Effectiveness of recombinant human FSH: recombinant human LH combination treatment versus recombinant human FSH alone for assisted reproductive technology in women aged 35-40 years.

RESEARCH QUESTION: According to real-world data, is recombinant human FSH (r-hFSH) combined with recombinant human LH (r-hLH) or r-hFSH alone more effective for women of advanced maternal age (AMA) in terms of live birth? DESIGN: Non-interventional study comparing the effectiveness of r-hFSH and recombinant r-hLH (2:1 ratio) versus r-hFSH alone for ovarian stimulation during ART treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register. RESULTS: Overall clinical pregnancy (29.8%, 95% CI 28.2 to 31.6 versus 27.8%, 95% CI 26.5 to 29.2) and live birth (20.3%, 95% CI 18.7 to 21.8 versus 18.0%, 95% CI 16.6 to 19.4) rates were not significantly different between the combined r-hFSH and r-hLH group and the r-hFSH alone group (P = 0.269 and P = 0.092, respectively). Treatment effect was significantly higher for combined r-hFSH and r-hLH compared with r-hFSH alone for clinical pregnancy (33.1%, 95% CI 31.0 to 35.0 versus 28.5%, 95% CI 26.6 to 30.4; P = 0.001, not adjusted for multiplicity) and live birth (22.5%, 95% CI 20.5 to 24.2 versus 19.4%, 95% CI 17.6 to 20.9; P = 0.014, not adjusted for multiplicity) in a post-hoc analysis of women with five to 14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of combined r-hFSH and r-hLH for ovarian stimulation in women aged 35-40 years with normal ovarian reserve. CONCLUSIONS: Women of AMA with normal ovarian response benefit from treatment with combined r-hFSH and r-hLH in a 2:1 ratio versus r-hFSH alone in terms of live birth rate. The effectiveness of treatments is best assessed by RCTs; however, real-world data are valuable for examining the effectiveness of fertility treatment, especially among patient groups that are not well represented in clinical trials.

Dosing Characteristics of Recombinant Human Luteinizing Hormone or Human Menopausal Gonadotrophin-Derived LH Activity in Patients Undergoing Ovarian Stimulation: A German Fertility Database Study.

OBJECTIVES: The aim of the study was to evaluate dosing of recombinant human luteinizing hormone (r-hLH) or human menopausal gonadotrophin (hMG)-derived medications with LH activity in ovarian stimulation (OS) cycles for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: A non-interventional study was performed to analyse data from the German RecDate database (January 2007-December 2011). PARTICIPANTS/MATERIALS, SETTING, METHODS: Starting/total r-hLH/hMG dose, OS duration/cycle number, r-hLH/hMG initiation day (first day of administration), and population/cycle characteristics were assessed in women (≥18 years) undergoing OS for IVF/ICSI using r-hLH or hMG-derived medications (excluding corifollitropin alfa, clomiphene citrate, letrozole, mini/micro-dose human chorionic gonadotrophin, and urofollitropin alone). Data were summarized descriptively. RESULTS: 67,858 identified cycles utilized medications containing r-hLH (10,749), hMG (56,432), or both (677). Mean (standard deviation) OS duration with r-hLH and hMG was 10.1 (4.43) and 9.8 (6.16) days, respectively. Median (25th-75th percentile) r-hLH starting dose (75.0 [75.0-150.0] IU) was consistent across patients regardless of age, infertility diagnosis, or gonadotrophin-releasing hormone (GnRH) protocol. Median (25th-75th percentile) hMG-derived LH activity starting dose was 225.0 (150.0-300.0) IU, regardless of GnRH protocol, but was lower in women aged <35 years and those with ovulation disorders/polycystic ovary syndrome. Median (25th-75th percentile) total dose for r-hLH (750.0 [337.5-1,125.0] IU) and hMG-derived LH activity (1,575.0 [750.0-2,625.0] IU) varied according to patients' age, infertility diagnosis, cycle number, and r-hLH/hMG initiation day. GnRH antagonist use resulted in a numerically higher median total hMG-derived LH activity dose than GnRH agonist use. LIMITATIONS: The data used in this study were taken from electronic medical records relating to a specific timeframe (2007-2011) and therefore may not accurately reflect current clinical practice; however, it is likely that the differences between the two compounds would be maintained. Additionally, secondary data sources may suffer from uniformity and quality issues. CONCLUSIONS: The standard of care for OS cycles is described with respect to IVF/ICSI treatment including an LH component in Germany during the specified timeframe.

