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Background: Challenges in identifying microsatellite instability (MSI)/mismatch repair (MMR)-tested colorectal carcinoma (CRC) patients in electronic health records have led to gaps in the understanding of MSI-high/deficient mismatch repair prevalence. Methods: An algorithm to identify MSI-/MMR-tested Veterans Affairs patients was developed and an observational study of adult CRC patients with MSI/MMR testing from 2010 to 2018 was undertaken. Results: An optimized model to identify MSI-/MMR-tested patients yielded high positive predictive value (89.0%) and specificity (97.8%). The authors observed MSI-high/deficient mismatch repair CRC in 54 of 291 patients (18.6%); highest frequencies were observed in stages II (25.9%) and III (22.6%) and lowest in stage IV (5.8%). Conclusions: In this real-world study, the authors proposed a novel method of identifying MSI-/MMR-tested patients. Further validation and refinement of this model, and study in a larger CRC cohort, is warranted.

PURPOSE To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non–small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. METHODS Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. RESULTS At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. CONCLUSION Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.

UNSTRUCTURED Although randomized controlled trials (RCTs) are the gold standard for establishing the efficacy and safety of a medical treatment, real-world evidence (RWE) generated from real-world data has been vital in postapproval monitoring and is being promoted for the regulatory process of experimental therapies. An emerging source of real-world data is electronic health records (EHRs), which contain detailed information on patient care in both structured (eg, diagnosis codes) and unstructured (eg, clinical notes and images) forms. Despite the granularity of the data available in EHRs, the critical variables required to reliably assess the relationship between a treatment and clinical outcome are challenging to extract. To address this fundamental challenge and accelerate the reliable use of EHRs for RWE, we introduce an integrated data curation and modeling pipeline consisting of 4 modules that leverage recent advances in natural language processing, computational phenotyping, and causal modeling techniques with noisy data. Module 1 consists of techniques for data harmonization. We use natural language processing to recognize clinical variables from RCT design documents and map the extracted variables to EHR features with description matching and knowledge networks. Module 2 then develops techniques for cohort construction using advanced phenotyping algorithms to both identify patients with diseases of interest and define the treatment arms. Module 3 introduces methods for variable curation, including a list of existing tools to extract baseline variables from different sources (eg, codified, free text, and medical imaging) and end points of various types (eg, death, binary, temporal, and numerical). Finally, module 4 presents validation and robust modeling methods, and we propose a strategy to create gold-standard labels for EHR variables of interest to validate data curation quality and perform subsequent causal modeling for RWE. In addition to the workflow proposed in our pipeline, we also develop a reporting guideline for RWE that covers the necessary information to facilitate transparent reporting and reproducibility of results. Moreover, our pipeline is highly data driven, enhancing study data with a rich variety of publicly available information and knowledge sources. We also showcase our pipeline and provide guidance on the deployment of relevant tools by revisiting the emulation of the Clinical Outcomes of Surgical Therapy Study Group Trial on laparoscopy-assisted colectomy versus open colectomy in patients with early-stage colon cancer. We also draw on existing literature on EHR emulation of RCTs together with our own studies with the Mass General Brigham EHR.

Background: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population. Objective: To describe real-world medications use in this population. Methods: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015–Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Results: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD. Conclusion: In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients.

