Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes.

Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the oxidation of oxycodone to oxymorphone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clearance for CYP3A5 was slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O-demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both oxidative reactions in microsomes prepared from five human livers. Inhibition with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N-demethylation; ketoconazole inhibited >90% of noroxycodone formation at low substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean K(m) of 600 +/- 119 microM and a V(max) that ranged from 716 to 14523 pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of total intrinsic clearance for N-demethylation. Quinidine inhibition showed that CYP2D6 is the high affinity enzyme for O-demethylation with a mean K(m) of 130 +/- 33 microM and a V(max) that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O-demethylation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone formation across the five liver microsomal preparations (10.5 microl/min/mg versus 1.5 microl/min/mg). Experiments with human intestinal mucosal microsomes indicated lower N-demethylation activity (20-50%) compared with liver microsomes and negligible O-demethylation activity, which predict a minimal contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone.     

Incidence and mortality of female breast cancer in the AsiaPacific region

Objective： To provide an overview of the incidence and mortality of female breast cancer for countries in the Asia-Pacific region.Methods： Statistical information about breast cancer was obtained from publicly available cancer registry and mortality databases（such as GLOBOCAN）, and supplemented with data requested from individual cancer registries. Rates were directly age-standardised to the Segi World Standard population and trends were analysed using joinpoint models.Results： Breast cancer was the most common type of cancer among females in the region, accounting for 18% of all cases in 2012, and was the fourth most common cause of cancer-related deaths（9%）. Although incidence rates remain much higher in New Zealand and Australia, rapid rises in recent years were observed in several Asian countries. Large increases in breast cancer mortality rates also occurred in many areas, particularly Malaysia and Thailand, in contrast to stabilising trends in Hong Kong and Singapore, while decreases have been recorded in Australia and New Zealand. Mortality trends tended to be more favourable for women aged under 50 compared to those who were 50 years or older. Conclusion： It is anticipated that incidence rates of breast cancer in developing countries throughout the Asia-Pacific region will continue to increase. Early detection and access to optimal treatment are the keys to reducing breast cancerrelated mortality, but cultural and economic obstacles persist. Consequently, the challenge is to customise breast cancer control initiatives to the particular needs of each country to ensure the best possible outcomes.     

Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials

Background

Afatinib is approved in the US, Europe, and several other regions for first-line treatment for epidermal growth factor receptor mutation-positive (EGFRm⁺) non-small-cell lung cancer (NSCLC).

Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe

Survival rates of patients with either early and advanced stage non–small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.     

Efficacy and Feasibility of Proton Beam Therapy in Relapsed High-Risk Neuroblastoma-Experiences from the Prospective KiProReg Registry

Background: Despite an intensive multimodal treatment approach, approximately 50% of high-risk (HR) neuroblastoma (NB) patients experience progression. Despite the advances in targeted therapy, high-dose chemotherapy, and other systemic treatment options, radiation therapy (RT) to sites of relapsed disease can be an option to reduce tumor burden and improve chance for disease control. Methods: Patients who received salvage irradiation with proton beam therapy (PBT) for local or metastatic relapse of HR NB within the prospective registry trials KiProReg and ProReg were eligible for this retrospective analysis. Data on patient characteristics, multimodality therapy, adverse events, and oncologic endpoints were evaluated. Adverse events were assessed before, during, and after PBT according to common terminology criteria for adverse events (CTCAE) V4.0. Results: Between September 2013 and September 2020, twenty (11 male; 9 female) consecutive patients experiencing local (N = 9) or distant recurrence (N = 25) were identified for this analysis. Distant recurrences included osteomedullary (N = 11) or CNS lesions (N = 14). Salvage therapy consisted of re-induction chemo- or chemo-immuno-therapy (N = 19), surgery (N = 6), high-dose chemotherapy and stem cell transplantation (N = 13), radiation (N = 20), and concurrent systemic therapy. Systemic therapy concurrent to RT was given to six patients and included temozolomide (N = 4), carboplatine (N = 1), or anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKI) (N = 1). A median dose of 36 Gy was applied to the 34 recurrent sites. Local RT was applied to 15 patients, while five patients, received craniospinal irradiation for CNS relapse. After a median follow-up (FU) of 20 months (4–66), the estimated rate for local control, distant metastatic free survival, and overall survival at 3 years was 68.0%, 37.9%, and 61.6%, respectively. During RT, ten patients (50%) presented with a higher-grade acute hematologic adverse event. Late higher-grade sequelae included transient myelitis with transverse section (N = 2) and secondary malignancy outside of the RT field (N = 1). Conclusion: Our study demonstrates the efficacy and safety of RT/PBT for recurrent HR NB in a multimodality second-line approach. To better define the role of RT for these patients, prospective studies would be desirable.     