Incidence of safety events after immune checkpoint inhibitor initiation for advanced-stage non-small-cell lung cancer: a real-world study.

Aim: To describe the incidence of safety events after immune checkpoint inhibitor (ICI) initiation for advanced-stage non-small-cell lung cancer. Methods: Retrospective cohort study using the HealthCore Integrated Research Database in the USA to examine the incidence of prespecified safety events of interest after ICI initiation (n = 5278). Results: The most common safety events after ICI initiation included malaise/fatigue (incidence rate [IR]: 70.7 per 100 person-years; 95% CI: 66.5-75.1) and nausea/vomiting (IR: 32.4; 30.0-34.8). Other potential immune-mediated events, including colitis (IR: 7.11; 6.26-8.04) and pneumonitis (IR: 5.47; 4.76-6.25), were less frequent but higher than after any systemic anti-cancer therapy. No safety event rate substantially increased 6 months after ICI initiation. Conclusion: This large real-world study reports the incidence of safety events with ICI regimens for advanced-stage non-small-cell lung cancer.

Researchers wanted to investigate side effects identified with advanced lung cancer during treatment, particularly immunotherapy. To investigate these side effects, researchers examined health insurance claims records from patients who were diagnosed with advanced lung cancer between January 2010 and July 2019, and who received treatment at various clinics across the USA. Researchers identified records for 44,045 patients treated for advanced lung cancer, with 5278 being treated with immunotherapy. After patients started immunotherapy, the most commonly reported side effects were tiredness and nausea/vomiting. Other side effects possibly related to immunotherapy were inflammation of the large intestine and lung inflammation ­ these events were not reported very often and did not increase in frequency 6 months after start of treatment. This large real-world study provides estimates for the frequency of side effects for those treated for advanced lung cancer, and finds that there were no large increases in the occurrence of any particular side effect in the 6 months after patients started immunotherapy for advanced lung cancer.

Comparative effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG HP) in assisted reproductive technology (ART) treatments: a non-interventional study in Germany.

BACKGROUND: This study compared the effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa; GONAL-f®) with urinary highly purified human menopausal gonadotropin (hMG HP; Menogon HP®), during assisted reproductive technology (ART) treatments in Germany. METHODS: Data were collected from 71 German fertility centres between 01 January 2007 and 31 December 2012, for women undergoing a first stimulation cycle of ART treatment with r-hFSH-alfa or hMG HP. Primary outcomes were live birth, ongoing pregnancy and clinical pregnancy, based on cumulative data (fresh and frozen-thawed embryo transfers), analysed per patient (pP), per complete cycle (pCC) and per first complete cycle (pFC). Secondary outcomes were pregnancy loss (analysed per clinical pregnancy), cancelled cycles (analysed pCC), total drug usage per oocyte retrieved and time-to-live birth (TTLB; per calendar week and per cycle). RESULTS: Twenty-eight thousand six hundred forty-one women initiated a first treatment cycle (r-hFSH-alfa: 17,725 [61.9%]; hMG HP: 10,916 [38.1%]). After adjustment for confounding variables, treatment with r-hFSH-alfa versus hMG HP was associated with a significantly higher probability of live birth (hazard ratio [HR]-pP [95% confidence interval (CI)]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; relative risk [RR]-pFC [95% CI]: 1.09 [1.05, 1.15], ongoing pregnancy (HR-pP [95% CI]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; RR-pFC [95% CI]: 1.10 [1.05, 1.15]) and clinical pregnancy (HR-pP [95% CI]: 1.10 [1.05, 1.14]; HR-pCC [95% CI]: 1.14 [1.10, 1.19]; RR-pFC [95% CI]: 1.10 [1.06, 1.14]). Women treated with r-hFSH-alfa versus hMG HP had no statistically significant difference in pregnancy loss (HR [95% CI]: 1.07 [0.98, 1.17], were less likely to have a cycle cancellation (HR [95% CI]: 0.91 [0.84, 0.99]) and had no statistically significant difference in TTLB when measured in weeks (HR [95% CI]: 1.02 [0.97, 1.07]; p = 0.548); however, r-hFSH-alfa was associated with a significantly shorter TTLB when measured in cycles versus hMG HP (HR [95% CI]: 1.07 [1.02, 1.13]; p = 0.003). There was an average of 47% less drug used per oocyte retrieved with r-hFSH-alfa versus hMG HP. CONCLUSIONS: This large (> 28,000 women), real-world study demonstrated significantly higher rates of cumulative live birth, cumulative ongoing pregnancy and cumulative clinical pregnancy with r-hFSH-alfa versus hMG HP.