Temporal shifts in clinical knowledge and practice need to be adjusted for in treatment outcome assessment in clinical evidence.To use electronic health record (EHR) data to (1) assess the temporal trends in treatment decisions and patient outcomes and (2) emulate a randomized clinical trial (RCT) using EHR data with proper adjustment for temporal trends.The Clinical Outcomes of Surgical Therapy (COST) Study Group Trial assessing overall survival of patients with stages I to III early-stage colon cancer was chosen as the target trial. The RCT was emulated using EHR data of patients from a single health care system cohort who underwent colectomy for early-stage colon cancer from January 1, 2006, to December 31, 2017, and were followed up to January 1, 2020, from Mass General Brigham. Analyses were conducted from December 2, 2019, to January 24, 2022.Laparoscopy-assisted colectomy (LAC) vs open colectomy (OC).The primary outcome was 5-year overall survival. To address confounding in the emulation, pretreatment variables were selected and adjusted. The temporal trends were adjusted by stratification of the calendar year when the colectomies were performed with cotraining across strata.A total of 943 patients met key RCT eligibility criteria in the EHR emulation cohort, including 518 undergoing LAC (median age, 63 [range, 20-95] years; 268 [52%] women; 121 [23%] with stage I, 165 [32%] with stage II, and 232 [45%] with stage III cancer; 32 [6%] with colon adhesion; 278 [54%] with right-sided colon cancer; 18 [3%] with left-sided colon cancer; and 222 [43%] with sigmoid colon cancer) and 425 undergoing OC (median age, 65 [range, 28-99] years; 223 [52%] women; 61 [14%] with stage I, 153 [36%] with stage II, and 211 [50%] with stage III cancer; 39 [9%] with colon adhesion; 202 [47%] with right-sided colon cancer; 39 [9%] with left-sided colon cancer; and 201 [47%] with sigmoid colon cancer). Tests for temporal trends in treatment assignment (χ2 = 60.3; P .001) and overall survival (χ2 = 137.2; P .001) were significant. The adjusted EHR emulation reached the same conclusion as the RCT: LAC is not inferior to OC in overall survival rate with risk difference at 5 years of -0.007 (95% CI, -0.070 to 0.057). The results were consistent for stratified analysis within each temporal period.These findings suggest that confounding bias from temporal trends should be considered when conducting clinical evidence studies with long time spans. Stratification of calendar time and cotraining of models is one solution. With proper adjustment, clinical evidence may supplement RCTs in the assessment of treatment outcome over time.

Introduction Emergency contraceptive pill (ECP) use is reported to have increased in several countries over time. In this multi-country population-based questionnaire study, we aimed to describe the patterns of ECP use and identify factors associated with its use. Material and methods In 2011-2012, women aged 18-45 years were randomly selected from national registers in Denmark, Norway and Sweden and invited to respond to questions related to lifestyle and contraceptive use. We used generalized logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing women who had used ECP with women who had never used ECP. Results Of the 45 445 women, 33.9% (Denmark = 32.3%, Norway = 35.1%, Sweden = 34.6%) had used ECP at least once in their lifetime. Among ECP users, 15.8% had used ECP within the last year and 50.0% had used ECP more than once in their life. After adjusting for country, age at response and response type, ECP use was associated with higher education (OR 2.09, 95% CI 1.54-2.84) and being single, divorced or widowed (OR 3.17, 95% CI 2.87-3.49). Binge drinking and smoking increased the odds of ECP use. Furthermore, early age at first intercourse (OR 1.29, 95% CI 1.08-1.55), having a new partner in the last 6 months (≥3 partners: OR 6.44, 95% CI 5.46-7.60) and lack of condom use with a recent new partner (OR 1.42, 95% CI 1.22-1.66) were found to be associated with ECP use. Conclusions Our study shows that ECP use is common among Scandinavian women. Higher education and being single were associated with increased odds of ECP use. Risk behaviors such as smoking and early age at first sex were also associated with increased odds of ECP use. Since ECP use is not protective against sexually transmitted infections, our findings highlight the need to encourage awareness and regular use of condoms to prevent sexually transmitted diseases in women.

PURPOSE Given regulatory approval of immune checkpoint inhibitors in patients with mismatch repair–deficient (MMR-D) cancers agnostic to tumor type, it has become important to characterize occurrence of MMR-D and develop cost-effective screening approaches. Using a next-generation sequencing (NGS) panel (OncoPanel), we developed an algorithm to identify MMR-D frequency in tumor samples and applied it in a clinical setting with pathologist review. METHODS To predict MMR-D, we adapted methods described previously for use in NGS panels, which assess patterns of single base-pair insertion or deletion events occurring in homopolymer regions. Tumors assayed with OncoPanel between July 2013 and July 2018 were included. For tumors tested after June 2017, sequencing results were presented to pathologists in real time for clinical MMR determination, in the context of tumor mutation burden, other mutational signatures, and clinical data. RESULTS Of 20,301 tumors sequenced, 2.7% (553) were retrospectively classified as MMR-D by the algorithm. Of 4,404 samples with pathologist sign-out of MMR status, the algorithm classified 147 (3.3%) as MMR-D: in 116 cases, MMR-D was confirmed by a pathologist, five cases were overruled by the pathologist, and 26 were assessed as indeterminate. Overall, the highest frequencies of OncoPanel-inferred MMR-D were in endometrial (21%; 152/723), colorectal (9.7%; 169/1,744), and small bowel (9.3%; 9/97) cancers. When algorithm predictions were compared with historical MMR immunohistochemistry or polymerase chain reaction results in a set of 325 tumors sequenced before initiation of pathologist assessment, the overall sensitivity and specificity of the algorithm were 91.1% and 98.2%, respectively. CONCLUSION We show that targeted, tumor-only NGS can be leveraged to determine MMR signatures across tumor types, suggesting that broader biomarker screening approaches may have clinical value.

