Background: Japanese patients with prostate cancer are typically treated with primary androgen deprivation therapy (ADT), most commonly administered as a combination of a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen (AA). Since LHRH agonists and AA therapy can be maintained for several years, the long-term effects of these treatments on patients must be carefully considered, including the risk of concomitant central nervous system (CNS) conditions which could affect treatment choices.Objective: To describe CNS-related concomitant conditions during ADT and/or AA treatment and the subsequent healthcare resource utilization in Japanese nonmetastatic castration-resistant prostate cancer (nmCRPC) patients.Methods: Patients diagnosed with nmCRPC and CNS-related conditions while on ADT and/or AA therapy between April 2009 and August 2017 were retrospectively followed up for a maximum of 2 years using a claims database.Results: A total of 455 patients , were included. The 3 most common concomitant CNS-related conditions were pain (~60% of events), insomnia (~30%), and headache (2%-3%). The frequency of CNS-related conditions in these patients increased approximately threefold after starting AA therapy . On average, a patient had 10 episodes of concomitant CNS-related conditions in a year. Medical costs did not significantly increase due to CNS-related conditions.Discussion: The most frequently reported CNS-related conditions were pain, insomnia, and headaches. Furthermore, more concomitant CNS-related conditions 1 year after CRPC diagnosis and 1 year after starting AA treatment were recorded.Conclusion: Patients with nmCRPC experience an increase in the frequency of concomitant CNS-related conditions, including pain, insomnia, and headaches, after CRPC diagnosis or starting AA treatment. Future research should explore the causes of this increased frequency. Prostate cancer is the second most commonly diagnosed malignancy among males globally and was the most common cancer among males in Japan in 2022.CNS-related conditions among prostate cancer patients have gained attention in recent years.In Japan, a real-world comparison of effects of abiraterone and enzalutamide among men with metastatic castration-resistant prostate cancer (mCRPC) showed differing rates of fatigue among treated patients.The aim of the study was, therefore, to determine the occurrence of CNS-related conditions among nmCRPC patients in Japan. Second, we aimed to determine the healthcare resource utilization (HRU) and, exploratively, the real-world metastasis-free survival (MFS) of these patients.This was a retrospective cohort study from a commercially available hospital claims database managed by Medical Data Vision Co., Ltd. (MDV). The database consists of data from April 2008 to August 2018. The full database contains data on about 4.4 million patients in Japan, corresponding to approximately 3% of the total Japanese population. From this database, we selected patients who met the selection criteria described below.Patients were included into the study if they had been diagnosed with CRPC as defined by Japanese code 8848040 during the index period (April 2009 and August 2017). These patients must also have received at least 1 prescription of medical ADT and AAs within a year prior to diagnosis of CRPC. Medical ADT considered are leuprorelin (L02AE02), goserelin (L02AE03), and degarelix (L02BX02), and AAs included in this study were bicalutamide (L02BB03), flutamide (L02BB01), or enzalutamide (L02BB04). Patients were excluded from the study if they did not have any record of luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone agonist (GnRHa) and AA treatment within a year after being diagnosed with CRPC or had no record of any CNS-related conditions within a year after their diagnosis. They were also excluded if they had at least 1 metastatic event corresponding to disease codes C77 , C79 , and C79.5  in the year prior to and at CRPC diagnosis, so as to include only nmCRPC patients.Figure 1: 455 patients were included in the analysis, of which 313 patients in the reduced cohort size were included for the MFS analysis.The cohort of patients who met the above criteria were followed up for 1 year. However, to assess a 2-year MFS, we reduced the cohort size by shortening the index period to between April 2009 and August 2016. A 2-year MFS follow-up was chosen based on literature-based evidence reporting that, of those patients with no metastases present at diagnosis of CRPC, 33% could expect to develop them within 2 years.Figure 2).To identify nmCRPC patients with concomitant CNS-related conditions and the HRU associated with concomitant CNS-related conditions against GnRHa and AA therapy, the study observation period considered was set to 1 year pre-post CRPC therapy .Three outcome measures were included: the occurrence of concomitant CNS conditions in nmCRPC and their associated treatment history, HRU, and, exploratively, the length of MFS among these patients.International Classification of Diseases, Tenth Revision (ICD-10) as reference for conditions listed under “CNS-related conditions,” as previously cited.Appendix lists the CNS conditions considered in this study and their associated ICD-10 codes.CNS-related conditions were extracted using the For the second outcome measure, only the 3 metastatic ICD-10 codes used in the patient selection process were considered as metastatic outcomes for the MFS analysis .Lastly, healthcare costs were calculated in Japanese yen (JPY) and were presented for total direct medical costs, medication costs with CRPC treatment as a subset, diagnostic costs, hospitalization including intensive care unit (ICU) admission costs, and outpatient costs. These were assessed during the 1-year follow-up period. For CNS treatment–related costs, therapies that were included in the cost calculations were those listed as prescribed treatment for those indications in the MDV database. Although there were many possible therapeutic options for each CNS condition, only treatments that appeared in the database factored in the cost calculations. The costs in the database already reflected the Healthcare Fee System and NHI Drug Price List for the applicable year in Japan.We performed descriptive analyses and stratified the results by treatments taken, concomitant CNS-related condition, and whether the condition occurred before and after the first diagnosis of CRPC or the first prescription of AA treatment.http://www.python.org).To protect the anonymity of patients, the dates in the MDV dataset were partially masked. Only the month and year of each entry was available. Hence, we used a 12-month addition to calculate a 1-year follow-up period. All costs were calculated in JPY. These analyses were carried out using Python  was used.A logistic regression analysis was used to study the risk factors for the 3 most common concomitant CNS-related conditions. Age and comorbidities were included in the model as confounding variables. Additionally, the number of CNS symptom events and treatments taken were used as explanatory variables. The most parsimonious model was selected. To study the variables associated with total direct medical costs, a generalized linear model with gamma distribution and log link was used. This was because the outcome of interest, healthcare cost, had a long right-tail distribution. Most statisticians and health economists recommend this model instead of log transformation of the data as, in most cases, it does not normalize the variable. All variables were kept in this model to facilitate comparison between the 3 CNS-related conditions. For Kaplan-Meier analysis, a different cohort was used, utilizing patients who had at least 2 years of post-CRPC diagnosis data. The event of interest was metastatic events based on ICD-10 codes C770, C790, and C795. The date of death or the end of the 2-year follow-up period or the date of the last data point available, whichever came earliest, was used to censor patients. All patients were analyzed in the same group. For these analyses, R version 3.6.1  in Tokyo, Japan. This study used only anonymized retrospective data from a commercially available secondary database source (MDV) using only existing materials.Table 1 shows the demographic characteristics of the cohort on the index date and at the end of 1 and 2 years of follow-up. The average age of patients with nmCRPC diagnosis on the index date was 78.5 years . The mean Charlson Comorbidity Index (CCI) score was 1.8 on the index date and increased by 0.1 with each year of follow-up.Table 2). Pain conditions retrieved included low back pain, lumbar region; chest pain, unspecified; other chronic pain ; and unspecified pain .There were 4822 concomitant CNS diseases recorded. The most common concomitant CNS diseases were pain, insomnia, and headaches, affecting 76.7%, 34.5%, and 7.0% of patients, respectively. These 3 CNS diseases accounted for