limb US assessments. Only patients with a high clinical probability and both tests negative, or positive D-dimer and negative US assessments, underwent CT. This was deemed necessary in 114 patients (42%). At baseline, venous thromboembolism (VTE) was detected in 110 patients (40%), either by US showing proximal (n=65) or distal (n=36) thrombosis, or by CT (n=9). Anticoagulant was withheld in the remaining patients with negative results in both D-dimer and US but a non-high clinical probability (n=59), or in both US and CT (n=90), or with negative US (n=6) and inadequate CT (n=9). All patients underwent a three-month clinical follow-up. VTE occurred in one patient with inadequate CT, yielding an incidence of 0.6% [95% confidence interval: 0.1-3.4]. No patient died from VTE or had major bleeding. Using clinical probability, ELISA D-dimer and complete US before helical CT is a safe strategy resulting in a substantial reduction in CT scans.

Numerical modeling of DNA-chip hybridization with chaotic advection.

We present numerical simulations of DNA-chip hybridization, both in the "static" and "dynamical" cases. In the static case, transport of free targets is limited by molecular diffusion; in the dynamical case, an efficient mixing is achieved by chaotic advection, with a periodic protocol using pumps in a rectangular chamber. This protocol has been shown to achieve rapid and homogeneous mixing. We suppose in our model that all free targets are identical; the chip has different spots on which the probes are fixed, also all identical, and complementary to the targets. The reaction model is an infinite sink potential of width dh , i.e., a target is captured as soon as it comes close enough to a probe, at a distance lower than dh . Our results prove that mixing with chaotic advection enables much more rapid hybridization than the static case. We show and explain why the potential width dh does not play an important role in the final results, and we discuss the role of molecular diffusion. We also recover realistic reaction rates in the static case.

[Heterogeneity in the handling of vitamin-K-antagonists and of INR: the example of Quercy-Rouergue]. / Hétérogénéité du maniement des antivitamines K et de l'INR : l'exemple du Quercy-Rouergue.

Using a questionnaire, we have evaluated how VKA and INR are handled by medical doctors in Quercy-Rouergue. This evaluation is part of an international post-analytical quality assessment survey in laboratory medicine supervised by Noklus (http://www.noklus.no/). The original questionnaire designed by Noklus has been adapted to our local practices in replacing warfarin by fluindione. The « Centre de référence et d'éducation aux antithrombotiques d'Ile de France ¼ (Creatif) also participated. Of 282 medical doctors who were sent the questionnaire 109 filled it in, 62% of them being general practitioners. For a target INR at 2.5, the thresholds used to change the dose of VKA range between 1.3 and 2.3 for low values, and between 2.8 and 4 for high values. The bleeding or ischemic risks of being under VKA, versus of not being under VKA, are largely overestimated. INR measurements also tend to be too frequent in stable, and even more so in overdosed, patients. In case of INR at 4.8 only 59% of the participants implement the recommendation of la Haute autorité de santé (HAS) and le Groupe d'étude sur l'hémostase et la thrombose (GEHT) which consists of skipping one dose of VKA, and the attitudes also diverge regarding the importance of the VKA dose reduction, and the number of days under reduced dose before the next INR measurement, the attitude of the Creatif being barely predominant among the participants, and slightly different from that recommended by the HAS and the GEHT. In conclusion, despite the limitations of our methods (the analysis of a questionnaire being less close to the truth than an analysis of actual practices), our evaluation points to the heterogeneity in the knowledge about, and in handling, VKA and INR regarding more particularly management of overdosing, and the estimation of bleeding or ischemic risks, despite the availability of supposedly clear and simple practice guidelines.

Population based incidence and age distribution of spermatocytic seminoma.