Background: The prevalence of treatment-resistant depression (TRD) among patients with pharmaceutically treated depression (PTD) varies greatly in publications. The aim of this study is to estimate the prevalence of TRD using 2 large claims databases in the US. Methods: This cross-sectional study used data from the Humana and Optum databases. Patients aged ≥ 18 years who had at least 1 diagnosis of major depressive disorder (ICD-10-CM codes: F32.xx, F33.xx) and 1 antidepressant prescription filled in 2018 were identified as having PTD. Among patients with PTD, TRD was defined as experiencing failure of treatment with at least 2 antidepressants with ≥ 4 weeks of adequate treatment. We estimated the age- and gender-standardized prevalence of TRD and then used logistic regression to investigate if TRD risk varies by age, sex, race, and geographic region. Finally, we described the timeline of TRD development in incident PTD patients. Results: We identified 296,055 and 277,941 patients with PTD in the Humana and Optum databases, among whom 17,640 (6.0%) and 16,131 (5.8%) had TRD. After age and sex standardization, TRD prevalence among PTD patients was 6.8% in Humana vs 5.8% in Optum. Females, middle-aged adults, and White patients had higher risk of TRD. The median time from index antidepressant use to TRD was about 6 months in incident PTD patients. Conclusions: The prevalence of TRD among patients with PTD was similar in the 2 databases. TRD prevalence varies by sex, race, and age, with a higher prevalence in females, White patients, and those in the age group of 45-64 years. However, the absolute differences were small.

INTRODUCTION Sexual behavior at the population level impacts on public health. Recent representative sexual behavior data are lacking. MATERIAL AND METHODS Cross-sectional surveys in 2005 and 2012 on women age 18-45 years randomly selected from the general population in Denmark (n = 40 804), Norway (n = 30 331) and Sweden (n = 32 114). RESULTS Median (interquartile range) age at first intercourse was 16 (15-18) years in Denmark, 17 (16-18) years in Norway, and 17 (15-18) years in Sweden. Women in the most recent birth cohort had sexual debut at the lowest age, and were most likely to have sexual debut before the legal age of consent. Proportions with debut age ≤14 years among women born 1989-1994 vs 1971-1976, odds ratio (95% confidence interval) were: 18.4% vs 10.9%, 1.95 (1.74-2.18) in Denmark, 12.9% vs 6.3%, 2.38 (2.01-2.82) in Norway, 17.8% vs 11.4%, 1.75 (1.55-1.98) in Sweden. Median (interquartile range) number of lifetime sexual partners was 6 (3-10) in Denmark, 5 (2-10) in Norway, and 6 (3-11) in Sweden. The proportion of women reporting >10 sexual partners was also highest in the most recent survey. The percentage with odds ratio (95% confidence interval) in 2012 vs 2005 surveys were: 24.9% vs 22.8%, 1.13 (1.07-1.18) for Denmark; 23.8% vs 19.8%, 1.27 (1.19-1.34) for Norway; and 28.3% vs 23.8%, 1.31 (1.24-1.38) for Sweden. Similarly, the proportion of women reporting ever having had a sexually transmitted infection among women age

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology.