over 90% of concomitant CNS disease events, with the bulk being pain (65.7%). On average, each patient experienced about 10 CNS symptoms during the 1-year follow-up period. Seizures were also observed . The median time to the first CNS-related condition from the time of CRPC diagnosis was about 6 months. This was noted to be the same median time regardless of the nature of the CNS symptom (table not shown).When we compared the number of patients with concomitant CNS-related conditions before and after CRPC diagnosis and AA treatment, we observed that rarely do concomitant CNS-related conditions stop once they begin for patients in the cohort. Among patients without previous CNS-related conditions, 157 (34.5%) developed said conditions after CRPC diagnosis and 162 (35.6%) after the start of AA treatment; 298 (65.5%) experienced CNS-related conditions prior to CRPC diagnosis or AA treatment, and 138 (30.3%) continued to experience these post-CRPC and post-AA treatment , insomnia , and headaches . Combined, these 3 CNS-related conditions accounted for about 90% of the total number of events. Our results also show that most patients will report almost 10 concomitant CNS-related conditions in the 1 year after AA treatment begins.Supplementary Table S3). Patients also had no recorded diagnosis of CNS metastatic disease (ICD-10 G96.9), although they tended to have other CNS-related conditions such as pain and insomnia, at around the same time as the seizures .Seizures were diagnosed in 10 patients, with 4 patients having previously experienced seizure events prior to the start of AA therapy and continuing to experience seizures after AA therapy was started, while 6 patients were newly diagnosed with seizure events within the year after AA therapy was started. Due to the very small sample size of patients with seizure events, our analyses are exploratory at best. However, patients diagnosed with seizure tended to be older  compared with the overall population in this study  (p < .0001) while prior incidence of insomnia  and headaches  were protective for pain incidence during follow-up. A similar trend was also observed for insomnia, where prior incidence of insomnia had an extremely large OR  while prior pain diseases were protective  and decreased the odds of future concomitant insomnia events substantially. Prior headaches were also very good predictors of headache recurrence , but no other concomitant CNS-related condition showed the protective effect (Supplementary Table S4).We then investigated the possible risk factors for concomitant CNS-related conditions: pain, insomnia, and headaches. These included age, comorbid conditions, treatment types, and prior CNS-related conditions. Results showed that prior pain incidence increased a patient’s odds of pain recurrence significantly  but could reach in excess of 56 million JPY (US $390 000) in a year. Most of the cost was attributable to medication. Onaverage, medicines cost approximately 3 million JPY (US $21 000) over a 1-year period, of which about 2 million JPY was for CRPC medication. Consequently, other healthcare resources accounted for a smaller proportion of the total direct medical costs. Claims for laboratory tests and diagnostic imaging were 0.14 and 0.1 million JPY (US $900), respectively. Hospitalization costs were higher at approximately 1.6 million JPY per patient (US $11 000). Patients were on average hospitalized twice during the follow-up year. ICU events were rare: only 6 patients were admitted to the ICU, and their mean cost was about 0.6 million JPY (US $4000). Patients had regular outpatient clinic visits, averaging 20 outpatient clinic visits each during the follow-up period.However, Japan has universal health insurance coverage, as well as a high cost-benefit medical insurance system that can offset patients’ direct out-of-pocket costs; hence, the costs here do not directly reflect how much a patient actually pays for treatment.Next, we quantified the effect of concomitant CNS-related conditions on medical costs to patients. The final model consisted of 2 of the most commonly seen concomitant CNS-related conditions in this data set (pain and insomnia) and CRPC treatments. Neither the number of concomitant CNS-related conditions nor CRPC treatment duration led to noticeable differences in the total direct medical cost.Supplementary Figure S2). The average time to metastatic event in the 2-year follow-up was 8.3 months, and 6.2 months for events that occurred in the first 12 months. It is worthwhile to note that this estimate is only for nmCRPC patients with CNS-related conditions, which may differ from nmCRPC patients without these conditions (beyond the scope of this study). We also did not qualify whether patients were considered high- or low-risk nmCRPC patients, as only limited PSA data were available (and no imaging results available) in the database.Our exploratory analysis using Kaplan-Meier curves showed that 102 of 313 patients had a metastatic event in the 2-year follow-up (~30%), of which about 80% of metastatic events occurred within the 12 months after the index date; only 19 additional patients progressed to metastasis in the second year ; and unspecified pain . Interestingly, this result is highlighted by qualitative literature on nmCRPC patients’ most commonly reported symptoms being “pain” as well.A literature review by Ryan et alThe incidence of seizures in patients on higher doses of some AAs has led to suggestions that they can cross the blood-brain barrier, and by extension other treatments may also have the same potential, although their ability to penetrate may vary significantly.In contrast, several studies have also shown that androgens were protective against neurodegeneration.Despite a plausible biological explanation for a causal relationship between ADT and CNS conditions among prostate cancer patients, it is still unclear if there is a causal relationship.The model findings also showed that prior concomitant CNS-related conditions were risk factors for future occurrence. This was not unexpected, as a similar pattern is seen for many other diseases, including heart diseases like stroke and heart attacks. It merely indicates that the causal pathway of these concomitant CNS-related conditions remained active and therefore may have led to recurrence.We showed that the average annual costs of treatment were substantial, in the range of 3 million to 5 million JPY (US $20 000-$34 000), which is almost the same range as the reported annual income of Japanese CRPC patients.Lastly, the number of patients who progressed to metastasis was sizeable, and the time to metastatic event was short—about 8 months on average. The median MFS rates reported by Hussain et al,The study has several limitations. First, as a medical claims database, the population within this database may not be representative of the general Japanese population, nor would it be similar to clinical trial populations of androgen receptor inhibitors, where CNS-related adverse events were closely monitored. Second, diagnosis of CRPC and CNS-related conditions is dependent on clinicians accurately and timely reporting, and in some cases, patients declaring their symptoms. Hence, the patient numbers could be underestimated. Third, our sample size is relatively small, and only patients with concomitant CNS-related conditions were selected. Fourth, the follow-up period was short, and patients frequently changed treatments during the follow-up period, thereby complicating the relationship between treatment and CNS disease. Finally, patients who changed hospitals and for whom data were lost in the 1-year follow-up period would also have been omitted, resulting in possible bias in the results.Patients with nmCRPC with concomitant CNS-related conditions have greater morbidity 1 year after CRPC diagnosis and 1 year after starting AA treatment, with increased frequency of concomitant CNS-related conditions, although we observed that they had similar MFS as nmCRPC patients in other studies. The presence of pain and the short time to metastatic event within our observation period highlights the need for diagnostic imaging to be conducted at the proper time to be able to potentially improve patients’ prognoses. The presence of concomitant CNS-related conditions should be carefully considered in treatment decision-making for nmCRPC patients, as nmCRPC treatment duration is relatively long, and these occurrences will affect patients’ quality of life.D.L. conceived of the study and its design, led the coordination of the study, and helped draft the manuscript. J.C., X.W.L., and S.T. participated in the development of the study design, carried out the statistical analysis, and helped draft the manuscript.J.C., X.W.L., and S.T. were employees of IQVIA, Real World Insights at the time of conduct of this study, which was commissioned by Bayer Yakuhin, Ltd. D.L. is a full-time employee of Bayer Yakuhin, Ltd.


