Impact of the Coronavirus Disease 2019 pandemic on neoadjuvant chemotherapy use in patients diagnosed with epithelial type ovarian cancer.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic posed critical challenges in providing care to ovarian cancer (OC) patients, including delays in OC diagnosis and treatment initiation. To accommodate for delays in OC surgery, the Society of Gynecologic Oncology (SGO) recommended preferential use of neoadjuvant chemotherapy during the pandemic. The purpose of this study was to assess the association of the COVID-19 pandemic with neoadjuvant chemotherapy use in patients diagnosed with OC. Methods: This retrospective cohort study included patients diagnosed with stage II-IV ovarian cancer of epithelial subtype between 01/01/2017-06/30/2021 at Kaiser Permanente Southern California (KPSC), a large integrated healthcare system in the United States. Ovarian cancer patients diagnosed between 2017-2020 were identified from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. Patients diagnosed in 2021 were identified from the electronic medical records (EMR) using ICD-10 diagnosis codes, followed by medical chart review to validate diagnosis and extract information on histology and stage at diagnosis. March 4, 2020 was used as the cut-off to define pre-pandemic and pandemic periods. Patients diagnosed with COVID-19 between OC diagnosis and treatment completion were excluded. Data on neoadjuvant chemotherapy use were extracted from the cancer registry and EMR, supplemented by chart review. Modified Poisson regression was used to evaluate the association of the pandemic with neoadjuvant chemotherapy use. Results: Of 566 OC patients, 160 (28.3%) were diagnosed in the pandemic period. Patients diagnosed in the pandemic period were slightly younger (mean age 62.7 vs 64.9 years, p=0.07) and had a higher burden of Charlson comorbidities (p=0.05) than patients diagnosed in pre-pandemic period. No differences in time to treatment initiation were observed by pandemic periods. Neoadjuvant chemotherapy use was documented in 58.7% patients during the pandemic period compared to 47.3% in pre-pandemic period (p=0.01). After adjusting for covariates, patients diagnosed in the pandemic period were 29% more likely to receive neoadjuvant chemotherapy than patients diagnosed in pre-pandemic period [RR(95%CI): 1.29(1.12-1.49)]. Discussions: Ovarian cancer patients diagnosed in the COVID-19 pandemic were more likely to receive neoadjuvant chemotherapy than patients diagnosed before the pandemic. Future research on patient outcomes and trends in the post-pandemic period are warranted.

Methotrexate did not add skin cancer risk in patients with psoriasis receiving narrow-band ultraviolet B phototherapy: a nationwide retrospective cohort study.

BACKGROUND: In the era of biologic therapy, phototherapy and methotrexate (MTX) are still commonly employed for patients with moderate-to-severe psoriasis. However, the skin cancer risk following a combination of MTX and narrow-band ultraviolet B (NB-UVB) has rarely been explored. OBJECTIVES: To investigate whether MTX plus NB-UVB increases skin cancer risk in patients with psoriasis. METHODS: We conducted a retrospective cohort study of data in Taiwan National Health Insurance Research Database from 1997 to 2013. We performed cumulative incidences and multivariate analysis using competing risk regression model, comparing skin cancer risk between cohorts of combination therapy and using NB-UVB alone, matched by relative confounders. We further conducted sensitivity analysis for those receiving higher MTX dosage. Standardized incidence ratio (SIR) was calculated for skin cancer risk. RESULTS: We enrolled 3203 subjects in each cohort. No significant differences in skin cancers were noted between the two cohorts in the cumulative incidences (log-rank test, p = 0.282) and hazard ratio (HR) (adjusted HR = 0.50, 95% CI 0.15, 1.63, p= 0.247) on the competing risk regression model. There were also no significant differences between those receiving higher dose MTX and UVB alone in the cumulative incidences of skin cancers (p = 0.227) and HR (adjusted HR = 0.29, 95% CI 0.04, 2.21, p = 0.231) in the multivariate analysis. There was no significant difference of SIR between the two cohorts compared to the general population. CONCLUSIONS: MTX does not increase skin cancer risk in patients with moderate-to-severe psoriasis receiving NB-UVB in the Taiwanese population.

Involvement of Mitochondrial Damage and Oxidative Stress in Apoptosis Induced by Betulin Plus Arsenic Trioxide in Neuroblastoma Cells.