Combining the HYM (Healthy Young Men’s) Cohort Study and the TRUTH (A Trans Youth of Color Study): Protocol for an Expanded Mixed Methods Study Renewal

BackgroundAs we enter the fifth decade of the AIDS epidemic, health researchers and AIDS activists reflect both on the progress that has been made and the importance of continued prevention efforts for those most at risk. As HIV infection rates continue to fluctuate across communities, a trend has emerged with new HIV infections becoming increasingly concentrated—with cascading effects—among people aged <30 years, from marginalized racial and ethnic groups, and who are sexual or gender minorities.ObjectiveIn this paper, we discuss the renewal of the Healthy Young Men’s (HYM) Cohort Study and the addition of a subcohort—TRUTH: A Transgender Youth of Color Study. The overarching aim of our renewed study was to inform new intervention strategies; understand linkage to care; and examine changes over time with respect to minority-related stress and intersectional identities and their relationship with substance use, mental health, and HIV risk. Findings from this study will help to inform the development of new interventions designed to engage African American and Black and Latino young men who have sex with men (YMSM) and transgender and gender minority youth in the HIV prevention and care continua and to reduce risk by addressing pathways of minority-related stress and intersectional stigma.MethodsLongitudinal study (baseline and follow-up assessments every 6 months for a total of 8 waves of data collection) is ongoing with reconsented cohort from the last iteration of HYM Cohort Study. This study protocol includes self-report survey, collection of urine to assess recent use of illicit drugs, and collection of blood and rectal and throat swabs to test for current sexually transmitted infection and HIV infection. An additional sample of blood and plasma (10 mL for 4 aliquots and 1 pellet) is also collected and stored in the HYM Cohort Study biorepository for future studies. This mixed methods study design includes collection of triangulated analysis of quantitative, qualitative, and biological measures (ie, drug use, sexually transmitted infection and HIV testing, and adherence to antiretroviral therapy among participants who are HIV+) at baseline and every 6 months.ResultsAs of February 2022, participants from the past 4 years of the HYM Cohort Study and TRUTH: A Transgender Youth of Color Study Cohort have been reconsented and enrolled into the renewal period of longitudinal data collection, which is projected from summer of 2020 until summer of 2025. Recruitment is ongoing to reach our target enrollment goal of YMSM and transgender minority youth.ConclusionsThe findings from this study are being used to inform the development of new, and adaptation of existing, evidence-based HIV prevention interventions designed to engage populations of transgender and gender minority youth and YMSM in the HIV prevention and care continua.International Registered Report Identifier (IRRID)DERR1-10.2196/39232     

Causes and trend of maternal death in a local obstetric unit in Hong Kong

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Success of targeted transperineal biopsy in patients on surveillance for grade group 1 prostate cancer

IntroductionWe aimed to determine the minimum cross-sectional ellipsoid area on magnetic resonance (MR) of intraprostatic nodules that best predicts for subsequent targeted biopsies revealing ≥ grade group (GG) 2 disease.MethodsForty-six patients previously diagnosed with GG 1 prostate adenocarcinoma who received cognitively fused, MR-guided, transperineal targeted biopsies in addition to six random biopsies were included in this analysis. A Youden cutpoint analysis was used to determine the ellipsoid area in the axial plane best predicting for ≥GG 2 disease within the targeted biopsy cores and logistic regression used to assess the result.ResultsMedian time from MR imaging to targeted biopsy was 2.4 (1.4–5.5) months. Forty of 46 (87%) patients had one nodule and 6/46 (13%) had two separate nodules on MR that received targeted biopsy. Of the 52 nodules, five (10%), 33 (63%), and 14 (27%) were Prostate Imaging-Reporting and Data System (PI-RADS) 3, 4, and 5, respectively. Thirteen (25%), six (12%), and 33 (64%) were in the anterior, medial, and posterior regions of the prostate, respectively. Median area was 0.72 (0.49–1.29) cm² (average diameter 9.5 mm). Fifteen of 46 (33%) patients had ≥1 random biopsy and 20/52 (38%) nodules had ≥1 targeted biopsy revealing ≥GG 2 disease. The optimal area cutpoint was ≥0.7 cm², with an area under the curve of 0.671 (0.510–0.832). On logistic regression, area ≥0.7 cm² was solely predictive of targeted biopsy revealing ≥GG 2 disease (odds ratio 6.5, 1.3–32.4, p=0.022).ConclusionsNodule area ≥0.7 cm² may predict for transperineal-based targeted biopsies being positive for ≥GG 2 disease when 1–2 cores are taken.