Coronavirus disease 2019 (COVID-19) pandemic has influenced health-care organization worldwide, including management of non-communicable diseases. The aim of this study was to determine the impact of COVID-19 pandemic on cardiac implantable electronic devices’ (CIEDs) implantation rates in Croatia.A retrospective, observational, national study was conducted. The data on CIEDs’ implantation rates from 20 Croatian implantation centres, between January 2018 and June 2021, were extracted from the national Health Insurance Fund registry. Implantation rates before and after COVID-19 pandemic started, were compared.The overall numbers of CIED implantations in Croatia during COVID-19 pandemic were not different in comparison to 2 years pre-COVID-19 time . The pacemaker implantation rates decreased significantly (by 45%) during April  and May 2020 , as well as during November 2020 , but significantly increased during summer months 2020 comparing to 2018 and 2019 . The ICD implantation rates decreased significantly by 59% in April 2020 .To the authors best knowledge this is a first study including complete national data on CIED implantation rates and COVID-19 pandemic impact. A significant reduction in number of both pacemaker and ICD implants during specific months of the COVID-19 pandemic was determined. However, afterwards compensation in implants resulted in similar total number when the complete year was evaluated. Coronavirus disease 2019 (COVID-19), caused by the novel SARS-CoV2 virus, started to spread all over the world in December 2019, and has soon confirmed its pandemic potential. The first cases reported in Europe were on 24 January 2020, and by the end of February, more than 1500 daily new cases were reported –6. MoreoThis retrospective, observational study considered the total number of CIED implants and its generator replacements in 20 Croatian implantation centres between January 2018 and June 2021. The data were extracted from the Croatian Health Insurance Fund registry, in which the rates of implants and replacements from all centres in Croatia are recorded. Croatian Health Insurance Fund is one obligatory health insurance in Croatia and all the centres are required to report the procedures and the underlying diagnoses for all patients. These data are public and could be accessed on web . The datth, and the COVID-19 epidemic was officially declared on March 16th, 2020. Hence, data from March 2020 were excluded from the statistical analysis to avoid over- or under-estimation bias.For the purposes of this study, time has been divided into two periods: "before COVID-19 period" (BCP) and "COVID-19 period" (CovP). In Croatia the first COVID-19 case was diagnosed on February 26Sestre milosrdnice University Hospital, Zagreb) was consulted waiving the need for approval given the nature of the data.The Ethics Committee of the coordinating centre .Continuous variables were presented as means with standard deviations or median with interquartile range in case of skewed distribution. Continuous variables were compared with nonparametric Mann-Whitney U test. Categorical variables were presented as absolute values and/or percentages and were compared using Pearson χThe total number of pacemaker implantations during 2020 was lower when compared to an average number of implants in two earlier years, however it did not reach statistical significance . There was no other statistically significant difference between the BCP and CovP regarding ICD implants, including monthly, bimonthly, quarterly number or any other combination Tables . HoweverThe main findings of this multi-centre, national, registry-based study, which included data from all 20 CIED implanting centres in Croatia, are the following: 1) the overall numbers of CIED implants during COVID-19 pandemic were not different in comparison to 2 years pre-COVID time; 2) the pacemaker implantation rates decreased significantly during two months after the official declaration of COVID-19 epidemics (April and May 2020), as well as during November 2020; 3) the pacemaker implantation rates significantly increased during summer months 2020 in comparison to 2018/2019; 4) the ICD implantation rates decreased significantly during April 2020.We analysed the overall national CIED implantation activity in Croatia before and during the COVID-19 pandemic. A significant reduction in a pacemaker implantation rates first two months after the official declaration of COVID-19 epidemic was determined. That was the period of the strictest anti-COVID-19 measures in Croatia. During these periods there was a significant decrease in number of visits in emergency departments that were not related to COVID-19 which we detected as a main reason of the observed decrease in implantation rate. The same trend was observed in November 2020 occurring during the peak of the second “COVID-19 wave” in Croatia which led to the second “lock down” in our country . MonthlySimilarly, the ICD implantation rates declined continuously, but the statistically significant decrease was noted only in April 2020, whereas this was not noted in the rest of the following months of COVID-19 pandemic, including first 6 months of 2021. However, in one third of Croatian implantation centres in April and May 2020, no ICD implants were reported. Regarding ICD implantation, our data are also in line with previous results collected in Italy, Spain and Peru –10. HoweThis multicentre retrospective study has several limitations. First, due to the limitation in registry’s data, especially during the COVID-19 pandemic, we have not been able to extract detailed data on relevant variables such as patients’ socio-demographic status, indication for CIED implantation, device type or clinical presentation. Second, the observational nature of the study did not allow any conclusion to be drawn in relation to the underlying causes for the significant variations in CIED implantation rates during the COVID-19 pandemic.A significant reduction in total number of pacemaker implants during April, May and November 2020 was determined in Croatia during the COVID-19 pandemic, whereas an increase of pacemaker implants was observed in the period between two “COVID-19 waves”. Regarding the ICD implants, significant decrease was noted only in April 2020, with no significant, but gradual compensation afterwards. Further studies are needed to elucidate the underlying causes of these trends.S1 Table(PDF)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.


The effect of risk factors on ovarian cancer differs by histotype, and the prevalence of such risk factors varies by race/ethnicity. It is not clear how ovarian cancer incidence has changed over time by histotype and race/ethnicity.N = 19,691, endometrioid N = 3,212, and clear cell N = 3,275) and four racial/ethnic groups . Joinpoint and age-period-cohort analyses were conducted to analyze ovarian cancer incidence trends.We used the Surveillance, Epidemiology, and End Results Program (SEER-12) 1992–2019 data to examine the trend of ovarian cancer incidence for three histotypes , −8.0 to −4.2). Conversely, clear cell cancer was most common in the Asian/Pacific Islanders, and its incidence has increased over time, particularly among Hispanic and Asian/Pacific Islander women . Endometrioid cancer incidence has decreased in non-Hispanic White but increased in Hispanic women .The differential incidence trends by histotype and race/ethnicity underscore the need to monitor incidence and risk factor trends across different groups and develop targeted preventive interventions to reduce the burden of ovarian cancer and disparity by race/ethnicity.During 1992–2019, high-grade serous ovarian cancer incidence has decreased while clear cell cancer incidence has increased regardless of race/ethnicity. Endometrioid cancer incidence has decreased in non-Hispanic White but increased in Hispanic women. Differential ovarian cancer incidence trends highlight the need for targeted preventive interventions by histotype and race/ethnicity. Approximately 22,000 women in the United States are diagnosed with ovarian cancer annually , equatinThe declines in ovarian cancer rates have been mainly attributed to increasing parity during the 1940s to 1960s baby boom  and the Notably, there has been a sea change in our understanding of ovarian cancer over the past two decades. Ovarian cancer is now largely thought of as five distinct histotypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous, depending on different cells of origin. Many high-grade serous cancers likely arise in the fallopian tube fimbriae, whereas endometriosis is widely considered the tissue of origin for clear cell and endometrioid cancers . Many riOvarian cancer incidence is highest among non-Hispanic White women and lowest among non-Hispanic Black and Asian/Pacific Islander women . Wu and It is crucial to analyze the trends of ovarian cancer incidence by histotype and race/ethnicity as the risk factors vary by histotype and the prevalence of risk factors differs by race/ethnicity. Some previous studies have examined the trends of ovarian cancer in the United States. However, limitations of these studies include not evaluating the trends by histotypes , and resTo understand both historical and current trends in ovarian cancer rates and to overcome the limitations of the previous studies, we have conducted Joinpoint regression and age-period-cohort analyses using the most recent data from SEER during 1992–2019 . We evalAll analyses are based on publicly available data; therefore, Institutional Review Board approval was not required.Data for ovarian cancer cases and population denominators were obtained from the SEER-12 registry November 2021 submission using SEER*Stat software  were excluded from the main analysis. All clear cell cancers were considered as such regardless of their grade. Our study included 19,691 high-grade serous, 3,212 low-grade endometrioid, and 3,275 clear cell ovarian cancer cases from the SEER-12 registry. The flow chart of inclusion is presented in Epithelial ovarian cancer cases meeting the following criteria were extracted from the SEER-12 registry: microscopically confirmed invasive ovarian cancer (primary site: C56.9 ovary), diagnosed between 1992 and 2019, and ages 30–84 years. We excluded women younger than 30 due to the very low incidence of ovarian cancer in this age group . We focuAge-standardized incidence rates (ASIR) for invasive epithelial ovarian cancer for each histotype  were calculated separately for four racial/ethnic groups . Other racial/ethnic groups were excluded because of the small sample size . ASIRs wTrend analyses were performed using Joinpoint Regression Program software .Age-period-cohort analyses were performed by fitting a log-linear model with a Poisson distribution to the observed data to estimate age, period, and cohort effects. To address the well-known nonidentifiability problem of age-period-cohort models, we fitted models with either cohort or period constrained to be zero on average with a slope equal to zero. The final selected model was the one with the lowest Akaike information criterion (AIC). Age-period-cohort analyses were conducted for women ages 30–84 by histotype and race/ethnicity. Age, period, and cohort effects were modeled with natural splines. The birth cohort 1935 and the calendar period 2010 were the reference groups. The analyses were conducted using the In the SEER-12 registry dataset, there were 5,092 patients with serous ovarian cancer with missing grade, but stage data available, among whom 4,725 were at the distant or regional stage. Most distant or regional stage cases are high grade. We, therefore, conducted a sensitivity analysis including these distant or regional stage cases with a missing grade as high-grade serous cases to increase the sample size.In the main analysis above, we included high-grade endometrioid cancer into high-grade serous cancer as the literature suggests that the majority of high-grade endometrioid cancers are high-grade serous cancers. However, we acknowledge that some true high-grade endometrioid cancers exist. Thus, we also conducted a sensitivity analysis in which high-grade endometrioid cancer was not included as high-grade serous cancer.We also conducted a sensitivity analysis using SEER-17 data (previously SEER-18), which includes more registries but a shorter time frame compared with