The ENCePP Code of Conduct: A best practise for scientific independence and transparency in noninterventional postauthorisation studies.

PURPOSE: The ENCePP Code of Conduct provides a framework for scientifically independent and transparent pharmacoepidemiological research. Despite becoming a landmark reference, practical implementation of key provisions was still limited. The fourth revision defines scientific independence and clarifies uncertainties on the applicability to postauthorisation safety studies requested by regulators. To separate the influence of the funder from the investigator's scientific responsibility, the Code now requires that the lead investigator is not employed by the funding institution. METHOD: To assess how the revised Code fits the ecosystem of noninterventional pharmacoepidemiology research in Europe, we first mapped key recommendations of the revised Code against ISPE Good Pharmacoepidemiology Practices and the ADVANCE Code of Conduct. We surveyed stakeholders to understand perceptions on its value and practical applicability. Representatives from the different stakeholders' groups described their experience and expectations. RESULTS: Unmet needs in pharmacoepidemiological research are fulfilled by providing unique guidance on roles and responsibilities to support scientific independence. The principles of scientific independence and transparency are well understood and reinforce trust in study results; however, around 70% of survey respondents still found some provisions difficult to apply. Representatives from stakeholders' groups found the new version promising, although limitations still exist. CONCLUSION: By clarifying definitions and roles, the latest revision of the Code sets a new standard in the relationship between investigators and funders to support scientific independence of pharmacoepidemiological research. Disseminating and training on the provisions of the Code would help stakeholders to better understand its advantages and promote its adoption in noninterventional research.

Leveraging patient experience data to guide medicines development, regulation, access decisions and clinical care in the EU.

Patient experience data (PED), provided by patients/their carers without interpretation by clinicians, directly capture what matters more to patients on their medical condition, treatment and impact of healthcare. PED can be collected through different methodologies and these need to be robust and validated for its intended use. Medicine regulators are increasingly encouraging stakeholders to generate, collect and submit PED to support both scientific advice in development programs and regulatory decisions on the approval and use of these medicines. This article reviews the existing definitions and types of PED and demonstrate the potential for use in different settings of medicines' life cycle, focusing on Patient-Reported Outcomes (PRO) and Patient Preferences (PP). Furthermore, it addresses some challenges and opportunities, alluding to important regulatory guidance that has been published, methodological aspects and digitalization, highlighting the lack of guidance as a key hurdle to achieve more systematic inclusion of PED in regulatory submissions. In addition, the article discusses opportunities at European and global level that could be implemented to leverage PED use. New digital tools that allow patients to collect PED in real time could also contribute to these advances, but it is equally important not to overlook the challenges they entail. The numerous and relevant initiatives being developed by various stakeholders in this field, including regulators, show their confidence in PED's value and create an ideal moment to address challenges and consolidate PED use across medicines' life cycle.

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

Pharmacoepidemiology studies: what levels of evidence and how can they be reached?

In pharmacoepidemiology studies, the nature of the research question will dictate the choice of methodological approach and the conditions for optimizing the level of evidence. Thus, to document the treated population and the modes of use of a new drug in real-life prescribing conditions, a descriptive approach through cross-sectional or longitudinal studies conducted on databases, or else ad-hoc studies, will be preferred. On the other hand, evaluation of the real-life "effectiveness" of a new drug will be based on cohort, case-control or scientific modeling, depending on the drug and the disease of interest. For questions involving drug risks and safety, it is the adverse effects profile that will guide the choice of study design, both for identification of the effect (signal) and assessment of causation. In all cases, in the post-marketing authorization (MA) setting, the evidence acquired in pre-MA studies serves as the basis for generating hypotheses. Whatever the research question and the method chosen to address it, the potential biases and their impact on the results need to be identified. In certain cases, a combination of several complementary approaches may prove preferable to a single study.

Principles for Good Practice in the Conduct of Non-interventional Studies: The View of Industry Researchers.

This reflection paper presents a consolidated view of EFPIA on the need for principles for good practice in the generation and use of non-interventional studies (NIS), including overarching principles such as the registration of hypothesis evaluating treatment effect (HETE) studies. We first define NIS and the important adjacencies to clinical trials and relationship with real-world evidence (RWE). We then outline the principles for good practice with respect to appropriate research design, study protocol, fit-for-purpose variables and data quality, analytical methods, bias reduction, transparency in conduct and use, privacy management and ethics review. We conclude with recommendations for action for the research community to promote trust and credibility in the use of NIS.

