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.

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.

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.

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.

Trends in anemia treatment among patients with five non-myeloid malignancies treated with chemotherapy in a large integrated health care delivery system in California, 2000-2013.

PURPOSE: The aim of this study is to examine treatment patterns for chemotherapy-induced anemia (CIA) between calendar periods when the changes in the US prescribing information, for erythropoiesis-stimulating agents (ESAs) took place. METHODS: Patients diagnosed with breast, lung, colorectal, ovarian, or gastric cancer (2000-2012) who developed grade 2+ CIA (hemoglobin (Hb) <10 g/dl) were identified from Kaiser Permanente Southern California Health Plan. We estimated the proportions of CIA episodes with ESA use, red blood cell (RBC) transfusion, or prescription nutritional supplements in three calendar periods: January 1, 2000-December 31, 2006 (P1), January 1, 2007-March 24, 2010 (P2), and March 25, 2010-June 30, 2013 (P3). Multivariable regressions were used to test the differences of CIA treatment approaches and Hb concentration prior to CIA treatment across these calendar periods. RESULTS: The proportions of CIA episodes with ESA use were 28 % in P1, 21 % in P2, and 3 % in P3. For RBC transfusion, they were 8 % in P1, 14 % in P2 and 16 % in P3. The trend of decreasing ESA use and increasing transfusion use were statistically significant. Relative to P1, the odds ratio (OR) was 0.69 (95% CI: 0.55, 0.86) for P2 and 0.08 (0.30, 0.88) for P3 for ESA use. For RBC transfusion, OR was 2.00 (1.56, 2.56) for P2 and 2.37 (1.88, 3.00) for P3. Use of prescription nutritional supplement was rare across calendar periods. There was a decreasing trend of Hb concentration prior to ESA use (p value <0.01), but no difference in Hb concentrations prior to transfusion. CONCLUSION: In the management of CIA, use of ESA has decreased over time, while use of RBC transfusion has increased.

Long-term Health Outcomes in Survivors of Childhood Cancer Diagnosed Between 1990 and 2000 in a Large US Integrated Health Care System.

We evaluated the long-term health outcomes of childhood cancer survivors (CCS) using data from the Kaiser Permanente Southern California (KPSC) health plan, whose members have similar health care coverage. Five-year survivors of invasive cancer diagnosed at ages 0 to 18 years between 1990 and 2000 at KPSC were identified and followed to December 31, 2010. A group of KPSC members without history of cancer were 10:1 matched to each CCS for comparison. Health outcomes of interest included mortality, second cancer, and chronic comorbidities. Incidence rate ratio (IRR) was estimated using multivariable Poisson regression. Cumulative incidence of each health condition over time was calculated. A total of 652 CCS and 6520 noncancer subjects were included. Compared with the noncancer subjects, IRR was significantly elevated among CCS for mortality (IRR=14.1), second cancer (IRR=10.0), cerebrovascular disease (IRR=10.1), dyslipidemia (IRR=1.9), hearing/vision loss (IRR=5.1), heart disease (IRR=3.9), hypogonadism (IRR=4.2), renal failure (IRR=13.4), and thyroid disorder (IRR=6.4). Approximately 40% of CCS developed at least 1 chronic health condition within 15 years of cancer diagnosis. Cumulative incidence curves showed different risk trajectories of various comorbidities which may inform screening schedule. These data suggested that CCS treated in a more contemporary era continued to experience substantial disease burden in their adolescent and young adulthood.

An LC/MS quantitative and microdialysis method for cyclovirobuxine D pharmacokinetics in rat plasma and brain: The pharmacokinetic comparison of three different drug delivery routes.

To explore the brain-targeting of cyclovirobuxine D(CVB-D) after administered intranasally, the pharmacokinetics of CVB-D via three different drug delivery routes: intragastric (i.g.), intranasal (i.n.), and intravenous (i.v.) in rat brain and blood was compared. Firstly, an in vivo microdialysis method for sampling CVB-D in both plasma and brain of the rat was established. Secondly, a liquid chromatography-tandem mass spectrometry method has been developed and validated for determination of CVB-D in microdialysis samples. For plasma and brain microdialysis samples, liquid-liquid extraction was used and donepezil was chosen as internal standard. Both were followed by HPLC separation and positive electrospray ionization tandem mass spectrometry detection (ESI-MS/MS). Chromatographic separation was achieved on a agilent C18 column with a mobile phase of methanol-water (50:50, v/v) (pH 3.2) containing 0.1% formic acid and 5mM ammonium acetate. Mass spectrometric detection in the positive ion mode was carried out by selected reaction monitoring (MRM) of the transitions at m/z 403.4→372.3 for CVB-D and m/z 380.2→243.1 for donepezil (IS). Good linearities were obtained in the range of 10-4000ng/mL in rat microdialysates for CVB-D. The lowest limit of quantitation was 5ng/mL, with an extraction recovery >75%, and no significant matrix effects. Intra- and inter-day precisions were all <15% with accuracies of 97.26-116.20%. All of which proved that the established method was successfully applied to the pharmacokinetic study of CVB-D. Simultaneously, brain uptake and pharmacokinetic studies were performed by determination of CVB-D concentration in blood and brain respectively for CVB-D i.g., i.n. and i.v.. Results showed that the intranasal CVB-D could improve brain targeting and had advantages for direct nose to brain transport of CVB-D when compared with injection and oral delivery routes, which indicates that intranasal administration of CVB-D could be a promising approach for the treatment of cerebrovascular disease.

[Determination of six C-Glycoside flavones and antitumor activity of water-soluble total flavonoids from Isodon lophanthoides var. gerardianus].