SEER-12. Sensitivity analyses using the SEER-17 registry included women diagnosed between 2000 and 2019 with the same eligibility criteria described above for SEER-12 analysis. Although the period of SEER-17 is shorter than SEER-12, the number of cases is greater for every histotype and racial/ethnic group because it includes more registries. The Joinpoint analyses using the SEER-17 registry set a maximum of three Joinpoints due to the shorter study period (2000–2019).The data analyzed in this study were obtained from the SEER-12 registry November 2021 submission using SEER*Stat software  use is associated with an increased risk of high-grade serous cancer . In 2002Another driver for the decreasing trend in high-grade serous cancer incidence could be the increase in opportunistic salpingectomy, which is the removal of the fallopian tubes during abdominal surgery or in lieu of tubal ligation. High-grade serous cancer is thought to arise from the fallopian tube fimbriae ; thus, sWe also found an increasing trend in clear cell cancer incidence for all racial/ethnic groups, especially among Asian/Pacific Islanders. This may also be explained by improvement in the diagnosis of this histotype. There was a pattern of shifting away from classifying tumors as “carcinoma, not otherwise specified” (NOS) to clear cell carcinoma in all racial/ethnic groups, but most striking in Asian/Pacific Islanders. Using SEER-12 registry data, we found that during 1992–2019, the proportion of NOS among Asian/Pacific Islanders decreased from 20% to 11%, while the proportion of clear cell cancer increased by the same amount, from 9% to 18% . This paPrevious temporal trends in declining ovarian cancer incidence in the 1970s and 1980s were attributed to increasing parity and combined oral contraceptive use, both protective factors for all ovarian cancer histotypes. However, more recently, combined oral contraceptive use prevalence has decreased in non-Hispanic Black and Hispanic women and the fertility rate in all racial/ethnic groups has been decreasing. The impact of such decreases may differ by histotype as the magnitude of the associations for high-grade serous cancer is weaker than one for clear cell cancers (odds ratio (OR) for one birth vs. nulliparous: 0.89 and 0.39 for serous and clear cell cancer, respectively; OR for 2–4.99 years of combined oral contraceptive use vs. never use: 0.65 and 0.55 for serous and clear cell cancers, respectively; ref. Two additional interesting observations for birth cohort effects are the small but noticeable peak around birth cohorts 1950–1955 for clear cell cancer in all racial/ethnic groups and that the peak for high-grade serous cancer incidence is about 10 years later in non-Hispanic Black women compared with non-Hispanic White women. The peak in clear cell cancer incidence might partially be explained by the exposure to diethylstilbestrol (DES), a potent synthetic estrogen, which was given to pregnant women in the United States from the early 1940s through the 1960s for the prevention of spontaneous abortion and premature delivery . Use of There are some limitations of the study. First, the ecologic nature of the study does not allow for causal inferences. The SEER data do not contain information on risk factors for ovarian cancer. Second, U.S.-born and foreign-born women may have different cohort effects, but we could not examine the difference because the SEER registry removed the country of birth variable in recent submissions due to bias . Third, there might be a risk of misclassifying ovarian cancer histotypes across the registries. To minimize this risk, we conducted a sensitivity analysis including patients with advanced-stage serous cancer  with a missing grade as high-grade serous cases. Despite these limitations, the SEER data used in our study are the gold standard for cancer registration .In conclusion, this study provides the most current overview of ovarian cancer trends by histotype and race/ethnicity in the United States and examines the influence of period and birth cohort on the trends. We found that high-grade serous cancer incidence has decreased overall, while clear cell cancer incidence has increased. The differences in the trends by histotype and race/ethnicity can partially be explained by the variations in the prevalence of risk factors by year and cohort across race/ethnicity and their different effect magnitudes by histotype, as well as the changes in diagnostic classification. It is crucial to develop targeted preventive interventions to effectively reduce the burden of ovarian cancer and disparity by race/ethnicity. There is a need to continue monitoring the incidence trends of ovarian cancer, particularly clear cell cancer to understand whether the increase in incidence was due to changes in risk factor prevalence or the shift in histotype classification. In addition, it is important to keep monitoring the incidence trends of ovarian cancer by race/ethnicity to develop targeted prevention strategies.Supplementary Table ST1Supplementary Table 1 shows Registries included in SEER-12 and SEER-17Click here for additional data file.Supplementary Table ST2Supplementary Table 2 shows Akaike Information Criteria (AIC) for Age-Cohort models and Age-Period-Cohort models and their differences, SEER-12, 1992-2019Click here for additional data file.Supplementary Figure S1Supplementary Figure 1 shows the flow chart of case exclusion for analysis, SEER-12, 1992-2019Click here for additional data file.Supplementary Figure S2Supplementary Figure 2 shows age effects in the age-cohort models, SEER-12, 1992-2019Click here for additional data file.Supplementary Figure S3Supplementary Figure 3 shows period effects in the age-period models, SEER-12, 1992-2019Click here for additional data file.Supplementary Figure S4Supplementary Figure 4 shows age-standardized incidence rate  of high-grade serous ovarian cancer by race/ethnicity. The incidence in the left panel did not include high-grade endometrioid cancer. The incidence in the right panel included high-grade endometrioid cancer in high-grade serous cancer.Click here for additional data file.Supplementary Figure S5Supplementary Figure 5 shows the distribution of histotype by race/ethnicity, SEER-12, 1992-2019Click here for additional data file.


Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave.This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using  linear mixed-effect models and ANOVAs.p = 0.001), higher age , pre-existing asthma , and pre-existing kidney disease  were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home  but was not associated with length of stay in ICU  and hospital  or mortality  when adjusted for covariates.Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission .The online version contains supplementary material available at 10.1186/s13613-023-01201-1. Infection with the SARS-CoV-2 virus can lead to respiratory failure, requiring respiratory support and admission to an intensive care unit (ICU) . Due to With the SARS-CoV-2 pandemic starting in 2019, the number of patients with critical COVID-19 and severe acute respiratory syndrome increased rapidly . At the The present study aimed to determine the implementation of EM in critically ill COVID-19 patients during the first wave of the pandemic in ICUs worldwide. Second, the study explored the factors associated with the implementation of EM and the outcomes of critically ill COVID-19 patients who underwent mobilisation.An international steering committee was established in 2020 by the European Society of Intensive Care Medicine (ESICM) to determine the burden of the novel COVID-19 disease in ICUs worldwide. ICUs were invited to participate in an international, multicenter, observational study (ESCIM UNITE-COVID study). The methodology and data collection have been extensively described by Greco et al.  in the fData were collected from patients who met all of the following inclusion criteria: (1) age 18 years or older; (2) admission to an ICU or another area in the hospital under the care of the intensive care team on the day of the ICU’s highest number of COVID-19 patients between February 15th and May 15th 2020; and (3) confirmed SARS-CoV2 infection by polymerase chain reaction or equivalent. Patients with SARS-CoV-2 infection but without COVID-19 diagnosis were excluded. In keeping with the observational study design, no additional interventions or measurements were performed, and patient care was delivered to local standards.Patient data were extracted from medical records from the day of admission up to day 60 of the ICU stay. Patient data were collected in the individual centres and submitted to a secure data-sharing platform . The data were then curated according to the DAQCORD checklist; details were published previously . The curA priori, we selected relevant variables and cofactors for the analysis. To avoid any bias, we did not perform an imputation of missing data. Therefore, we excluded variables with more than 100 missing values to sustain an adequate number of observations. Control variables were then divided into: (1) demographics/admission data: sex, age, secondary comorbidities at admission (yes/no for each variable): chronic cardiac disease, chronic liver disease, history of hypertension, chronic neurological disease, chronic pulmonary disease, diabetes, asthma, malignant neoplasm, chronic kidney disease, immunosuppression, thromboembolic complications at admission, infection at admission, and country; (2) medications and supportive care during ICU stay at any point (yes/no for each variable) including antivirals, corticosteroids, antimalarial drugs, sedation, renal replacement therapy (RRT), inotropes/vasopressors, and tracheostomy.The primary outcome was the implementation of EM (yes/no) and influencing factors. EM included passive mobilisation, assisted-active mobilisation, and active mobilisation performed within 72 h after admission to the ICU, regardless of the duration , 28. PasStatistical analyses were done in R [version R 4.1.1. (2021-08-10)]. Descriptive statistics: categorical variables are expressed as frequencies (percentages), and continuous variables are described with median and interquartile ranges. Significance testing for group differences was done with Chi-square tests for categorical data and Wilcoxon signed-rank test for continuous data using the tableone-package  and baseFor primary analysis with EM as outcome, we only considered the effect of demographics, comorbidities and admission data; medication and supportive care received during the stay could have been received before or after the initiation of mobilisation since we did not record the exact dates and time of these interventions in our dataset. Therefore, we did not include them in the primary analysis. However, to present a comprehensive picture, we performed an association analysis comparing treatment differences and EM status.p-value to account for heterogeneity and differences in sample sizes between countries.The analysis considered guidelines identified through a systematic review by Lang et al.  and a liA nominal alpha level of 0.05 was considered statistically significant.In total, data from 4190 critically ill patients with COVID-19 admitted to 280 ICUs in 45 countries were analysed after excluding patients with missing mobilisation data (EM yes/no) or with secondary ICU admission to capture EM accurately , age , pre-existing asthma  and pre-existing kidney disease . The variable positively associated with the initiation of EM was cardiac disease . There were differences in the type of supportive care and medications received during ICU admission when comparing patients receiving EM to those not receiving EM  for critical care had significantly higher EM rates than countries without . Countries' EM rates are visualised in Additional file Variables present at admission that were associated with lower odds of initiating EM  or hospital  when adjusted for covariates  when adjusted for covariates. Patients who received EM were more likely to be discharged home than those not receiving EM  and less likely to be discharged to another care facility . In Fig. There was no significant difference in mortality between patients receiving EM and those not receiving EM  and pub-med search). Table S6. Variables with the count of missing data and included observations in the analysis of the 60 day outcomes.