There is increasing interest in utilizing real-world data (RWD) to produce real-world evidence (RWE) on the benefits and risks of medical products that could support regulatory approval decisions. The field of pharmacoepidemiology has a long history of focusing on data and evidence that would now be termed "real-world," including evidence from healthcare claims, registries, and electronic health records. However, several emerging trends over the past decade are converging to support the use of these and other RWD sources for approval decisions, and there are several recent examples and ongoing research that demonstrate how RWE may be used to support regulatory approval of new or expanded indications. The goal of this article is to review the current landscape and future directions of the use of RWE in this context. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

To monitor the changes in prevalence of human papillomavirus (HPV) infections in women50 years of age, participating in cervical screening programs of Denmark, Norway, and Sweden, before and after introduction of quadrivalent HPV (qHPV) vaccination.Liquid-based cytology samples were collected from 6538 women who attended cervical screening in Denmark, Norway, and Sweden in 2006-2008 and from 6332 similarly enrolled women in 2012-2013. Denmark started organized qHPV vaccination in 2008, Norway in 2009, and Sweden in 2012. All HPV testing and genotyping was performed using identical enrollment and analysis methods, by accredited general primer polymerase chain reaction methods with typing using the Luminex system.Overall HPV positivity declined slightly from 36.5% in 2006-2008 to 34.5% in 2012-2013. The decline was most pronounced among women 18-26 years of age: from 54.4% to 48.1% (P 0.001). The decline was substantial for vaccine HPV types (HPV6/11/16/18: decline from 22.3% to 16.6%; P 0.001) and was seen for both low-risk vaccine types (HPV6/11 declined from 5.0% to 2.5%) and high-risk vaccine types (HPV16/18 declined from 18.9% to 14.9%). Among women 27-50 years of age, there was no change between the time periods (22.5% and 21.6%, respectively). The significant decline in the younger age group was different in the 3 countries.This population-based study enrolling12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008-2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population.

ObjectiveThis study examined the associations between current behaviours/characteristics and self-perceived risk for STIs, among randomly selected women aged 18–45 years from Denmark, Norway and Sweden.MethodA population-based, cross-sectional, questionnaire study (paper based, web based and telephone based) was conducted during 2011–2012. We compared medium–high STI risk perception with no/low risk perception. The associations were explored for women who had ever had sexual intercourse and for women with a new partner in the last 6 months using multivariable logistic regression.ResultThe overall prevalence of medium–high STI risk perception was 7.4%. It was highest among women aged 18–24 years (16.2%) and among the Danish women (8.8%). Number of new sexual partners in the last 6 months (≥3vs 0 partners, OR 14.94, 95% CI 13.20 to 16.94) was strongly associated with medium–high STI risk perception. Among women with a new partner in the last 6 months, lack of condom use increased medium–high STI risk perception (OR 1.73, 95% CI 1.52 to 1.96). Genital warts in the last year, binge drinking and being single were associated with increased risk perception and remained statistically significant after additional adjustments were made for number of new partners and condom use with new partners in the last 6 months.ConclusionSubjective perception of risk for STI was associated with women’s current risk-taking behaviours, indicating women generally are able to assess their risks for STIs. However, a considerable proportion of women with multiple new partners in the last 6 months and no condom use still considered themselves at no/low risk for STI.

Background. Given limited data on the epidemiology of MSI-H and dMMR across solid tumors (except colorectal cancer (CRC)), the current study was designed to estimate their prevalence. Materials and Methods. A structured literature review identified English language publications that used immunohistochemistry (IHC) or polymerase chain replication (PCR) techniques. Publications were selected for all tumors except CRC using MEDLINE, EMBASE, and Cochrane databases and key congresses; CRC and pan-tumor genomic publications were selected through a targeted review. Meta-analysis was performed to estimate pooled prevalence of MSI-H/dMMR across all solid tumors and for selected tumor types. Where possible, prevalence within tumor types was estimated by disease stages. Results. Of 1,176 citations retrieved, 103 and 48 publications reported prevalence of MSI-H and dMMR, respectively. Five pan-tumor genomic studies supplemented the evidence base. Tumor types with at least 5 publications included gastric (n = 39), ovarian (n = 23), colorectal (n = 20), endometrial (n = 53), esophageal (n = 6), and renal cancer (n = 8). Overall MSI-H prevalence (with 95% CI) across 25 tumors was based on 90 papers (28,213 patients) and estimated at 14% (10%–19%). MSI-H prevalence among Stage 1/2 cancers was estimated at 15% (8%–23%); Stages 3 and 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), respectively. Overall, dMMR prevalence across 13 tumor types (based on 54 papers and 20,383 patients) was estimated at 16% (11%–22%). Endometrial cancer had the highest pooled MSI-H and dMMR prevalence (26% and 25% all stages, respectively). Conclusions. This is the first comprehensive attempt to report pooled prevalence estimates of MSI-H/dMMR across solid tumors based on published data. Prevalence determined by IHC and PCR was generally comparable, with some variations by cancer type. Late-stage prevalence was lower than that in earlier stages.