Treatment effectiveness in a rare oncology indication: Lessons from an external control cohort study.

Real-world data (RWD) reflecting patient treatment in routine clinical practice can be used to develop external control groups for single-arm trials. External controls can provide valuable benchmark results on potential comparator drug effectiveness, particularly in rare indications when randomized controlled trials are either infeasible or unethical. This paper describes lessons learned from a descriptive real-world external control cohort study conducted to provide benchmark data for a single-arm clinical trial in a rare oncology biomarker driven disease. Conducting external control cohort studies to evaluate treatment effectiveness in rare indications likely will present data and analysis challenges as seen in the example study. However, there are mitigating measures that can be applied in the study design, identification of RWD sources, and data analysis. The lessons learned and reported here with a proposal of an external control study framework can provide guidance for future research in this area, and may be applicable as well in other rare indications. Taking these learnings into consideration, the use of real-world external controls to contextualize treatment effectiveness in rare indications is a valuable approach and warrants further application in the future.

Identifying Valid Algorithms for Number of Lines of Anti-Neoplastic Therapy in the Danish National Patient Registry Among Patients with Advanced Ovarian, Gastric, Renal Cell, Urothelial, and Non-Small Cell Lung Cancer Attending a Danish University Hospital.

PURPOSE: To develop algorithms to identify number of lines of anti-neoplastic therapy per patient based on the Danish National Patient Registry (DNPR) and identify which algorithm has the highest percentage agreement with a reference standard of documentation in medical records. PATIENTS AND METHODS: We included 179 patients diagnosed between January 1, 2012, and December 31, 2016, with stage II, III, or IV urothelial cell carcinoma or stage III or IV epithelial ovarian cancer, gastric adenocarcinoma, renal cell carcinoma, or non-small cell lung cancer (NSCLC). We developed two algorithms for number of lines of anti-neoplastic therapy based on dates and treatment codes (eg, "treatment with cisplatin" or "cytostatic treatment") in the DNPR. First, to denote a change in line of therapy the "Time-based algorithm" used the number of days between consecutive administrations. Second, the "Drug-based algorithm" used information on drug names if available or the number of days between consecutive administrations if no drug names were specified. We calculated the percentage agreement between the algorithms setting the number of allowed days between consecutive administrations from 28 to 50 and the reference standard - information on anti-neoplastic therapy drugs abstracted from medical records and subsequently coded according to lines of anti-neoplastic therapy. RESULTS: For the "Time-based algorithm", the highest percentage agreement with the reference standard was found when using <45 days between consecutive administrations (67.6%; 95% CI: 60.1-73.8%). However, the percentage agreement was higher for the "Drug-based algorithm" using <45 days between consecutive administrations for registrations where the drug name was unspecified (90.5%; 95% CI: 85.0-93.7%). CONCLUSION: The algorithm for number of lines of anti-neoplastic therapy that had the highest percentage agreement with the reference standard (medical records) incorporated both registration of specific drug names and <45 days between consecutive administrations if the drug name was unspecified in routinely recorded data from DNPR.

High-dose corticosteroid use and risk of hospitalization for infection in patients treated with immune checkpoint inhibitors--A nationwide register-based cohort study.

High-dose corticosteroids have been associated with increased risk of serious infection in patients with metastatic melanoma treated with immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4. This potential association needs to be examined further among patients with other cancer types and for other immune checkpoint inhibitors. We examined whether receipt of high-dose corticosteroids was associated with increased rates of hospitalization for infection among 981 Danish renal, urothelial, and lung cancer patients followed from first administration of programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors. Our cohort analysis was based on the information from national medical registries. During follow-up, 522 patients (53.2%) initiated treatment with high-dose corticosteroids and 317 patients (32.3%) experienced at least one hospitalization for infection. In analyses adjusted for age, sex, and previous use of chemotherapy/targeted therapy, initiation of high-dose systemic corticosteroids was associated with increased rate of hospitalization for infections (hazard ratio (HR) = 2.96, 95% confidence interval (CI) = 2.41-3.65) even in patients not receiving any chemotherapy/targeted therapy (HR = 3.66, 95% CI = 2.25-5.96). Our findings showed that high-dose corticosteroid initiation is associated with hospitalization for infection in patients treated with PD-1/PD-L1 immune checkpoint inhibitors. Clinicians and patients should be aware of this risk of infection when initiating treatment with high-dose corticosteroids.