Growing evidence has suggested that parental mental illness and child internalizing and externalizing problems tend to co-occur and engender risk for adverse child outcomes; however, there is considerable heterogeneity in their joint developmental trajectories. This study aimed to evaluate the joint developmental trajectories of maternal and paternal psychological distress and child internalizing and externalizing problems from early childhood to middle adolescence. Given that suicide and self-harm are major public health issues in adolescence and often occur in the context of other mental health issues, we also examined the association between these joint trajectories and these outcomes in adolescence. Parallel-process latent class growth analysis was applied to 14 years of follow-up data from a large-scale, nationally representative sample of youths participating in the UK’s Millennium Cohort Study . Results showed the best-fitting solution had four trajectory classes: (1) low symptoms, 59.0%; (2) moderate symptoms in children, 22.5%; (3) notable symptoms in fathers, 10.7%; and (4) co-occurring maternal and child symptoms, 7.8%. The trajectory groups differed in their self-harm and suicide attempts in adolescence, underscoring the possible importance of the roles of both parental distress and child problem behaviors processes in these outcomes. Future studies will be valuable to rigorously test the directionality and the respective roles of parents and children in this association. Our findings suggest the need for two-generation mental health intervention programs that are tailored based on co-developmental trajectory group membership.The online version contains supplementary material available at 10.1007/s10802-023-01034-3. Children of parents with psychological distress are often at a heightened risk of internalizing and/or externalizing problems in childhood and adolescence , ample evidence has also indicated the substantial between-family heterogeneity in the (co-)development of youth internalizing and externalizing problems. Identified trajectory groups have included, for example, pure and co-occurring internalizing and/or externalizing problems at high or moderate levels (or with some changes when transitioning to adolescence) and low symptoms  maternal or paternal symptoms trajectory groups  and self-harm . It should be noted that there is some debate in the literature regarding self-harm measurement, with many examining suicidal and non-suicidal self-harm  separately, and others questioning the reliability of measuring a person’s intent during self-harm, particularly in adolescent populations  is a valuable technique for these types of explorations, i.e., examining co-developmental patterns of parent and child mental health issues. This is because it facilitates the inclusion of multiple variables in a single model to examine their co-changes and takes into account the heterogeneity of individual development by summarizing them in terms of a small number of trajectory subgroups. Previous studies have shown the value of parallel-process LCGA and closely related techniques for shedding light on how the co-development of multiple different variables impact on different outcomes. For example, research has indicated that youth with co-occurring internalizing and externalizing problems persisting from childhood and/or adolescence displayed more delinquency, social exclusion , using a nationally representative sample. This study also evaluated how co-developmental trajectory groups are associated with lifetime suicide attempts (reported at age 17) and past-year self-harm  in adolescence. This study hypothesized that trajectory classes with  high levels of maternal and/or paternal psychological distress would be accompanied by elevated levels of internalizing and/or externalizing problems in their children from early childhood to adolescence, which would be associated with greater adolescent suicide attempts and self-harm.www.cls.ioe.ac.uk/mcs. The current study included data on children aged 3, 5, 7, 11, 14, and 17 years , because variables of interest were collected at these ages. The analytic sample for the current study was determined by meeting the following two conditions: (1) Data on the mother  in a household were provided by a single person across Sweeps 2–6Participants were from the MCS, an ongoing nationally representative cohort study of children born in 2000–2002 in the UK. The latest Sweep was collected when children were approximately 17 years of age , with 18,522, 15,590, 15,246, 13,857, 13,287, 11,714, and 10, 625 productive families participating in Sweeps 1–7, respectively. Details of this cohort study design, variables, and demographic information can be found at: Of the total 12,520 mothers and fathers, 99.7% were biological mothers, 92.5% were biological fathers (see online Supplementary Tables S2 and S3 for parents’ characteristics).not true”) to 2 (“certainly true”). Parent reports of youth problem behaviors were used because youth reports are not available until age 17. Following recommended practice for population-based samples  in the current analytic sample cross Sweeps 2–6.Maternal and paternal psychological distress were both assessed by the 6-item Kessler Psychological Distress Scale . At age 17, self-harm was assessed by the item “during the last year, have you hurt yourself on purpose in any of the following ways?” and providing a checklist of six self-harm behaviors . At age 17, youth also self-reported their lifetime history of suicide attempts in response to the yes-or-no question, “Have you ever hurt yourself on purpose in an attempt to end your life?” These single-item assessments of suicide attempts or self-harm have been widely used in large population-based surveys  but differs from it in disallowing within-group variation in trajectories. It is sometimes necessary to constrain within-group variation to zero to facilitate estimation, especially for more complex models. Given that our models combine the developmental trajectories of multiple variables and were fit for the purpose of summarizing sets of trajectories to facilitate new insights, we opted for an LCGA approach. The main implication of this choice is that it is likely that more trajectory groups emerge than would using a GMM approach. Models with one to eight latent classes (models with linear only and both linear and quadratic growth) were evaluated, both considering the exploratory nature of this study and model parsimony.All models were fit using Mplus, with robust maximum likelihood (MLR) estimation. In using MLR, missing data were handled using full information maximum likelihood (FIML) estimation that provides unbiased parameter estimates when data are missing at random (MAR) in Rubin’s  terms  the Akaike’s Information Criterion (AIC), Bayesian Information Criterion (BIC), and sample size adjusted BIC (SaBIC), with lower values indicating better fit, (3) adequate classification diagnostics (entropy).Several criteria were used to select an optimal model: (1) the Lo-Mendall-Rubin (LMR) testing whether the superiority of a k-class trajectory model is against a k-1 class trajectory model, with a significant Having identified an optimal model, we used the automatic Bolck-Croon-Hagenaars procedures , but the effect sizes were modest (r = .02-0.17).https://osf.io/q36gp/files/ Growth parameters for the four-class model are provided in online Supplementary Table S7 and visualized in Fig. Fit statistics for the joint trajectory models are provided in online Supplementary Table S6. The four-class model with both linear and quadratic growth was identified as the optimal model based on the fact that LMR-test indicated that the four-class linear and quadratic growth model was better than its three-class counterpart; it has lower AIC, BIC, and SaBIC values than other solutions suggested by the LMR test; and in models with more than six trajectories, the number of participants in some classes was very low. Entropy values were consistently above 0.80, indicating high classification accuracy. Full output for all models is provided at: The first trajectory class (59.0% of the sample) was characterized by initially very low and slightly fluctuating maternal and paternal distress and child internalizing problems, and initially moderate-low and decreasing child externalizing problems; thus, it was labeled “low symptoms”. The second class (22.5%) showed initially moderate and increasing child internalizing problems, initially moderate-high and decreasing child externalizing problems, initially moderate-low and increasing maternal distress, and initially low and slightly increasing paternal distress, and was, therefore, labeled “moderate symptoms in children”. The third class (10.7%) was characterized by initially relatively high and increasing, then slightly decreasing paternal distress, initially moderate/moderate-low and increasing maternal distress/child internalizing problems, and initially moderate and decreasing child externalizing problems, which