e15562 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancers exhibit high mutational load and are observed in colorectal carcinomas (CRC). The objectives of this study were to determine the proportion of MSI-H/dMMR in CRC and to describe clinical and demographic characteristics among MSI-H/dMMR and non-MSI-H/dMMR CRC patients receiving standard of care in an equal access health care system. Methods: Using the Veteran Affairs (VA) Healthcare system data, we conducted a retrospective study of patients, aged ≥18 years old, diagnosed with CRC who underwent MSI/MMR testing from January 1, 2010 to December 31, 2018. MSI/MMR testing was defined as having received an MSI status determined by polymerase chain reaction and/or next-generation sequencing test or an MMR status determined by immunohistochemistry test. Median and interquartile range (IQR) were calculated for continuous variables while frequencies and percentages were calculated for categorical variables. Results: A total of 291 patients diagnosed with CRC who underwent MSI/MMR testing between 2010-2018 were identified from VA centers. The majority of patients were white (69.8%) and male (95.5%), with median (IQR) age of 65 (56-70) years at diagnosis. Sixty-four (22.0%) patients had stage I CRC at diagnosis, 84 (28.9%) stage II, 87 (29.9%) stage III, and 45 (15.5%) stage IV; 11 (3.7%) had no stage information. Fifty-four (18.6%) patients were reported to have MSI-H and/or dMMR CRC, with rates similar for MSI-H [17.4% (21/121)] vs. dMMR [19.7% (44/223)] alone. The proportion of MSI-H/dMMR varied by CRC stage, and was more common in stage II (26%) and stage III (23%) than in stage IV (6%). Patients were similar between MSI-H/dMMR and non-MSI-H/dMMR with regards to age at diagnosis, gender, race, and ethnicity. Of 54 patients with MSI-H/dMMR CRC, three had metastatic CRC (mCRC) at diagnosis and seven progressed to mCRC. Among 51 MSI-H/dMMR patients without metastatic disease at diagnosis, 18 (35%) underwent chemotherapy and 44 (86%) underwent curative surgery. A similar pattern was also observed among non-MSI-H/dMMR CRC patients. Conclusions: In this real-world observational study in a VA population, we found MSI-H/dMMR was present in 18.6% of CRC patients who received MSI testing, highest in stage II (26%) and stage III (23%) and lowest in stage IV (6%) disease. Results are consistent with published estimates seen across other populations and geographies. Additional research is needed in larger cohorts of patients to further assess utilization patterns and real-world clinical outcomes of newer treatments (immunotherapies) approved for MSI-H/dMMR CRC.