BACKGROUND/AIM: Arsenic trioxide (As2O3), a potent toxin in traditional Chinese medicine, has been utilized as an anticancer agent in Chinese culture for over a millennium. Betulin, commonly extracted from the bark of birch trees, has been identified for its pharmacological properties, including antibacterial, anti-inflammatory, antitumor, and antiviral activities. The aim of this study was to determine the efficacy and underlying anticancer signaling cascade induced by As2O3 and betulin in neuroblastoma cells. MATERIALS AND METHODS: SK-N-SH cells were treated with As2O3 with or without betulin. Cell viability and apoptotic signaling were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, measurement of mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS), and quantitative western blotting analysis. Student's t-test in addition to one- or two-way analysis of variance was used to examine significant differences between comparison groups. RESULTS: The combined treatment of As2O3 plus betulin was more effective than single treatments in suppressing cell viability and induction of apoptosis, which correlated well with elevated ROS levels. The apoptotic signaling cascade of As2O3 plus betulin was revealed as ROS elevation and relative loss of MMP, leading to the cleavage of caspase-3 and -9. As2O3 plus betulin treatment also reduced the expression of BCL2 apoptosis regulator, BH3-interacting domain death agonist, and BCL2-like-1. CONCLUSION: The novel combination of As2O3 plus betulin has the potential to serve as a practical anti-neuroblastoma drug.

Artesunate Exhibits Synergy With Cisplatin and Cytotoxicity for Upper Tract and Bladder Urothelial Carcinoma Cells.

BACKGROUND/AIM: Urothelial carcinoma (UC) may arise from the urothelium of the upper tract and the bladder. Cisplatin-based therapy remains the gold standard for UC treatment. The poor 5-year survival rate of UC patients creates an urgent need to develop new drugs for advanced UC therapy. Artesunate (ART), a traditional Chinese medicine for treating malaria, is a potential anticancer agent, but its antigrowth effects on upper tract and bladder UC have not been investigated. MATERIALS AND METHODS: The antigrowth effect of ART in HT 1376 (bladder UC cells) and BFTC 909 [upper tract urothelial carcinoma (UTUC) cells] was determined by the CCK-8 assay. Flow cytometric analysis was used to evaluate the cell cycle distribution and apoptosis. The cell cycle, apoptosis, and autophagy-related protein expression were analyzed by western blotting. The efficacy of combination treatment with cisplatin was determined by the Calcusyn software. RESULTS: ART induced HT 1376 and BFTC 909 cell death in a concentration- and time-dependent manner, inducing G2/M cell-cycle arrest. ART induced apoptosis and redox imbalance in HT 1376 and BFTC 909 cells. Application of the reactive oxygen species (ROS) scavenger, N-acetyl-L-cysteine (NAC), attenuated cell death in ART-treated UC cells. BFTC 909 cells show a better response after ART treatment. CONCLUSION: ART may be a candidate drug for treating UTUC and bladder UC while increasing the therapeutic effect of cisplatin.

Exposure to statins post localized prostate cancer diagnosis and risk of metastasis among men who did not receive curative prostate cancer treatment.

BACKGROUND: Few studies have evaluated the effect of statin exposure on metastasis risk among prostate cancer patients not receiving curative treatment. METHODS: We included men diagnosed with localized prostate cancer at an integrated health care system between 1997 and 2006 who did not receive curative treatment within 6 months of diagnosis. We followed these men until a metastatic event, disenrollment, death, or 12/31/2016. We collected all data from electronic health records supplemented by chart review. We used Cox regressions to examine the association between post-diagnostic statin exposure and metastasis, controlling for clinical characteristics and pre-diagnostic statin exposure. RESULTS: There were 4245 men included. Mean age of diagnosis was 68.02 years. 46.6% of men used statins after prostate cancer diagnosis. During follow-up, 192 men developed metastasis (cumulative incidence rate: 14.5%). In the adjusted Cox model, statin use post-prostate cancer diagnosis was not significantly associated with a metastatic event (HR = 0.97, 95% CI = 0.69, 1.36). Pre-diagnostic statin use was also not associated with development of metastasis (HR = 0.76, 95% CI = 0.53, 1.10). We did not observe a dose-response for the proportion of person-time at-risk post-prostate cancer diagnosis on statins (HR = 0.98 per 10% increase in person-time exposed [95% CI = 0.93, 1.03]). CONCLUSIONS: We did not find an inverse association between post-diagnosis statin exposure and metastasis development in localized prostate cancer patients who did not receive active treatment. Our results did not offer support to the chemopreventive potential of post-diagnostic statin use among men on active surveillance.

Identifying monoclonal gammopathy of undetermined significance from electronic health records.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies. AIMS: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk. METHODS AND RESULTS: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code. CONCLUSION: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation.