Treatment and Survival in Advanced Non-Small Cell Lung Cancer, Urothelial, Ovarian, Gastric and Kidney Cancer: A Nationwide Comprehensive Evaluation.

PURPOSE: Few studies have described real-world treatment patterns and survival before the widespread use of immune checkpoint inhibitors (ICIs). We aimed to describe anti-cancer treatment including the use of programmed cell death-1 and ligand-1 (PD-1/PD-L1) ICIs and overall survival (OS) in advanced cancer patients as a benchmarking real-world standard before widespread use of ICIs. PATIENTS AND METHODS: Using nationwide Danish medical registries, we assembled cohorts of Danish patients with advanced non-small cell lung cancer (NSCLC) (n=12,283), urothelial carcinoma (n=2504), epithelial ovarian cancer (n=1466), gastric adenocarcinoma (n=1457), and renal cell carcinoma (RCC) (n=1261) diagnosed between 1/1/2013 and 31/12/2017. We describe anti-cancer treatment and OS using proportions, medians, and Kaplan-Meier methods. RESULTS: Between 9% (ovarian cancer) and 25% (gastric adenocarcinoma) of patients did not receive anti-cancer treatment. The remaining patients received surgery, radiation therapy, and/or medical therapy. Chemotherapy was the most frequent medical therapy in all cohorts except for RCC (tyrosine kinase inhibitors). PD-L1/PD-1 ICIs were used in 7-8% of the NSCLC and RCC cohorts-mainly as second or higher line treatments. OS was longest in patients starting treatment with surgery (eg 25.6 months [95%-confidence interval (CI)=21.9-29.4] for NSCLC and 21.4 months [95%-CI=19.8-23.5] for urothelial carcinoma) and shortest for radiation therapy (eg 3.9 months [95%-CI=3.6-4.2] for NSCLC and 12.6 months [95%-CI=9.2-17.5] for urothelial carcinoma). NSCLC patients starting with medical therapy had OS between these limits. Median OS for NSCLC patients starting treatment with PD-L1/PD-1 ICIs was 21.4 months (95%-CI=13.9-not estimable). CONCLUSION: Most patients with advanced NSCLC, urothelial carcinoma, epithelial ovarian cancer, gastric adenocarcinoma and RCC had poor OS in an era where only a minority received PD-L1/PD-1 ICIs. This information on treatment patterns and survival is important as a benchmarking real-world standard before widespread use of ICIs.

A real-world study on characteristics, treatments and outcomes in US patients with advanced stage ovarian cancer.

BACKGROUND: Detailed epidemiologic descriptions of large populations of advanced stage ovarian cancer patients have been lacking to date. This study aimed to describe the patient characteristics, treatment patterns, survival, and incidence rates of health outcomes of interest (HOI) in a large cohort of advanced stage ovarian cancer patients in the United States (US). METHODS: This cohort study identified incident advanced stage (III/IV) ovarian cancer patients in the US diagnosed from 2010 to 2018 in the HealthCore Integrated Research Database (HIRD) using a validated predictive model algorithm. Descriptive characteristics were presented overall and by treatment line. The incidence rates and 95% confidence intervals for pre-specified HOIs were evaluated after advanced stage diagnosis. Overall survival, time to treatment discontinuation or death (TTD), and time to next treatment or death (TTNT) were defined using treatment information in claims and linkage with the National Death Index. RESULTS: We identified 12,659 patients with incident advanced stage ovarian cancer during the study period. Most patients undergoing treatment received platinum agents (75%) and/or taxanes (70%). The most common HOIs (> 24 per 100 person-years) included abdominal pain, nausea and vomiting, anemia, and serious infections. The median overall survival from diagnosis was 4.5 years, while approximately half of the treated cohort had a first-line time to treatment discontinuation or death (TTD) within the first 4 months, and a time to next treatment or death (TTNT) from first to second-line of about 6 months. CONCLUSIONS: This study describes commercially insured US patients with advanced stage ovarian cancer from 2010 to 2018, and observed diverse treatment patterns, incidence of numerous HOIs, and limited survival in this population.

Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease.

