Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVES: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSIONS: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

Investigating significant health trends in progressive fibrosing interstitial lung disease (INSIGHTS-ILD): rationale, aims and design of a nationwide prospective registry.

BACKGROUND: The progressive course of pulmonary fibrosis (PPF) is observed with variable prevalence in different entities of fibrosing interstitial lung disease (fILD). PPF is characterised by worsening respiratory symptoms, declining lung function and increasing extent of fibrosis on high-resolution computer tomography. In Germany, data are limited on the characteristics and management of such patients. METHODS/DESIGN: INSIGHTS-ILD is a prospective observational longitudinal registry designed to describe characteristics, management and course of newly diagnosed (incident) and prevalent patients with fILD on the long term. The registry uses a non-probability sampling approach to collect data on characteristics, therapeutic interventions, health-related quality of life and health economic parameters. It is planned to include 900 patients in ambulatory care in about 30 expert sites over three years. The study has been initiated in December 2021, and currently (January 2023) follows 360 patients. DISCUSSION: The registry is expected to provide much-needed data on the characteristics, management, and trajectories of patients fILD in Germany. The start of the study comes at a time when new treatment options are available for PPF. We hypothesize that PPF represents a broad clinical phenotype that is differentially influenced by inflammatory and fibrotic pathomechanisms that need to be treated with anti-inflammatory and/or anti-fibrotic treatment strategies. This registry will allow comparisons with other countries. Gap analyses based on current guidelines for management of these patients will be possible. Trial registration DRKS00027389 (registered on 7.12.2021), BfArM NIS 7562.

Clinical Opinion: The diagnosis and management of suspected fetal growth restriction: an evidence-based approach.

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is frequently defined as one with an estimated fetal weight of <10th percentile. This condition has been considered syndromic and has been frequently attributed to fetal growth restriction, a constitutionally small fetus, congenital infections, chromosomal abnormalities, or genetic conditions. Small for gestational age is not synonymous with fetal growth restriction, which is defined by deceleration of fetal growth determined by a change in fetal growth velocity. An abnormal umbilical artery Doppler pulsatility index reflects an increased impedance to flow in the umbilical circulation and is considered to be an indicator of placental disease. The combined finding of an estimated fetal weight of <10th percentile and abnormal umbilical artery Doppler velocimetry has been widely accepted as indicative of fetal growth restriction. Clinical studies have shown that the gestational age at diagnosis can be used to subclassify suspected fetal growth restriction into early and late, depending on whether the condition is diagnosed before or after 32 weeks of gestation. The early type is associated with umbilical artery Doppler abnormalities, whereas the late type is often associated with a low pulsatility index in the middle cerebral artery. A large randomized clinical trial indicated that in the context of early suspected fetal growth restriction, the combination of computerized cardiotocography and fetal ductus venosus Doppler improves outcomes, such that 95% of surviving infants have a normal neurodevelopmental outcome at 2 years of age. A low middle cerebral artery pulsatility index is associated with an adverse perinatal outcome in late fetal growth restriction; however, there is no evidence supporting its use to determine the time of delivery. Nonetheless, an abnormality in middle cerebral artery Doppler could be valuable to increase the surveillance of the fetus at risk. We propose that fetal size, growth rate, uteroplacental Doppler indices, cardiotocography, and maternal conditions (ie, hypertension) according to gestational age are important factors in optimizing the outcome of suspected fetal growth restriction.

Effective Treatment of Lymphogranuloma venereum Proctitis With Azithromycin.

BACKGROUND: Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis (CT) serovars L1, L2, and L3 and is endemic among men who have sex with men (MSM) in Europe. We evaluated weekly oral azithromycin 1 g for 3 weeks as a treatment for LGV proctitis. METHODS: This is an open clinical trial with convenience allocation according to treating physician preferences. Adults with clinical proctitis received a single dose of 1 g of intramuscular ceftriaxone and were subsequently allocated to receive (i) doxycycline 100 mg twice daily for 21 days (Doxycycline group) or (ii) azithromycin 1 g orally once weekly for 3 weeks (Azithromycin group). LGV cure (primary endpoint) was defined as resolution of symptoms at week 6 (clinical cure, LGV-CC), with an additional supporting negative rectal polymerase chain reaction (PCR) at week 4 (microbiological cure, LGV-MC), if available. RESULTS: One hundred and twenty-five individuals with LGV clinical proctitis were included. All were MSM, and 96% were living with human immunodeficiency virus (HIV). Eighty-two were in the Azithromycin group, and 43 were in the Doxycycline group. LGV cure on a modified intention-to-treat analysis (primary endpoint), occurred in 80 of 82 (98%) in the Azithromycin group versus 41 of 43 (95%) in the Doxycycline group (treatment difference [95% confidence interval {CI}] 2.2% [-3.2, 13.2]). LGV-MC occurred in 70 of 72 (97%) vs 15 of 15 (100%) in the Azithromycin group and Doxycycline group, respectively (treatment difference [95% CI] -2.8% [-9.6; 17.7]). Adverse events were similar in both treatment groups. CONCLUSIONS: Our findings support extended azithromycin dosing as an alternative treatment option for symptomatic LGV proctitis and provides the rationale for future randomized trials.

Eribulin in brain metastases of breast cancer: outcomes of the EBRAIM prospective observational trial.