was, thus, labeled “notable symptoms in fathers”. The fourth class (7.8%) showed initially high and slightly increasing maternal distress, initially high-moderate and increasing child internalizing problems, initially high and decreasing child externalizing problems, and initially moderate and increasing paternal distress. This class was, therefore, labeled “co-occurring maternal and child symptoms”. Taken together, even though the mean levels at each age and across each class vary, trajectories of change over time for each type of symptom/reporter/target were fairly consistent.Table Youth in the group of co-occurring maternal and child symptoms were more likely to engage in self-harm at age 14 and lifetime suicide attempts (reported at age 17) than those in the other three groups identified in this study, and they also reported more self-harm at age 17 than children in the low symptoms group. Youth in the class of moderate symptoms in children had a higher likelihood of self-harm at age 14, compared to the class of notable symptoms in fathers  and low symptoms, and at age 17, they reported more past-year self-harm and lifetime suicide attempts than those in the low symptoms group. Youth in the trajectory of notable symptoms in fathers showed greater self-harm at age 17 and lifetime suicide attempts than youth in the low symptoms group.Supplementary exploratory analyses were conducted to provide additional information into the findings, including sex-stratified analyses; the relation between demographic factors and trajectory class membership; the results adjusted for stratification, clustering, and weighting; and the analyses limited to biological parents .This study examined the longitudinal patterns of co-developing parental psychological distress and child internalizing and externalizing difficulties during children’s childhood and adolescence , using a parallel process LCGA and over 14 years of follow-up data. It also investigated how the identified groups differed in adolescents’ outcomes of suicide attempts and self-harm. Results suggested a four-class solution fitted the data best, and these classes differed in their risk of self-harm and suicide attempts.Reflecting the normative nature of the sample, the biggest group were not substantially affected by parental or child mental health issues. A small group of families with both mother and child displaying salient and developmentally persistent symptoms (7.8%) was also identified. The presence of this group implies that it is beneficial to consider mothers and children together as a subtype for routine screening and targeted intervention that specifically addresses this interaction. Several mechanisms may explain the co-occurrence between maternal distress and child mental health problems. For instance, maternal distress may put children at the risk of developing problem behaviors due to genetic transmission or chronic exposure to negative emotions  whose children only displayed moderate-low or moderate levels of internalizing and externalizing problems. This finding, along with the lack of a trajectory class with both high levels of distress in fathers and internalizing or externalizing problems in children, was in line with previous evidence that the association between paternal mental illness and child difficulties is of small magnitude  for mental health issues if a child or adolescent exhibits emotional or/and behavioral problems. Based on the finding on the co-occurring group, screening and treating both parents’ and children’s mental health issues is not only important for the outcomes of youth suicidality and self-harm but also for youth and parent psychopathology. Existing evidence has suggested that treating only parental psychopathology can benefit the untreated offspring  has been widely used and has generally demonstrated good psychometric properties, the Cronbach’s αs for the SDQ was low in the MCS study. Fourth, a parallel-process LCGA was applied to analyze the data. Although such analysis can reduce the computational burden , maternal psychological distress and children’s internalizing and externalizing problems persisted concurrently from early childhood to middle adolescence. More than 20% of children displayed moderate internalizing and externalizing behaviors, but their parents did not show mental health issues. Youth in problematic trajectory groups  reported a higher risk of engaging in self-harm and lifetime suicide attempts in adolescence. Together, these findings suggest that two-generation mental health intervention programs could be tailored based on the groups identified in the current study. They indicate that improving the mental health issues of both parents  and children during the offspring’s early developmental stage  may be particularly effective in reducing children’s risk of developing suicidality and self-harm in adolescence.Below is the link to the electronic supplementary material.Supplementary Material 1


Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC. Lung cancer is the leading cause of cancer deaths in the world . Non-smaDifferent preoperative strategies with neoadjuvant therapies have been explored with the aims to downstage the tumor before surgery, allow the use of minimally invasive surgery, inhibit the early development of micro-metastases, thus reducing the incidence of systemic relapse, and improve patients’ survival. These approaches have been associated with limited efficacy. The phase III North American Intergroup 0139 trial evaluated the impact of surgery in 396 patients with T1-3 N2 disease who received radiotherapy up to 45 Gy, concurrent with two cycles of cisplatin and etoposide [The current review provides an overview of the rationale for the design of clinical trials exploring the efficacy of immune checkpoint inhibitors (ICIs) in the neoadjuvant and adjuvant settings.in vivo radiological and adaptive responses of tumors to systemic therapy. As a consequence, it can be potentially used to identify prognostic and predictive factors to tailor subsequent adjuvant treatment strategies [Preoperative treatment offers the opportunity to study rategies .p < 0.05). The greatest number of tumor-infiltrating lymphocytes (TILs) and highest CD8+ TIL density found in resected primary tumors from mice receiving neoadjuvant ICIs represent the immunological bases for the major benefit observed with neoadjuvant strategies [Preclinical data from syngeneic mice models of NSCLC showed that the administration of three doses of neoadjuvant nivolumab or ipilimumab + nivolumab significantly prolonged survival over three doses of adjuvant nivolumab or ipilimumab + nivolumab . Among the enrolled patients, ten carried EGFR-activating mutations and six carried EML4-ALK translocations. No radiological response or MPR was registered. Lesser pathologic responses were identified in patients harboring STK11 mutations compared with wild-type. Encouraging 3-year disease-free survival (DFS) and OS of 72% and 80%, respectively, were reported. A significant expansion of peripheral blood-activated CD8+ T cells was observed in patients obtaining tumor regression.Similar findings were observed in the phase II LCMC3 trial , which iThe phase II IFCT-IONESCO study was designed to evaluate the feasibility of the anti-PD-L1 agent durvalumab as a neoadjuvant therapy in 46 resectable patients with stage IB-IIIA NSCLC . The priThe phase II NEOMUN study explored the safety of two cycles of another monoclonal antibody targeting PD-1, pembrolizumab, when administered as a neoadjuvant treatment in resectable NSCLC patients with stage IIA-IIIA cancers . Co-primAll these data indicate that treatment with ICIs in the neoadjuvant setting is associated with a high percentage of resection rates, a good safety profile and a significant probability of prolonging patients’ survival. Data from the literature indicate that intratumoral immune cell infiltration, as a consequence of the treatment with ICIs, is associated with pseudo-progression in approximately 0.6–5.8% of patients with NSCLC ,15. NodaIn order to improve the efficacy of ICIs as a therapeutic strategy in the neoadjuvant setting, different combinatorial treatments have been evaluated, including concurrent chemotherapy and immunotherapy or the combination of dual ICIs.NEOSTAR was a phase II trial comparing the efficacy of nivolumab to nivolumab + ipilimumab in 44 resectable NSCLC patients with stage IA-IIIA cancers . NivolumWith the aim to increase the percentage of complete pathologic responses and allow curative resection in a higher proportion of patients with stage IIIA NSCLC, the efficacy of ICIs with platinum-doublet chemotherapy was evaluated. The open-label, multicenter, single-arm, phase II NADIM study tested the activity of carboplatin and paclitaxel combined with nivolumab, administered for three cycles, in 46 patients with stage IIIA, resectable NSCLC . FollowiAnother open-label, multicenter, single-arm, phase II study investigated the efficacy of atezolizumab in combination with carboplatin nab-paclitaxel in 30 patients with