Background: Interstitial lung disease (ILD) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). To further understand this patient population, we present the first systematic review on the epidemiology of SSc and SSc-associated ILD (SSc-ILD). Methods: Bibliographic databases and web sources were searched for studies including patients with SSc and SSc-ILD in Europe and North America (United States and Canada). The systematic review was limited to publications in English, German, French, Spanish, Italian, and Portuguese, published between January 1, 2000 and February 29, 2016. For all publications included in the review, the methodologic quality was assessed. For each dimension and region, data availability in terms of quantity and consistency of reported findings was evaluated. Results: Fifty publications reporting epidemiologic data (prevalence, incidence, demographic profile, and survival and mortality) were included; 39 included patients with SSc and 16 included patients with SSc-ILD. The reported prevalence of SSc was 7.2-33.9 and 13.5-44.3 per 100,000 individuals in Europe and North America, respectively. Annual incidence estimates were 0.6-2.3 and 1.4-5.6 per 100,000 individuals in Europe and North America, respectively. Associated ILD was present in ~35% of the patients in Europe and ~52% of the patients in North America. In Europe, a study estimated the prevalence and annual incidence of SSc-ILD at 1.7-4.2 and 0.1-0.4 per 100,000 individuals, respectively. In both Europe and North America, SSc-ILD was diagnosed at a slightly older age than SSc, with both presentations of the disease affecting 2-3 times more women than men. Ten-year survival in patients with SSc was reported at 65-73% in Europe and 54-82% in North America, with cardiorespiratory manifestations (including ILD) associated with poor prognosis. Conclusion: This systematic review confirms that SSc and SSc-ILD are rare, with geographic variation in prevalence and incidence.

Results and validation of an index to measure health state of patients with depression in automated healthcare databases.

Background and objective: A Depressive Health State Index (DHSI) based on 29 parameters routinely collected in an automated healthcare database (AHDB) was developed to evaluate the health state of depressive patients, and its evolution. The study objective was to describe and validate this DHSI. Methods: A historical cohort of patients with at least one episode of depression was identified in the Clinical Practice Research Datalink (CPRD). The DHSI was calculated for each episode of depression. Validation was performed by comparing the DHSI between subgroups and using validated definitions of remission (proxy and PHQ-9). Robustness was studied by assessing the impact of modifying parameters of the DHSI. Results: 309,279 episodes of depression were identified in the CPRD between 1 January 2006 and 31 December 2012. Remission was observed in 8% of the patients showing the lower DHSI scores and in 88% of the patients showing the higher DHSI scores. The DHSI was robust to a modification of the most frequent variables and to the removal of rare parameters. Conclusion: The DHSI is specific to depression severity (with remission rates in accordance with the expected variations of the DHSI) and robust. It represents a promising tool for the analysis of AHDBs.

Development of predictive models to identify advanced-stage cancer patients in a US healthcare claims database.

BACKGROUND: Although healthcare databases are a valuable source for real-world oncology data, cancer stage is often lacking. We developed predictive models using claims data to identify metastatic/advanced-stage patients with ovarian cancer, urothelial carcinoma, gastric adenocarcinoma, Merkel cell carcinoma (MCC), and non-small cell lung cancer (NSCLC). METHODS: Patients with ≥1 diagnosis of a cancer of interest were identified in the HealthCore Integrated Research Database (HIRD), a United States (US) healthcare database (2010-2016). Data were linked to three US state cancer registries and the HealthCore Integrated Research Environment Oncology database to identify cancer stage. Predictive models were constructed to estimate the probability of metastatic/advanced stage. Predictors available in the HIRD were identified and coefficients estimated by Least Absolute Shrinkage and Selection Operator (LASSO) regression with cross-validation to control overfitting. Classification error rates and receiver operating characteristic curves were used to select probability thresholds for classifying patients as cases of metastatic/advanced cancer. RESULTS: We used 2723 ovarian cancer, 6522 urothelial carcinoma, 1441 gastric adenocarcinoma, 109 MCC, and 12,373 NSCLC cases of early and metastatic/advanced cancer to develop predictive models. All models had high discrimination (C > 0.85). At thresholds selected for each model, PPVs were all >0.75: ovarian cancer = 0.95 (95% confidence interval [95% CI]: 0.94-0.96), urothelial carcinoma = 0.78 (95% CI: 0.70-0.86), gastric adenocarcinoma = 0.86 (95% CI: 0.83-0.88), MCC = 0.77 (95% CI 0.68-0.89), and NSCLC = 0.91 (95% CI 0.90 - 0.92). CONCLUSION: Predictive modeling was used to identify five types of metastatic/advanced cancer in a healthcare claims database with greater accuracy than previous methods.

Progranulin null mutations in both sporadic and familial frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.