Introduction The aim of this study was to describe recent patterns of contraceptive use at first sexual intercourse and to examine whether selected factors are associated with non-use and emergency contraceptive pill use at first sexual intercourse, among 18- to 26-year-old women from Denmark, Norway and Sweden. Material and methods This was a population-based, questionnaire study of randomly chosen 18- to 26-year-old Scandinavian women. The prevalence of contraception methods used at first sexual intercourse was calculated. Factors associated with contraceptive non-use and emergency contraceptive pill use at first sexual intercourse were determined using log binomial models. Results The prevalence of contraceptive non-use and emergency contraceptive pill use was lowest in Denmark (9.6 and 2.1%, respectively) compared with Norway (14.1 and 4.4%) and Sweden (16.6 and 4.5%). The risk of contraceptive non-use increased in women who had first sexual intercourse at or before 14 years of age (13–14 years: prevalence ratio 1.40; 95% confidence interval 1.24–1.58). The risk of both non-use and emergency contraceptive pill use increased when the partner at first sexual intercourse was 20 years or older, and with increasing age difference between the partner and the woman at her first sexual intercourse. Smoking initiation prior to first sexual intercourse increased risk of contraceptive non-use (prevalence ratio 1.70; 95% confidence interval 1.50–1.92), and alcohol initiation prior to first sexual intercourse increased risk of emergency contraceptive pill use at first sexual intercourse (prevalence ratio 1.95; 95% confidence interval 1.49–2.54). Conclusions Contraceptive non-use at first sexual intercourse was strongly associated with early age at first sexual intercourse. Emergency contraceptive pill and contraceptive non-use at first sexual intercourse were both strongly associated with increasing partner age and an increasing difference in age between the woman and her partner. Hence, young women should be educated to negotiate contraceptive use with their partners.

Objective Women's contraceptive use at first sexual intercourse (FSI) may be associated with subsequent sexual behaviors. We examined associations between contraceptive methods used at FSI and subsequent number of lifetime partners, induced abortions and sexually transmitted infections (STIs). Study design During 2011–2012, we collected questionnaire data from a random sample of women aged 18–45 years from Denmark, Norway and Sweden. We used logistic regression and discrete-time proportional hazards models to estimate odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs), comparing different contraceptive methods used at FSI in the whole study sample and in women with FSI in 2001 or later [when emergency contraceptive pills (ECPs) were available without prescription]. Results Of 45,361 women in the study sample, those who did not use contraception at FSI (n=8155; 18.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.34; 95% CI 1.27–1.42), induced abortions (HR=1.62; 95% CI 1.53–1.71) and STIs (HR=1.15; 95% CI 1.10–1.20). ECP users (n=440, 1.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.76; 95% CI 1.40–2.22), induced abortions (HR=1.44; 95% CI 1.11–1.86) and STIs (HR=1.84; 95% CI 1.56–2.16). A similar pattern was seen in safe periods/withdrawal users. The associations did not change among women with FSI in 2001 or later (n=14,445). Conclusions Compared with condom use, contraceptive nonuse, safe periods/withdrawal use and ECP use at FSI were associated with subsequent number of sexual partners, induced abortions and STIs. Implications Contraceptive method used at first intercourse was associated with subsequent sexual behaviors in women. This study highlights the importance of early sexual behaviors and may help understand patterns of women's sexual behaviors.

Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.

The active component of the herpes zoster vaccine (ZVL), licensed for people ≥50 years of age, is a live attenuated varicella-zoster virus. ZVL is contraindicated for immune compromised individuals, with limited regard to the degree of immunosuppression. Areas covered: This review evaluates phase I and II and observational studies for ZVL, and published reports of the off-label use of ZVL, for conditions and therapies for which investigators considered the risk-benefit for using ZVL to be favorable. It also discusses exploratory trials of ZVL for additional immune compromising conditions, and summarizes clinical guidelines from many countries and professional societies that are based upon recent investigations. Studies in immune compromised patients of investigational vaccines that do not contain live virus are reviewed. Expert commentary: It is likely that past and ongoing research with ZVL will define immune compromising diseases and/or therapies for which the risk-benefit for using ZVL vaccine is favorable. The main variables to consider in this assessment in immune compromised patients are safety, immunogenicity, protection against herpes zoster, and persistence of protection. Vaccination against herpes zoster prior to suppressing immunity is an important clinical strategy, although efficacy of this approach has not been evaluated in a clinical trial.

