Clinical application of whole-genome sequencing of solid tumors for precision oncology.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Batch-to-Batch Consistency of SB4 and SB2, Etanercept and Infliximab Biosimilars.

BACKGROUND: Biosimilars must meet stringent regulatory requirements, both at the time of authorization and during their lifecycle. Yet it has been suggested that divergence in quality attributes over time may lead to clinically meaningful differences between two versions of a biologic. Therefore, this study investigated the batch-to-batch consistency across a range of parameters for released batches of the etanercept biosimilar (SB4) and infliximab biosimilar (SB2). METHODS: SB4 (Benepali®) and SB2 (Flixabi®) were both developed by Samsung Bioepis and are manufactured in Europe by Biogen at their facility in Hillerød, Denmark. A total of 120 batches of SB4 and 25 batches of SB2 were assessed for consistency and compliance with specified release parameters, including purity, post-translational glycosylation (SB4 only), protein concentration, and biological activity. RESULTS: The protein concentration, purity, tumor necrosis factor-α (TNF-α) binding, and TNF-α neutralization of all batches of SB4 and SB2 were within the strict specification limits set by regulatory agencies, as was the total sialic acid (TSA) content of all batches of SB4. CONCLUSIONS: Quality attributes of SB4 and SB2 batches showed little variation and were consistently within the rigorous specifications defined by regulatory agencies.

HIV-1 integrase strand-transfer inhibitor resistance in southern Taiwan.

The use of antiretroviral therapy has reduced rates of mortality and morbidity in patients with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS). However, transmission of drug-resistant strains poses a challenge to control the spread of HIV-1. Primary resistance to integrase strand-transfer inhibitors (INSTIs) is rare despite their increased use. The prevalence of transmitted drug resistance (TDR) to INSTIs was 0.9% in northern Taiwan. This study was to analyse the prevalence and risk factors of TDR to INSTIs in southern Taiwan. In this study, we enrolled antiretroviral treatment-naïve HIV-1-infected subjects who underwent voluntary counselling and testing from 2013 to 2016 in southern Taiwan. Genotypic drug resistance, coreceptor tropism (CRT) and INSTI resistance were determined. Logistic regression was used to analyse the risk factors for INSTI polymorphic substitution. Sequences were obtained from 184 consecutive individuals, of whom 96.7% were men who have sex with men and 3.3% were heterosexual. Of the patients, 10% (19/183) had hepatitis B and 33.3% (61/183) had syphilis infection. Subtype B HIV-1 strains were found in 96.1% of the patients. Fifteen patients (8.4%, 15/178) harboured nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or protease inhibitors resistance. CCR-5 coreceptors were used by 71.4% (130/184) of the patients. None of the patients had INSTI resistance-associated mutations, however 16 patients had INSTI polymorphic substitutions, and they were associated with a higher HIV viral load (p = 0.03, OR 2.4, CI 1.1-5.3) and syphilis infection (p = 0.03, OR 3.7, CI 1.1-12.0). In conclusion, no signature INSTI resistance-associated mutations were detected in our cohort. Continued monitoring of TDR to INSTI is needed due to the increased use of INSTIs.

Primary deep cutaneous candidiasis caused by Candida duobushaemulonii in a 68-year-old man: the first case report and literature review.

Superficial candida infections of the skin are common, but deep cutaneous candidiasis, including secondary dissemination to the skin from systemic candidiasis, candidaemia or primary invasion due to skin defects such as trauma, is rare. These patients are usually immunosuppressed, but immunocompetent hosts can be affected as well. Candida albicans is the most common pathogen. However, non-albicans Candida species can cause deep skin invasion in rare circumstances. We report a case of deep cutaneous candidiasis caused by Candida duobushaemulonii in a 68-year-old man. Deep tissue invasion was confirmed by skin histopathology examination. The pathogen was initially identified as C. haemulonii using the VITEK® 2 system for microbial identification, but was later determined to be C. duobushaemulonii based on sequencing of the internal transcribed spacer region of ribosomal DNA and D1/D2 region of 26S rDNA. The patient was successfully treated with amphotericin B, followed by fluconazole and surgical intervention. To the best of our knowledge, this is the first case of deep cutaneous infection by C. duobushaemulonii.

The relationship of self-reported sleep disturbance, mood, and menopause in a community study.