This research established an HPLC method for determination of six C-Glycoside flavones of warer-soluble total flavonoids from Isodon lophanthoides var. gerardianus (Benth.) H. Hara, and studied the antitumor activity of the warer-soluble total flavonoids. The HPLC system consisted of Kromasil 100-5 C18 (4.6 mm x 250 mm, 5 microm) column and a solution system of methanol, acetonitrile and 0.5% formic acid gradient elution at a flow rate of 0. 8 mL x min(-1) and the wavelength of detector was at 334 nm. The column temperature was 25 degrees C. The antitumor activity of water-soluble flavonoids was assayed using HepG2 cell as the tested cell. The linear ranges of vicenin II, vicenin III, isoschaftoside, schaftoside, vitexin, 6, 8-di-C-a-L-arabinosylapigenin were 0.25-2.53, 0.12-1.20, 0.37-3.69, 0.16-1.63, 0.19-1.92, 0.14-1.42 microg, respectively. The average recoveries (n = 6) were 99.6% (RSD 0.87%), 100.2% (RSD 2.0%), 99.6% (RSD 1.8%), 97.9% (RSD 1.5%), 98.8% (RSD 1.2%), 98.6% (RSD 1.2%), respectively. After exposure in 24, 48, 72 h, the total flavonoids showed inhibitory effect on the proliferation of HepG2 cells with IC50 as the evaluation index, the IC50 values of 1.89, 1.71, 1.51 g x L(-1), respectively. The method is quick, simple and accurate with good re- producibility, and can be used for determination of vicenin II, vicenin III, isoschaftoside, schaftoside, vitexin, 6, 8-di-C-a-L-arabino- sylapigenin in the warer-soluble total flavonoids from L lophanthoides var. gerardianus. The warer-soluble total flavonoids from L lophanthoides have inhibitory effect on the proliferation of HepG2 cells.

A laboratory evaluation of medicinal herbs used in china for the treatment of hand, foot, and mouth disease.

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the causative agents of hand, foot, and mouth disease (HFMD). During recent epidemics of HFMD in China, medicinal herbals and preparations containing herbal extracts have demonstrated therapeutic efficacy with relative safety profiles. There have been no microbiological studies to validate their usefulness for HFMD. We selected 12 commonly used herbs for HFMD from government recommended guidelines as well as published reports and tested for their antiviral activity and anti-inflammatory activity. A water extract of Houttuynia cordata Thunb. (HCT) inhibited EV71 infection significantly and was marginally active against CVA16 infection. The IC50 (concentration to have 50% inhibitory effect) values of HCT against a Fuyang strain and a BrCr strain of EV71 were determined at 8.9 µ g/mL and 20.6 µ g/mL, respectively. Mentha haplocalyx Briq. (MHB) water extract was active against CVA16, with an IC50 value of 70.3 µ g/mL. The extract did not exhibit activity against EV71 infection. Although the majority of the extracts showed no activity against viral infection, several extracts demonstrated activity in blocking proinflammatory response by viral infection. This study therefore validates the effectiveness of Chinese herbs for HFMD since some formulations containing the correct combination of the herbs can block viral replication as well as proinflammatory response of HFMD.

Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy.

OBJECTIVE: To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. uninfected patients from the same integrated healthcare system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy. DESIGN: A cohort study. METHODS: Incident NHL diagnosed between 1996 and 2005 were identified from members of Kaiser Permanente California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma, and HIV-related characteristics for the same outcomes were also examined. RESULTS: A total of 259 HIV-infected and 8230 HIV-uninfected incident NHL patients were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis as compared with 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (relative risk = 2.0, 95% confidence interval 1.7-2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages, and histologic subtypes. HIV-infected patients with CD4 cell count below 200 cells/microl, prior AIDS-defining illness, or both were also at increased risk for lymphoma-specific mortality as compared with HIV-uninfected patients. Among HIV-infected NHL patients, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt's subtype. CONCLUSION: HIV-infected patients with NHL in the combined antiretroviral therapy era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.

Percutaneous penetration kinetics of lidocaine and prilocaine in two local anesthetic formulations assessed by in vivo microdialysis in pigs.

The aim of this study was to characterize and compare the percutaneous penetration kinetics of lidocaine (L) and prilocaine (P) in two local anesthetic formulations by in vivo microdialysis coupled with HPLC. The microdialysis system for studying lidocaine and prilocaine was calibrated by a no-net-flux method in vitro and retrodialysis method in vivo, respectively. A dosage of 0.2 g/cm2 of an in-house P-L formulation (2.5% lidocaine and 2.5% prilocaine, methylcellulose-based) and commercially available Eutectic Mixture of Local Anesthesia (EMLA, 2.5% lidocaine and 2.5% prilocaine, carbopol-based) was separately but symmetrically applied in the dorsal region of pigs. Saline (0.9%, w/v) was perfused into the linear microdialysis probe at a flow rate of 1.5 microl/min. Dialysate was collected upon topical application up to 6 h at 20-min intervals and assessed by HPLC. The results demonstrated the area under the concentration-time curve (AUC(0-6 h)) of lidocaine and prilocaine in EMLA was 71.95+/-23.36 microg h/ml and 38.01+/-14.8 microg h/ml, respectively, in comparison to 167.11+/-56.12 microg h/ml and 87.02+/-30.38 microg h/ml in the P-L formulation. The maximal concentrations (Cmax) of lidocaine and prilocaine in the dermis were 29.2+/-9.08 microg/ml and 16.54+/-5.31 microg/ml in EMLA and 80.93+/-17.98 microg/ml and 43.69+/-12.87 microg/ml in the P-L formulation, respectively. This study indicates a well-calibrated microdialysis system can provide vital real-time information on percutaneous drug delivery and specifically a methylcellulose-based P-L formulation can increase percutaneous absorption of both lidocaine and prilocaine in pigs compared to carbopol-based EMLA.