Purpose Given the high prevalence of MSI-H/dMMR in gastrointestinal and gynecologic cancers we systematically collected published studies and investigated its’ prevalence for Chinese CRC, GC, EC, OC subjects to better understand the size of potential target population available for pembrolizumab treatment in China. Experimental Design Both Chinese and English literature were searched in WanFang and PubMed database respectively. Studies were included if they assessed prevalence of MSI-H by PCR based method investigating 5 markers from NCI or Promega panel, and/or dMMR by immunohistochemistry (IHC) for all 4 MMR proteins. Studies focusing only on hereditary or sporadic cancer were filtered out. Among eligible studies, meta-analyses (DerSimonian Laird random effect model) were performed on the proportion of MSI-H/dMMR for each tumor type by R metafor package. Prevalence for advanced stage (III/IV) were also extracted if the data were available. Results For CRC, the prevalence of MSI-H estimated from 11 studies (13.7% [10.2-17.6%]) was similar as that of dMMR from 22 studies (14.6% [12.3-17.1%]). Pooled prevalence of MSI-H/dMMR from 32 studies (12,341 subjects) was estimated at 14.1% (12.2-16.1%), and 9.7% (7.2-12.5%) from 17 studies (3,933 subjects) for advanced stage CRC. The prevalence estimation for GC, EC and OC were 18.5%, 26% and 12.9% respectively. Further, the prevalence in advanced stage cancer, regardless of the cancer type, tended to be numerically lower than the all-stage combined prevalence. Conclusions This was the first study comprehensively integrating published studies to estimate prevalence of MSI-H/dMMR across 4 main tumor types for Chinese subjects. The meta-analysis indicated the prevalence of MSI-H/dMMR for all or advanced stage Chinese cancer patients might be similar as that for western population. Citation Format: Xiaoqiao Liu, Jiaqi Fan, Kai-Li Liaw, Mo Xu, Yu Zhou, Mayur Amonkar, Gefei Zeng. Literature review and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) for colorectal (CRC), gastric (GC), endometrial (EC) and ovarian cancers (OC) in Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 616.

e15074 Background: Pembrolizumab is approved in the US for treatment of unresectable/metastatic MSI-H/dMMR solid tumors progressing after standard prior treatment. While some data exist on MSI-H/dMMR prevalence in colorectal cancer (CRC), data on other gastrointestinal (GI) cancers is sparse. Methods: An SLR covering solid tumor types identified English language publications using immunohistochemistry (IHC) for all 4 MMR proteins or polymerase chain reaction (PCR) techniques using specified NCI or Promega marker panels. A targeted review was conducted for CRC due to larger volume of publications in this tumor type. MEDLINE, EMBASE, Cochrane databases and key cancer congresses were searched for relevant articles. Among eligible studies, meta-analyses were performed (random effects model) on the prevalence of MSI-H and dMMR among gastric, colorectal and esophageal cancers. If possible, prevalence estimates were also obtained by geography, disease stage, and histology. Results: Of 1,176 citations retrieved in the full review, 35, 17 and 6 studies reported prevalence of MSI-H and/or dMMR in gastric, CRC, and esophageal cancers, respectively. Among gastric cancers, MSI-H pooled prevalence (with 95% CI) from 32 studies (16,308 patients) was estimated at 11% (9-12%) and dMMR pooled prevalence from 4 studies (854 patients) was estimated at 8% (2-17%); in stage 4 cancers, the prevalence was 7% (4-9%; 10 studies; 383 patients). In CRC, MSI-H pooled prevalence from 14 studies (8,156 patients) was estimated at 13% (10-16%) and dMMR pooled prevalence from 4 studies (11,434 patients) was estimated at 10% (5-15%). For stage 4 CRC, the prevalence was 5% (1-10%; 4 studies; 252 patients). Among esophageal cancers, MSI-H pooled prevalence from 6 studies (731 patients) was estimated at 4% (0-11%). Conclusions: This comprehensive SLR provides prevalence estimates of MSI-H and dMMR across 3 key GI tumors based on published data. The prevalence estimates of MSI-H among gastric cancer and CRC were similar to their corresponding dMMR prevalence estimates. MSI-H prevalence appeared to be lower for advanced stage gastric cancer and CRC.