resectable stage IB-IIIA NSCLC . Non-smop = 0.005)). At 1 and 2 years, the estimated percentage of patients surviving without disease progression or disease recurrence was 76.1% and 63.8% with nivolumab plus chemotherapy and 63.4% and 45.3% with chemotherapy alone. The EFS benefit with nivolumab plus chemotherapy was maintained after adjustment for adjuvant therapy, which was administered in 11.9% of the patients in the nivolumab plus chemotherapy group and 22.2% of those in the chemotherapy alone group. Of note, EFS across most key prespecified subgroups favored nivolumab and chemotherapy. However, the magnitude of benefit was greater in the subgroup of patients with stage IIIA NSCLC, in those with PD-L1 ≥ 1% and in those with non-squamous histology. The percentage of patients with a pCR was 24.0% with nivolumab plus chemotherapy and 2.2% with chemotherapy alone (p < 0.001). Significantly higher MPR were observed in the nivolumab plus chemotherapy arm over chemotherapy (36.9% versus 8.9%). The benefit of the combination arm on pathological response was observed regardless of PD-L1 expression. At the first prespecified interim analysis, OS data were not mature. Of note, the addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of AEs or impede the feasibility of surgery. Interestingly, in an exploratory analysis, EFS was longer in patients with a pCR than in those without, suggesting a promising role of pCR as an early indicator of therapeutic efficacy in resectable NSCLC. Additionally, the depth of pathological regression appeared to be predictive of improved EFS in the nivolumab and chemotherapy group [These findings were confirmed in the randomized, phase III CheckMate 816 study, which was designed to demonstrate the major efficacy of three cycles of chemotherapy plus nivolumab over chemotherapy alone in patients with resectable stage IB-IIIA NSCLC . PatientAn overview of the main phase II and phase III clinical trials exploring the efficacy of ICIs in the neoadjuvant setting is shown in www.ema.europa.eu, accessed on 3 January 2023).For more than 20 years, platinum-doublet chemotherapy has represented the standard treatment in the adjuvant setting, with unsatisfactory results in terms of OS. Based on positive efficacy results with the use of ICIs in the metastatic setting, these agents have been tested in the curative setting in order to improve clinical outcomes. Results from the phase III IMpower-010 trial demonstrated the efficacy of the use of ICIs as an adjuvant strategy in resected NSCLC patients. This multicenter, open-label trial randomized 1005 patients with stage 1B (tumors ≥ 4 cm) to IIIA NSCLC between atezolizumab, administered for one year, or best supportive care (BSC), following one to four cycles of platinum-doublet chemotherapy . This stSimilar results were found in the phase III PEARLS/KEYNOTE-091, which was designed to evaluate the efficacy of pembrolizumab in completely resected, pathologically confirmed stage IB (tumors of ≥4 cm in diameter), II or IIIA NSCLC. Conversely to IMpower-010, adjuvant chemotherapy was not mandatory, but to be considered for stage IB and strongly recommended for stage II and IIIA NSCLC. Overall, 1177 patients, stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression and geographical region, were randomized to receive pembrolizumab or placebo for up to 18 cycles. Co-primary endpoints were DFS in the overall population and in the population with PD-L1 ≥ 50%. Pembrolizumab significantly prolonged DFS in the overall population. Results from the subgroup with PD-L1 ≥ 50% are still not mature . An overview of the clinical trials exploring the efficacy of ICIs in the adjuvant setting is shown in www.clinicaltrials.gov, accessed on 10 March 2023).In addition, there are several ongoing clinical trials evaluating the role of adjuvant immunotherapy in patients undergoing surgery for earlier-stage NSCLC. Among these, the phase II BTCRC-LUN18-153 trial (NCT04317534) was designed to evaluate whether administering pembrolizumab once every four weeks following surgical resection for up to nine cycles improves DFS compared to observation following surgical resection in patients with primary tumors measuring less than 4 cm (stage I) .There are also some studies that are evaluating the association between immunotherapy and stereotactic body radiotherapy (SBRT) in early-stage NSCLC patients. In the phase III trial Keynote-867 (NCT03924869), approximately 530 patients with stage I/II NSCLC are randomized 1:1 to receive SBRT and either pembrolizumab 200 mg or placebo every 3 weeks for 17 cycles (approximately 1 year) until disease recurrence or development of unacceptable toxicity. The primary endpoints are EFS by blinded indipendent central review (BICR) and OS, and the study is still ongoing. The ongoing phase III trial PACIFIC-4 RTOG 3515 (NCT03833154) has been designed to assess the efficacy and safety of durvalumab with SBRT versus placebo with SBRT in patients with unresected clinical stage I/II lymph node-negative (T1 to T3N0M0) NSCLC. The primary endpoint is PFS; other endpoints include OS and safety. Another ongoing phase III study, SWOG/NRG S1914 (NCT04214262), is evaluating the association of SBRT with atezolizumab in patients with T1-3N0M0 NSCLC who are medically inoperable or decline surgery. Patients are randomized 1:1 to standard-of-care SBRT or to neo-adjuvant, concurrent and adjuvant atezolizumab 1200 mg IV Q3 weekly with SBRT initiated with cycle 3. The primary endpoint is OS, secondary endpoints are PFS and safety . The molecular and immunological bases responsible for sensitivity or resistance remain to be fully determined; however, emerging biomarkers have been described. In order to identify molecular markers for patient selection, tumor samples from patients enrolled in the NADIM study were analyzed . ResultsMoreover, in the NADIM trial, baseline circulating tumor DNA (ctDNA) levels were significantly associated with tumor size. Patients characterized by ctDNA levels < 1% mutant allele fraction (MAF) at baseline showed significantly improved PFS and OS compared to patients with increased ctDNA levels. In addition, further improvements in PFS and OS were found in patients with undetectable ctDNA after neoadjuvant treatment . LikewisThese data suggest the use of blood-based biomarkers to identify those patients who could benefit more from neoadjuvant chemoimmunotherapy. Further studies are needed to confirm these findings.ICIs have been demonstrated to play a meaningful role in resectable patients with NSCLC. Data from preclinical studies demonstrated the major efficacy of ICI therapy in the prolongation of OS when administered in the neoadjuvant compared with adjuvant setting due to the higher probability of inducing peripheral tumor-specific immune responses. Indeed, neoadjuvant immunotherapy provides an effective strategy to early treat micrometastatic disease and enhances the immune response when bulk tumor and tumor antigens are still present during treatment. Results from phase II and phase III clinical trials have shown that immunotherapy or chemo-immunotherapy or dual ICIs significantly improve the percentage of pCR and MPR. It is important to underline that, across all studies, there was high heterogeneity in the selection of primary endpoints, which included EFS, DFS or PFS. However, the pathologic assessment of response has been incorporated into all the trials, since it can be considered a surrogate endpoint of survival benefit, as previously demonstrated in different studies, including CheckMate 816 . Indeed,Open questions remain about the scoring approaches to be used in the clinical practice for pathological response assessments to neoadjuvant immunotherapy in NSCLC, the optimal duration of neoadjuvant/adjuvant therapy, the role of adjuvant treatment following neoadjuvant strategies, the identification of plasma or tissue biomarkers to select those patients who could benefit more from ICIs and the efficacy of targeting PD-1 or PD-L1 in patients carrying targetable molecular alterations, including EGFR mutations, HER2 mutations and EML4-ALK, ROS1, NTRK or RET rearrangements. There is a need to define a diagnostic methodology that would yield reproducible information of clinical value. In patients with metastatic NSLC, PD-L1 still represents the only validated biomarker used to select immunotherapy. Discordant results on the role of PD-L1 expression have been found in trials with ICIs in the early stages of disease. In some cases, the efficacy was independent of PD-L1 status , while iFinally, novel strategies to monitor tumor recurrence are required. Circulating tumor DNA (ctDNA) has been extensively used in metastatic patients, and recently its prognostic and predictive value has been evaluated in the early stages. Its quantification might indicate a non-response to neoadjuvant therapy or its presence might be the signal of an early recurrence. This could be particularly useful in cases developing nodal immune flare, in order to distinguish pseudo-progression from progression.