Trends in HPV vaccine administration and HPV vaccine coverage in children by race/ethnicity and socioeconomic status during the COVID-19 pandemic in an integrated health care system in California.

BACKGROUND: We sought to evaluate the trends of HPV vaccination between 03/2019-09/2021 and whether the impact of the COVID pandemic on HPV vaccination varied by race/ethnicity and neighborhood deprivation index (NDI). METHODS: Electronic medical records at Kaiser Permanente Southern California were used to assess monthly volume of HPV vaccine doses administered among children aged 9-12.9yrs, and up-to-date coverage (% vaccinated) by age 13 between 03/2019-09/2021. Modified Poisson models were used to evaluate the interactions between race/ethnicity, NDI and the pandemic periods on HPV vaccine coverage. RESULTS: HPV vaccine doses administered in 2020/2021 have returned to the 2019 level after the initial drop. The average up-to-date coverage in 05/2021-09/2021 (54.8%) remained lower than the pre-pandemic level (58.5%). The associations between race/ethnicity, NDI and HPV vaccine coverage did not vary due to the pandemic. CONCLUSION: HPV vaccine promotion efforts are needed to address COVID-19 pandemic's lasting impact on HPV vaccination coverage.

Effects of Solanum undatum extract (SR-T100) on photocarcinogenesis and photoaging of actinic keratosis.

SR-T100 gel, containing solamargine extracted from Solanum undatum (synonym: Solanum incanum), had good therapeutic effects on actinic keratosis (AK) in human and ultraviolet B-induced papilloma in mice. This study aimed to investigate the immunohistochemical changes in the human skin after SR-T100 treatment. An immunohistochemical study was performed and the changes in photocarcinogenesis and photoaging markers after 16-week SR-T100 gel treatment were documented. SR-T100 gel treatment for 16 weeks resulted in complete remission in nine AK lesions and partial remission in four AK lesions. SR-T100 gel abolished the expression of mutant p53 and SOX2 and restored the expression of NOTCH1. Additionally, SR-T100 gel improved wrinkling in human skin, while restoring the expression of lamin B1 and increasing synthesis of new elastic fibers. SR-T100 gel had therapeutic effects on photocarcinogenesis and photoaging of photodamaged skin with AK.

Impact of COVID-19 on Cervical Cancer Screening Rates Among Women Aged 21-65 Years in a Large Integrated Health Care System - Southern California, January 1-September 30, 2019, and January 1-September 30, 2020.

On March 19, 2020, the governor of California issued a statewide stay-at-home order to contain the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19).* The order reduced accessibility to and patient attendance at outpatient medical visits,† including preventive services such as cervical cancer screening. In-person clinic visits increased when California reopened essential businesses on June 12, 2020.§ Electronic medical records of approximately 1.5 million women served by Kaiser Permanente Southern California (KPSC), a large integrated health care system, were examined to assess cervical cancer screening rates before, during, and after the stay-at-home order. KPSC policy is to screen women aged 21-29 years every 3 years with cervical cytology alone (Papanicolaou [Pap] test); those aged 30-65 years were screened every 5 years with human papillomavirus (HPV) testing and cytology (cotesting) through July 15, 2020, and after July 15, 2020, with HPV testing alone, consistent with the latest recommendations from U.S. Preventive Services Task Force.¶ Compared with the 2019 baseline, cervical cancer screening rates decreased substantially during the stay-at-home order. Among women aged 21-29 years, cervical cytology screening rates per 100 person-months declined 78%. Among women aged 30-65 years, HPV test screening rates per 100 person-months decreased 82%. After the stay-at-home order was lifted, screening rates returned to near baseline, which might have been aided by aspects of KPSC's integrated, organized screening program (e.g., reminder systems and tracking persons lost to follow-up). As the pandemic continues, groups at higher risk for developing cervical cancers and precancers should be evaluated first. Ensuring that women receive preventive services, including cancer screening and appropriate follow-up in a safe and timely manner, remains important.

Adherence to cardiomyopathy screening guidelines among adolescent and young adult cancer survivors exposed to chest radiation and/or anthracyclines.