The epidemiology of herpes zoster (HZ) in contemporary autologous hematopoietic cell transplant (HCT) recipients, and the impact of acyclovir (ACV)/valacyclovir (VACV) prophylaxis, is not well described. In this observational study from 2002 to 2010, we retrospectively identified 1000 varicella zoster virus (VZV)–seropositive autologous HCT recipients with up to 5 years of follow-up. The incidence of HZ and use of ACV/VACV prophylaxis were determined through review of medical records and mailed questionnaires. Risk factors for HZ were determined by multivariable Cox regression. Over a period of 5 years after autologous HCT, 194 patients developed at least 1 HZ episode, with a cumulative incidence of 21%; 159 of 194 (82%) were not on prophylaxis at the time of HZ. A second episode of HZ occurred in 31 of 194 (16%) patients. Patients taking ACV/VACV had reduced risk for HZ (adjusted hazard ratio [aHR], .59; 95% confidence interval [CI], .37 to .91), whereas those older than the median age (≥55.5 years) had increased risk (aHR, 1.42; 95% CI, 1.05 to 1.9). Disseminated VZV was reported in 8% and postherpetic neuralgia in 13% of patients. We demonstrate a high burden of HZ late after autologous HCT, despite long-term antiviral prophylaxis. Improved prevention strategies are needed to provide sustained protection against HZ after autologous HCT.

Using a large, population-based survey, we assessed the levels and correlates of human papillomavirus (HPV) awareness among Scandinavian women after introduction of HPV vaccination. In 2011-2012, a random sample of women aged between 18 and 45 years from Denmark, Sweden and Norway received a questionnaire on lifestyle, health and HPV awareness. We included 47 895 women (response rate 60.6%) in our study. Country-specific and age-specific proportions of women who had heard of HPV in 2011-2012 (postvaccination survey) were compared with corresponding proportions in an identical survey from 2004-2005 (prevaccination survey, n=54 079, response rate 71.3%). Correlates of HPV awareness in the postvaccination survey were assessed by logistic regression. In all countries and age groups, awareness of HPV increased from the prevaccination to the postvaccination survey. In the postvaccination survey, HPV awareness was higher in Denmark (75.8%) and Sweden (74.8%) compared with Norway (62.4%), with greatest discrepancy among women aged between 18 and 19 years (Denmark: 74.9%, Sweden: 70.4%, Norway: 39.6%). Variables associated with low HPV awareness included the following: low education [≤12 vs.16 years of schooling: odds ratio (OR)=0.45, 95% confidence interval (CI): 0.42-0.48], being a virgin (vs. nonvirgins: OR=0.74, 95% CI: 0.66-0.83), never having used condoms (vs. ever: OR=0.62, 95% CI: 0.56-0.67), nonuse of contraception at first intercourse (vs. use: OR=0.83, 95% CI: 0.79-0.88) and daily smoking (vs. never: OR=0.86, 95% CI: 0.80-0.92). HPV awareness in Scandinavia has increased since the introduction of HPV vaccination. However, 24-38% of Scandinavian women still have never heard of HPV. Future information efforts should target groups with low HPV awareness.

Background Cervical cancer is the most common cancer among women of reproductive age in Thailand. However, information on the prevalence and correlates of anogenital HPV infection in Thailand is sparse. Methods HPV genotype information, reproductive factors, sexual behavior, other STI and clinical information, and cervical cytology and histology were assessed at enrollment among one thousand two hundred and fifty-six (n = 1,256) HIV negative women aged 20–37 from Thailand enrolled in a prospective study of the natural history of HPV. The type-specific prevalence of HPV was estimated using cervical swab specimens from healthy women and women with a diagnosis of CIN 2/3 at baseline. Prevalence ratios (95% CI) were estimated using Poisson regression to quantify the association of demographic, behavioral, and clinical correlates with prevalent HPV infection. Results Overall, 307 (24.6%) and 175 (14.0%) of women were positive for any HPV type and any HR-HPV type, respectively; the most common types were 72, 52, 62, and 16. Among women diagnosed with CIN 2/3 at enrollment (n = 11), the most prevalent HPV types were 52 and 16. In multivariate analysis, HPV prevalence at enrollment was higher among women with: long-term combined oral contraceptive use, a higher number of lifetime sexual partners, a prior Chlamydia infection, and a current diagnosis of Bacterial Vaginosis. Conclusion The study findings provide important information that can be used in the evaluation of primary and secondary interventions designed to reduce the burden of cervical cancer in Thailand. Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-0886-z) contains supplementary material, which is available to authorized users.