Proton Pump Inhibitors (PPI) are among the most commonly used drugs to treat acid-related gastrointestinal disorders in the USA. Although PPI use has been linked to acute interstitial nephritis, the side effects of post-hospitalization acute kidney injury (AKI) and the progression of kidney disease still are controversial. We conducted a matched cohort study to examine the associations between PPI use and the side effects, especially in post-hospitalization AKI.We investigated 340 participants from the multicenter, prospective, matched-cohort ASSESS-AKI study, which enrolled participants from December 2009 to February 2015. After the baseline index hospitalization, follow-up visits were conducted every six months, and included a collection of self-reported PPI use by participants. Post-hospitalization AKI was defined as the percentage increase from the nadir to peak inpatient SCr value was ≥ 50% and/or absolute increase ≥ 0.3 mg/dL in peak inpatient serum creatinine compared with baseline outpatient serum creatinine. We applied a zero-inflated negative binomial regression model to test the relationship between PPI use and post-hospitalization AKI. Stratified Cox proportional hazards regression models also were conducted to examine the association between PPI use and the risk of progression of kidney disease.After controlling for demographic variables, baseline co-morbidities and drug use histories, there was no statistically significant association between PPI use and risk of post-hospitalization AKI . Stratified by AKI status at baseline, no significant relationships were confirmed between PPI use and the risk of recurrent AKI  or incidence of AKI . Similar non-significant results also were observed in the association between PPI use and the risk of progression of kidney diseases .PPI use after the index hospitalization was not a significant risk factor for post-hospitalization AKI and progression of kidney diseases, regardless of the AKI status of participants at baseline.The online version contains supplementary material available at 10.1186/s12882-023-03211-4. Acute kidney injury (AKI) is a significant complication for hospitalized patients and is related to severe short-term and long-term mortality and morbidity, including increased risk of death, progression of kidney disease, and heart failure , 2. PostProton pump inhibitors (PPI) are widely used for acid suppression therapy in the USA, with over 15 million adults using PPI every year . PPIs arPrevious epidemiological studies investigating the relationship between PPI use and AKI mainly were based on retrospective cohort analyses of data collected as part of routine clinical care . These sThe Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI) is a prospective cohort study of participants with and without an episode of AKI, who attended a baseline study visit 3 months after the index hospitalization , 17. ParFor this analysis, we matched participants with history of PPI use to participants without PPI use during the follow-up period Fig. . The exaInstitutional review boards at the participating centers  approved the ASSESS-AKI study, and all methods were conducted in accordance with relevant guidelines and regulations.Participants were identified as PPI users if they met both of two criteria: 1) participant’s self-reported or medical-recorded use of PPI  in peak inpatient serum creatinine compared with baseline outpatient serum creatinine. For two consecutive episodes of AKI to be considered distinct episodes, they have to meet criteria for non-AKI  between episodes. Meanwhile, two consecutive episodes should be separated by at least 30 days .We defined the incidence of AKI when participants without AKI at baseline were diagnosed with AKI during the follow-up period. Recurrent AKI was defined as participants with AKI at baseline who were diagnosed as AKI at least once during the follow-up period.Progression of kidney disease was included in this study as a secondary outcome. Progression of kidney disease was defined as the occurrence of ESKD  or halving of eGFR since the time of the baseline study visit .Demographic information and comorbidities were collected at the baseline study visit by participants’ self-report. All SCr results were performed using an isotope dilution mass spectrometry–traceable assay. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimating equation . Drug usWe performed a simulation study to assess the effect size that can be detected with 80% empirical power . UtiliziFor the 340 participants in this cohort study (68 PPI users and 272 PPI non-users), we summarized baseline participant characteristics across PPI users and non-users groups, with mean (SD) values for continuous variables, number and percentage for categorical variables.For the primary analysis, after examining the hyper-Poisson variability of AKI counts (mean [SD] counts 0.71 2.15]) and the dispersion statistic ((Pearson statistic)/(degree of freedom) = 1.66), an overdispersion of AKI counts was confirmed and negative binomial regression model would be an appropriate method . Zero-in.15) and After confirming no violations of the proportional hazards assumption, Cox proportional hazards regression models were conducted to examine the association between PPI use and the risk of progression of kidney disease, stratified by the matched covariates. For progression of kidney disease, participants were right-censored for death, loss to follow-up, or end of the study, whichever came first.We performed four distinct sensitivity analyses to evaluate the robustness of our findings under various scenarios.Scenario 1: Sensitivity analyses were performed by including covariates into the regression models, conducting multivariable ZINB regression analysis for post-hospitalization AKI, and multivariable Cox-proportional hazards regression analysis for progression of kidney disease.Scenario 2: Comorbidities were considered as time-dependent covariates, and we aimed to evaluate the impact of newly developed comorbidities during the follow-up period on the hazard ratios (HR). In this context, post-hospitalization AKI was analyzed as time-to-event data, and a multivariable stratified Cox proportional hazards regression model was employed to examine the HR associated with PPI use and AKI. Concurrently, diabetes, cardiovascular disease, and hypertension were incorporated into the regression model as time-dependent variables .Scenario 3: We matched six drug use histories, although there were additional medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, vasopressors, immunosuppressants, corticosteroids, and chemotherapeutics, that might influence the relationship between PPI use and AKI. To ensure optimal matching outcomes, we excluded these medications during the matching process. However, we were able to incorporate these drug use histories into the multivariable ZINB regression model.Scenario 4: For individuals who developed AKI 6 months after discontinuing PPI use, we excluded these PPI users (N = 3) and their four matched pairs (N = 12) from our regression analysis.We used R software version 3.6.2  for the power simulation and matching process, and SAS software  for further analyses with a two-tailed alpha level of 0.05.(Table 1).The cohort of 340 eligible participants included 68 who used PPI and 272 who did not use PPI during the follow-up periods, with a median follow-up of 4.9 years . Before matching, there were imbalanced distributions within the ASSESS-AKI data set (68 PPI users and 1470 PPI non-users) with respect to center (SMD = 0.316), gender (SMD = 0.109), race (SMD = 0.346), age (SMD = 0.273), hypertension (SMD = 0.159), diuretics use (SMD = 0.218) and insulin use (SMD = 0.147). After matching, the SMD of all these covariates became less than 0.1, indicating well-balanced distributions of each variable across 68 PPI users and 272 PPI non-users We assessed the median duration from cohort start, expressed in months, until the onset of post-hospitalization AKI for the study participants Table . The ove(Table 2).After controlling for demographic variables, baseline co-morbidities and drug use histories, there was no statistically significant association between PPI use and risk of post-hospitalization AKI . Stratified by AKI status at baseline, no significant relationships were confirmed between PPI use and the risk of recurrent AKI  or incidence of AKI  (Table 2).After controlling for demographic variables, baseline co-morbidities and drug use histories, there was no statistically significant association between PPI use and risk of kidney disease progression . Similar non-significant results also were observed in participants with AKI at baseline  and participants without AKI at baseline  Throughout the 10,000 simulation iterations, approximately 8,000 of the simulated data sets resulted in statistically significant rate ratios (P < 0.05). At this point, we achieved 80% empirical power. With 68 participants in the exposure group and 272 participants in the matched control group, we determined the detectable effect size (rate ratio) to be 1.40 in our study.Sensitivity analyses were conducted across four scenarios, and the outcomes consistently aligned with our primary findings , including the risk of recurrent AKI  and incidence of AKI . Our results are consistent with a recent self-controlled case series study. After controlling for drug use history and demographic information, PPI was not a risk factor for the incidence of AKI (adjusted rate ratio (aRR), 0.82; 95% CI, 0.60 to 1.13), with 3,685 participants .However, some previous retrospective cohort studies have shown that PPI use leads to the incidence of AKI based on retrospective data analysis , 27–29. In contrast to previous retrospective studies, we attribute the differences in our study’s results to several distinct perspectives, which also represent the novelty of our investigation. First, our study has strengths in study design, since we executed a systematically organized prospective cohort study with a structured research protocol, reducing ascertainment bias and minimizing the level of missing data. A valid estimation of AKI was conducted with longitudinal measurement of SCr to define the counts of recurrent AKI, instead of the classification code of disease. Additionally, we performed four sensitivity analyses to assess the robustness of our findings under various scenarios, including alternative statistical methods, the inclusion of three time-dependent covariates, the addition of six more medication use histories, and the exclusion of individuals with a long gap between PPI use and the onset of post-hospitalization AKI. The conclusions drawn from these four scenarios remained consistent with our primary analysis. To the best of our knowledge, our study is the first to examine the effect of time-dependent covariates on the relationship between PPI use and post-hospitalization AKI. The status of comorbidities can change over time; however, previous studies have only adjusted or matched for baseline covariates , 27–29. Second, we performed a mixed matching strategy to guarantee balanced distributions of covariates across the PPI use and non-use group. Besides demographic information and comorbidities, other drug use histories also are included as covariates of the propensity score matching strategy. Current studies found that ACE inhibitors , angioteThird, our study is the first one to analyze AKI as a count outcome to measure recurrent times, instead of a binary or time-to-event outcome as in previous studies. We believe we performed an appropriate estimation of the risk of recurrent AKI and our analysis is the first to use the ZINB regression model to measure the association between PPI use and the risk of recurrent AKI. We first tested the overdispersion of data to choose the negative binomial model instead of the Poisson model. Then, we expanded the negative binomial model to the ZINB model with “SAS PROC NLMIXED”  to estimIn our study, there was no statistically significant association between PPI use and risk of kidney disease progression, while most previous studies showed PPI as a significant harmful factor for kidney disease progression , 37. ParA clinical concern regarding our study is the possibility of insufficient PPI exposure, which could result in a non-significant impact on post-hospitalization AKI. Unlike retrospective studies, which can trace back to the initiation of PPI use, our prospective study can only capture the PPI use period after participant recruitment. We did not collect information as to when participants began using PPIs or their reasons for requiring PPIs. In our cohort, the median PPI exposure duration was 3.8 years . This exposure period is comparable to a previous study that reported 3.9 years  and demonstrated a significant HR of 2.89  for PPI use in relation to AKI events . TherefoOur study has several limitations. First, the relative small sample size in the PPI use group (N = 68) yields low statistical power . This paWith a prospective cohort study of 340 participants, after adjusting for demographic variables, baseline co-morbidities and drug use histories, PPI use after the index hospitalization was not a significant risk factor for post-hospitalization AKI and progression of kidney diseases, regardless of the AKI status of participants at baseline.Below is the link to the electronic supplementary material.Supplementary Material 1