PURPOSE: Cancer survivors are at risk for late effects from therapeutic exposures, including cardiovascular complications. To improve outcomes among adolescents and young adults (AYA) with cancer, the National Comprehensive Cancer Network (NCCN) released guidelines for screening services (based on the Children's Oncology Group Long-Term Follow-Up [LTFU] guidelines) for survivors of AYA cancer. To better understand survivorship care gaps, we conducted a baseline evaluation of cardiomyopathy screening among survivors of AYA cancers. METHODS: Members of Kaiser Permanente Southern California diagnosed with cancer between ages 15 and 39 from 2000 to 2010 with at least 5-year survival after diagnosis who were exposed to chest radiation and/or anthracyclines were included. We calculated the Prevention Index ([PI], proportion of person-time covered by receipt of preventive services relative to the total person-time eligible) to evaluate adherence to recommended cardiomyopathy screenings based on the LTFU through 2016. Predictors for screening were evaluated in multivariable logistic regression. RESULTS: Among 479 survivors recommended for cardiomyopathy screening, 28 received at least one screening, and the mean PI was 2.38% (SD = 13.05%, median = 0.00%). Compared to stage I, survivors of stage II (odds ratio [OR] = 5.56 [1.05-29.46]) and stage III/IV cancer (OR = 6.08 [1.10-33.54]) were more likely to receive cardiomyopathy screening. CONCLUSIONS: Cardiomyopathy screening among survivors was low around the time when NCCN AYA oncology guidelines were released. IMPLICATIONS FOR CANCER SURVIVORS: Our study highlights significant room for improvement for adherence to cardiomyopathy screening recommendations among survivors of AYA cancer. Attention is needed to ensure that recommended cardiomyopathy screenings are met for better management of cardiomyopathy late effects.

Effectiveness of 'catch-up' human papillomavirus vaccination to prevent cervical neoplasia in immunosuppressed and non-immunosuppressed women.

It is unknown whether the HPV vaccine is effective in immunocompromised women during catch-up ages. We performed a case-control study of 4,357 women with incident CIN2+ (cases) and 5:1 age-matched, incidence-density selected controls (N = 21,773) enrolled in an integrated health care system from 2006 to 2014. Vaccine effectiveness was estimated from multivariable conditional logistic regression models, with results stratified by immunosuppression history, defined as prior HIV infection, solid organ transplant history, or recently prescribed immunosuppressive medications. HPV vaccination resulted in a 19% reduction in CIN2+ rates for women without an immunosuppression history but a nonsignificant 4% reduction for women with an immunosuppression history. Further research is needed to evaluate whether catch-up HPV vaccine effectiveness varies by immunosuppression status, especially given the recent approval of the HPV vaccine for adults up to 45 years of age.

Chinese herbal medicine reduces the risk of urinary incontinence in patients with chronic obstructive pulmonary disease: A population-based retrospective cohort study.

OBJECTIVES: To investigate the effectiveness of Chinese herbal medicine for the treatment of urinary incontinence in patients with chronic obstructive pulmonary disease. METHODS: We carried out a retrospective cohort study using the National Health Insurance Research Database. From a cohort of 1 million records between 1996 and 2013, a total of 202 279 patients with newly onset chronic obstructive pulmonary disease were initially recruited. We matched with propensity score 3967 patients who received Chinese herbal medicine by age, sex, year of chronic obstructive pulmonary disease diagnosis, urbanization, comorbidities and chronic obstructive pulmonary disease medications. All participants received follow-up visits until the end of 2013 to record the incidence rate of urinary incontinence. The Cox proportional hazards model was applied to assess the association between Chinese herbal medicine use and the risk of urinary incontinence among chronic obstructive pulmonary disease patients. RESULTS: The incidence rates of urinary incontinence were 57.33 and 108.15 (per 10 000 person-years) in the Chinese herbal medicine and non-Chinese herbal medicine cohorts, respectively, showing a significantly lower risk of urinary incontinence in Chinese herbal medicine users (aHR = 0.56, 95% CI = 0.45-0.69, P < 0.001). The Chinese herbal medicine prescription pattern analysis showed that Fritillariae thunbergii bulbus (Zhebeimu), Semen armeniacae amarum (Kuxingren), Platycodonis radix (Jiegeng), Xiao Qing Long Tang and Ding Chuan Tang constituted the core of Chinese herbal medicine prescriptions applied to treat chronic obstructive pulmonary disease. CONCLUSION: The use of Chinese herbal medicine in chronic obstructive pulmonary disease patients can reduce their risk of urinary incontinence.

Cause-specific mortality in survivors of adolescent and young adult cancer.