OBJECTIVE: The aim of this study was to assess the relationship between sleep disturbance, mood, menopausal status, and vasomotor symptoms in middle-aged women in Kinmen. DESIGN: A community-based sample of 1,113 Taiwanese women aged 43 to 57 years who were living on the island of Kinmen were recruited in this cross-sectional study. Menopausal status was determined by menstrual history. Sleep quality was measured by self-reported sleep problems. Anxiety and depression were assessed by the Hospital Anxiety Depression Scale. RESULTS: Forty-six percent of middle-aged women reported feeling dissatisfied with their sleep. Total sleep hours were not significantly different as a function of menopausal status. Generally, the occurrence of sleep problems or poor sleep quality was most prevalent in the postmenopausal group and least prevalent in premenopausal women. After analysis by multiple logistic regression, menopausal status was the independent factor of difficulty initiating sleep and sleep fragmentation. The Hospital Anxiety Depression Scale anxiety score was related to all sleep problems except for "excessive daytime sleepiness" and "awakening without further sleep." CONCLUSIONS: Almost half of the Taiwanese middle-aged women felt dissatisfied with their sleep. Both menopausal status and higher anxiety score were associated with poor sleep quality of midlife women.

Does menopausal transition affect the quality of life? A longitudinal study of middle-aged women in Kinmen.

OBJECTIVE: The aim of this study was to investigate the role of menopausal transition and menopausal symptoms in relation to quality of life in a cohort of middle-aged women in Kinmen. DESIGN: A total of 734 premenopausal women participated in the baseline study, and 579 women (78.9%) completed a follow-up 2 years later. Quality of life was assessed by the Medical Outcomes Study Short Form-36. Participating women were asked for demographic data, about vasomotor symptoms, and to complete the Medical Outcomes Study Short Form-36 and the Hospital Anxiety and Depression Scale. RESULTS: There was no demographic difference between women who remained premenopausal and those who entered perimenopause except for age. Vitality deteriorated no matter whether the women stayed in premenopause or entered perimenopause. In multivariate analysis, only vasomotor symptoms had an adverse influence on role limitation of emotion after adjusting for age, education, menopausal status, baseline cognitive score, and Hospital Anxiety and Depression Scale score. The menopausal transition did not influence the eight domains of the Short Form-36 in the multivariate regression model. CONCLUSION: This longitudinal study found no significant effect of menopausal transition on quality of life among Taiwanese women. The decline in the role limitations due to emotional problems was related to vasomotor symptoms.

A longitudinal study of cognition change during early menopausal transition in a rural community.

OBJECTIVE: To characterize changes in cognition that occur during the hormonal transitions of menopause. METHOD: We conducted a longitudinal population-based study in Kinmen, Taiwan, recruiting all women age 40-54 years who were premenopausal and without a history of hormone replacement therapy (HRT) or hysterectomy. The cognitive measures used to assess function included the Auditory-Verbal Learning Test, visual memory, verbal fluency, Trail Making Test and digit span. RESULTS: A total of 694 eligible women participated in the baseline study, and 573 women (83%) completed follow-up 18 months later. After excluding 78 women who received hysterectomy or HRT, the final sample was composed of 495 subjects, of whom 114 (23%) progressed to perimenopause during follow-up. Women who remained premenopausal were younger than those who became perimenopausal (44.7 +/- 2.3 years versus 47.1 +/- 3.0 years, p < 0.01). All follow-up cognitive scores in women who entered perimenopause were slightly better than baseline measures except for Rey Auditory-Verbal Learning Test, which decreased by 0.23 (S.D. = 2.9, p = 0.3). At follow-up, cognitive function except for verbal fluency did not differ significantly between women who stayed premenopausal and those became perimenopausal after controlling for age, education, and baseline cognitive scores. Women who entered perimenopause have an average of 1.3 items (S.D. = 0.4) less in verbal fluency measures as compared with their premenopausal peers at the follow-up period. CONCLUSIONS: The menopausal transition might not accompany significant cognitive decline except for verbal fluency.

Hot flashes are associated with psychological symptoms of anxiety and depression in peri- and post- but not premenopausal women.

OBJECTIVE: To explore the relationship between anxiety, depression, vasomotor symptoms, and menopausal status among middle-aged women. DESIGN: A population-based study involving a rural Taiwanese population. Participants received a structured questionnaire, which included the hospital anxiety and depression scale (HADS), gynecological history and a checklist of menopausal symptoms in the most recent 2 weeks. RESULTS: A total of 1273 women with no history of surgical menopause and hormonal therapy history participated. The mean anxiety, depression, and total HADS scores were 4.3 +/- 3.3, 3.3 +/- 2.8 and 7.6 +/- 5.3, respectively, and did not differ according to menopausal status. A total of 10.5% participants reported hot flashes within the previous 2 weeks. After controlling for educational status and insomnia, anxiety (6.0 +/- 3.8 versus 4.1 +/- 3.1) and depression scores (4.0 +/- 3.3 versus 3.2 +/- 2.7) were significantly higher (p < 0.001) compared with those without hot flashes. These differences were attributed to peri- and postmenopausal subjects. CONCLUSIONS: Hot flashes in peri- and postmenopausal women were associated with anxious and depressive symptoms in East Asian population with low prevalence of vasomotor symptoms.