PURPOSE: Spermatocytic seminoma is a rare subtype of testicular germ cell tumor which has been reported to occur in elderly men. We report the first population based estimate of incidence, temporal trends and age distribution of this tumor. MATERIALS AND METHODS: All cases of primary testicular cancer identified by cancer registries in Australia between 1982 and 2002 were available for analysis. The International Classification of Diseases for Oncology code M-9063/3 was used to identify spermatocytic seminomas. Incidence trends were modeled using Poisson regression. RESULTS: There were 58 cases of spermatocytic seminoma out of 9,658 cases of primary malignant testicular neoplasms identified by the cancer registries. This tumor comprised 1.1% of all seminoma and the age standardized incidence rate was 0.4 per million (95% CI 0.3-0.6). A temporal increase in incidence was found but not one reaching statistically significance. Age at diagnosis ranged from 19 to 92 years with a mean of 53.5 (SD 16.7) and a median of 54 years. CONCLUSIONS: Spermatocytic seminoma should be considered in the differential diagnosis for testicular germ cell tumors presenting in young adults because this tumor occurs as often in men younger than 55 years as it does in older men. Although rare, the occurrence of this tumor is not as singular as the current literature suggests.

Cancer screening in Queensland men.

OBJECTIVES: To describe the self-reported use of prostate specific antigen (PSA) tests, faecal occult blood tests (FOBTs), and whole-body skin examinations among Queensland men, reasons for use, and the personal characteristics of men undergoing the tests for cancer screening. SETTING AND DESIGN: Data were obtained from the Queensland Cancer Risk Study (QCRS), a population-based telephone survey conducted in 2004, which used random sampling stratified by age, sex, and geographic location. PARTICIPANTS: All men aged 50-75 years who participated in the QCRS (n = 2336). MAIN OUTCOME MEASURES: Use of PSA test, FOBT, or whole-body skin examination, specifically as a screening procedure; the probability of being screened; and associations with sociodemographic factors, risk behaviour, and cancer experience. RESULTS: More than a third of men reported never having been screened for prostate, colorectal, or skin cancer. Of those who had been screened, the odds of PSA testing being reported were more than two times greater than the odds of whole-body skin examination (adjusted odds ratio [OR], 2.54; 95% CI, 1.49-4.32), and the odds of reporting an FOBT were less (adjusted OR, 0.48; 95% CI, 0.22-1.04). Men who participated in cancer screening tended to be older, white, living with a partner, and to have private health insurance. Smokers were less likely to be screened with any of the three screening tests. CONCLUSIONS: Of these three cancer screening tests, the FOBT has the best evidence for reducing mortality and yet is the least frequently used by Queensland men. There are disparities in reported screening prevalence between the specific tests and across certain population subgroups.

Comparison of peripheral blood progenitor cell yield from standard chemotherapy used in the treatment of lymphoid malignancies and high-dose cyclophosphamide: a retrospective review of 141 patients.

BACKGROUND: Peripheral blood progenitor cells (PBPCs) are often collected after mobilization with high-dose cyclophosphamide (HDC) combined with growth factors. HDC may not be needed for PBPC mobilization, and patients with lymphoid malignancies can be harvested with treatment regimens of chemotherapy. STUDY DESIGN AND METHODS: A retrospective analysis was performed on 141 patients with lymphoma or multiple myeloma whose PBPCs were harvested after chemotherapy. The PBPC yield and time to mobilization was compared between patients who received HDC (n = 51) and other chemotherapy regimens (n = 90) including high-dose cyclophosphamide and etoposide (HDC plus VP-16; n = 41), CHOP, ESHAP, ABVD, VAD, and others (n = 49). A multiple linear regression model and proportional hazards model determined factors influencing yield and time to mobilization, respectively. RESULTS: The difference in mean yield between HDC and all non-HDC regimens was significant, with HDC plus VP-16 resulting in the highest yields. The proportion of patients achieving a CD34 count in excess of 5 x 10(6) per kg did not differ significantly between the regimens. In a multiple linear regression model, HDC plus VP-16 resulted in a higher PBPC yield than HDC but all other regimens did not. In addition, patients exposed to more than one prior chemotherapy regimen had lower yield regardless of the mobilization regimen. The mean number of days to mobilization with HDC was 10.2 days, 17.1 days for HDC plus VP-16, and 14.2 days for all other regimens. The timing of mobilization was influenced by the chemotherapy used and the number of prior regimens in a proportional hazards model. CONCLUSION: These results demonstrate a higher mean yield of PBPCs with HDC plus VP-16 but no difference in yield between non-HDC plus VP-16 regimens used for first-line or relapse therapy and HDC, suggesting that HDC may be an unnecessary additional therapy.