BACKGROUND: Few studies have adequately addressed long-term survival (>20 years from diagnosis) among survivors of adolescent and young adult (AYA) cancers. METHODS: In this retrospective, population-based cohort study in a US integrated health care system, the authors examined cause-specific mortality in 2-year survivors of AYA cancers (patients aged 15-39 years who were diagnosed between 1990 and 2012; N = 10,574) matched (by age, sex, and calendar year) to individuals without cancer (N = 136,683) to determine whether mortality rates changed over time. Incidence rate ratios (IRRs) for mortality were estimated using multivariable Poisson regression. A multivariable Cox model was used to examine predictors of cause-specific mortality among AYA cancer survivors. RESULTS: Through December 31, 2014, 1352 deaths were observed among AYA cancer survivors, yielding an overall survival rate of 78.5% at 25 years after diagnosis. Overall, AYA cancer survivors were at 10.4-fold increased risk for death (95% CI, 9.7-fold to 11.2-fold increased risk for death) compared with the matched noncancer cohort, and this risk remained elevated at >20 years after diagnosis (IRR, 2.9; 95% CI, 2.0-4.3). The absolute excess risk for death from any cause was 12.7 per 1000 person-years (95% CI, 11.9-13.4 per 1000 person-years). Starting at 15 years after diagnosis, the incidence of second cancer-related mortality exceeded the rate of recurrence-related mortality, and similar trends were observed for deaths from other health-related conditions. The 8-year cumulative incidence of mortality declined over time (before 2000, 12.6%; 2000-2006, 10.1%; after 2006, 7.3%; P < .001), largely because of declines in recurrence-related mortality. Age, sex, race/ethnicity, cancer stage at diagnosis, and cancer treatment predicted cause-specific mortality. CONCLUSIONS: The current data highlight the need for specialized, long-term follow-up care for AYA cancer survivors.

Incidence, Risk Factors, and Mortality Associated With Second Malignant Neoplasms Among Survivors of Adolescent and Young Adult Cancer.

Importance: Detailed data describing the epidemiology of second malignant neoplasms (SMN) are needed for survivors of adolescent and young adult (AYA) cancer to inform the development of age-appropriate survivorship care guidelines. Objective: To describe the incidence, risk factors, and mortality for SMN in survivors of AYA cancer. Design, Setting, and Participants: This retrospective matched cohort study included 10 574 two-year survivors diagnosed with cancer between January 1, 1990, and December 31, 2012, at age 15 to 39 years in an integrated health care delivery system in Southern California. A comparison cohort without a history of cancer was individually matched 13:1 to survivors of AYA cancer by age, sex, and calendar year. Data analysis was completed in July 2018. Exposures: Secondary malignant neoplasm risk factors of interest included age, stage, and calendar year at first cancer diagnosis; sex; race/ethnicity; radiation therapy; and chemotherapy. Main Outcomes and Measures: Diagnoses of SMN were ascertained using cancer registries from the National Cancer Institute Surveillance, Epidemiology, and End Results Program through December 31, 2014. Poisson regression was used to evaluate the association between cancer survivor status and developing SMN and risk factors for SMN, while risk of all-cause mortality by SMN status was examined in Cox regression. Results: A total of 10 574 survivors of AYA cancer (6853 [64.8%] female; median [range] age, 33 [15-39] years; 622 with SMN) and 136 683 participants in the comparison cohort (88 513 [64.8%] female; median [range] age, 33 [15-39] years; 3437 with first cancer) were included. In survivors of AYA cancer, 20-year cumulative incidence of SMN was 12.5%. The incidence rate ratio (IRR) of developing SMN in survivors of AYA cancer was 2.6 (95% CI, 2.4-2.9) compared with the comparison cohort. Survivors of breast cancer, melanoma, and testicular cancer had substantially elevated risk for SMN of the same organ (IRR, 5.6 [95% CI, 4.6-6.8], 11.2 [95% CI, 7.3-17.2], and 16.2 [95% CI, 6.8-38.4], respectively). Among survivors of AYA cancer, older age (IRR for age 30-39 years, 1.79 [95% CI, 1.21-2.65]), female sex (IRR, 1.31 [95% CI, 1.09-1.57]), white race/ethnicity (IRR for Asian race, 0.61 [95% CI, 0.43-0.87]), advanced stage at first cancer diagnosis (IRR for stage II, 1.29 [95% CI, 1.11-1.65]), and use of radiotherapy (IRR, 1.50 [95% CI, 1.26-1.79]) were associated with increased risk of SMN. Survivors of AYA cancer who developed SMN had an all-cause mortality rate 7.2 (95% CI, 6.1-8.5) times greater than survivors without SMN. Conclusions and Relevance: This study suggests that SMN risk is elevated in survivors of AYA cancer and varies across survivor subgroups. Survival following SMN may be significantly compromised. These data may form the basis for identifying individuals at high risk, as well as informing screening for SMN.

Association of raltegravir use with long-term health outcomes in HIV-infected patients: an observational post-licensure safety study in a large integrated healthcare system.

BACKGROUND: Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest. OBJECTIVE: Assess raltegravir safety in clinical practice within an integrated health system. METHODS: We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding. RESULTS: The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events. CONCLUSIONS: The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.

Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance.

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo-/-) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo-/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3ß (GSK3ß) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo-/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3ß pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders.

Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: A Phase III randomized double-blind vehicle-controlled parallel trial.

BACKGROUND: Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects. OBJECTIVES: To evaluate the efficacy and safety of topical SR-T100 gel in treating AK. METHODS: A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing. RESULTS: 123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR-T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100. CONCLUSION: The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK.

Patterns and correlates of cervical cancer screening initiation in a large integrated health care system.

BACKGROUND: The latest 2012 US Preventive Services Task Force cervical cancer screening guidelines recommended screening initiation at age 21 years. Little is known about the cervical cancer screening initiation practices in the community and whether there are critical gaps with respect to adherence to current clinical guidelines. Despite an overall decline in cervical cancer incidence across women of all ages, the incidence rate has not declined among 24-25 year olds between 2000 (2.79 per 100,000) and 2013 (2.93 per 100,000). Thus, it is important to understand cervical cancer screening initiation in young women and how woman- and provider-level factors affect the timing of screening initiation to identify areas for improving cervical cancer prevention. OBJECTIVE: We examined patterns and correlates of cervical cancer screening initiation among women turning age 21 years in a large community-based practice. STUDY DESIGN: Female members of Kaiser Permanente Southern California who turned age 21 years (baseline) during 2013-2015 and had not previously received a Papanicolaou test were included. Cervical cancer screening initiation through October 2016 was captured using electronic health records. Incidence rate and cumulative incidence of screening initiation was calculated. Associations between patient and provider characteristics and screening initiation were evaluated using multivariable Cox models. RESULTS: A total of 38,257 women were included and the Papanicolaou screening initiation rate was 44 per 100 person-years during the study period. Approximately 40% initiated screening within 1 year after turning age 21 years. In multivariable analyses, Asian/Pacific Islanders (hazard ratio, 0.91; confidence interval, 0.86-0.96 compared with non-Hispanic whites); Medicaid enrollees (hazard ratio, 0.90; confidence interval, 0.83, 0.97); those whose primary language is not English (hazard ratio, 0.71; confidence interval, 0.67, 0.75); those who have a historical inpatient visit, primary care physician in pediatrics, internal medicine, or another specialty compared with family practice; and have a male rather than female primary care physician (hazard ratio, 0.46; confidence interval, 0.36, 0.57) less often initiated screening. On the other hand, those who used other preventive services such as getting a human papilloma virus and influenza vaccination and those with a history of pregnancy, contraception use, and sexually transmitted infections more often had timely screening initiation. CONCLUSION: Less than half of the women insured for preventative services initiated screening at age 21 years. Strategies to improve adherence to screening initiation guidelines should consider a tailored approach for at-risk subgroups and addressing initiation challenges associated with male physicians.

Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus Extracts Effectively Inhibit BK Virus and JC Virus Infection of Host Cells.

The human polyomaviruses BK (BKPyV) and JC (JCPyV) are ubiquitous pathogens long associated with severe disease in immunocompromised individuals. BKPyV causes polyomavirus-associated nephropathy and hemorrhagic cystitis, whereas JCPyV is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy. No effective therapies targeting these viruses are currently available. The goal of this study was to identify Chinese medicinal herbs with antiviral activity against BKPyV and JCPyV. We screened extracts of Chinese medicinal herbs for the ability to inhibit hemagglutination by BKPyV and JCPyV virus-like particles (VLPs) and the ability to inhibit BKPyV and JCPyV binding and infection of host cells. Two of the 40 herbal extracts screened, Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus, had hemagglutination inhibition activity on BKPyV and JCPyV VLPs and further inhibited infection of the cells by BKPyV and JCPyV, as evidenced by reduced expression of viral proteins in BKPyV-infected and JCPyV-infected cells after treatment with Rhodiolae Kirliowii Radix et Rhizoma or Crataegus pinnatifida Fructus extract. The results in this work show that both Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus may be sources of potential antiviral compounds for treating BKPyV and JCPyV infections.