Background: Eribulin shows some activity in controlling brain metastasis in breast cancer. Methods: This observational, multicenter study evaluated brain disease control rates, survival and safety in patients with brain metastatic breast cancer treated with eribulin in clinical practice. Results: A total of 34 patients were enrolled (mean age 49 years, 91% with visceral metastases) and 29 were evaluable for brain disease. Fourteen achieved disease control and showed a longer time without progression: 10 months (95% CI: 2.3-17.7) versus 4 months (95% CI: 3.3-4.7) in the control group (p = 0.029). Patients with clinical benefits at 6 months had longer survival. Leukopenia and neutropenia were the most frequent grade 3-4 toxicities. Conclusion: Eribulin confirms its effectiveness in patients with brain metastatic breast cancer. Further studies on larger cohorts are needed to confirm the results.

REALizing and improving management of stable COPD in China: a multi-center, prospective, observational study to realize the current situation of COPD patients in China (REAL) - rationale, study design, and protocol.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death in China with a reported prevalence of 8.2% people aged ≥40 years. It is recommended that Chinese physicians follow Global Initiative for Chronic Obstructive Lung Disease (GOLD) and national guidelines, yet many patients with COPD in China remain undiagnosed. Furthermore, missed diagnoses and a lack of standardized diagnosis and treatment remain significant problems. The situation is further complicated by a lack of large-scale, long-term, prospective studies of real-world outcomes, including exacerbation rates, disease severity, efficacy of treatment, and compliance of COPD patients in China. METHODS/DESIGN: The REALizing and improving management of stable COPD in China (REAL) study is a 52-week multi-center, prospective, observational trial. REAL aims to recruit approximately 5000 outpatients aged ≥40 years with a clinical diagnosis of COPD per GOLD 2016. Outpatients will be consecutively recruited from approximately 50 tertiary and secondary hospitals randomly selected across six geographic regions to provide a representative population. Patients will receive conventional medical care as determined by their treating physicians. The primary objective is to evaluate COPD patient outcomes including lung function, health status, exacerbations, hospitalization rate, and dyspnea following 1 year of current clinical practice. Secondary objectives are to assess disease severity, treatment patterns, adherence to medication, and associated risk factors. Data will be collected at two study visits, at patients' usual care visits, and by telephone interview every 3 months. DISCUSSION: Knowledge of COPD among physicians in China is poor. The REAL study will provide reliable information on COPD management, outcomes, and risk factors that may help improve the standard of care in China. Patient recruitment began on 30 June 2017 and the estimated primary completion date is 30 July 2019. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03131362. Registered on 20 March 2017.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS).

Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.

A non-interventional, observational study of a fixed combination of pepsin and amino acid hydrochloride in patients with functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a gastrointestinal disorder characterized by recurrent and diverse symptoms and pathophysiology that remains unexplained following routine clinical investigation. Enzynorm®f is a pharmaceutical preparation comprising fixed amounts of pepsin of biological origin and organically bound acid in the form of amino acid hydrochloride. It is traditionally used as a mild agent to support gastric function and to stimulate the stomach's proteolytic activities in FD. METHODS: In a non-interventional, observational, post-marketing surveillance study, patients with an established diagnosis of FD were treated with a fixed combination of pepsin and amino acid hydrochloride taken as tablets three times daily for 6 weeks. The primary objective of this study was to assess the change in symptoms using the validated Gastrointestinal Symptom Score (GIS©). Secondary objectives included patients' assessment of their gastrointestinal symptoms as well as treatment safety and tolerability. RESULTS: A total of 97 patients (mean age 58.4 ± 13.9 years; 63.2% females) were included in the study, with 72 data having GIS© score data at baseline and at 6 weeks, and 34 also at 3 weeks. The overall GIS© sum score decreased by 4.1 (p < 0.0001) from 11.6 (±4.8) at baseline to 7.4 (± 4.6) reflecting an improvement of clinical symptomatology after 6 weeks of treatment. In a subgroup of 70 patients who had FD meeting the Rome III criteria a GIS© score reduction of ≥50% was observed after 3 weeks treatment in 24% and in 30.8% after 6 weeks. Adverse events were mostly gastrointestinal in nature and consistent with the underlying disease; no unexpected adverse reactions were reported. Twenty-seven patients discontinued the study, mostly because of gastrointestinal symptoms. CONCLUSION: The results of this study support the efficacy of a fixed combination of pepsin and amino acid hydrochloride for the treatment of patients with FD and also suggest good to moderate treatment tolerability. These findings should be further explored in a randomised, placebo-controlled clinical trial. CLINICAL TRIAL REGISTRATION: This study has been retrospectively registered in the ClinicalTrials.gov registry, trial identifier NCT03076411 .

[Guided self-help interventions for parents of children with ADHD--concept, referral and effectiveness in a nationwide trial. An observational study]. / Angeleitete Selbsthilfe für Eltern von Kindern mit Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung--Konzept, Inanspruchnahme und Effekte eines bundesweiten Angebotes--eine Beobachtungsstudie.

OBJECTIVES: The effects of guided self-help interventions for parents of children with ADHD have already been proven in randomized controlled trials. The objective of this study was to assess the effectiveness of this novel form of intervention under routine care conditions in a nationwide trial. METHOD: Registered pediatricians as well as child and youth psychiatrists enrolled 274 children between 6 and 12 years old (83.6% male) diagnosed with ADHD to a self-help program for parents of children with ADHD. The program lasted for 1 year and consisted of eight booklets with advice for parenting children with ADHD as well as complementary telephone consultations (14 calls, up to 20 minutes each). The course of the ADHD symptoms and the comorbid symptoms as well as the development of the child's individual problems were assessed in a pre-post design. RESULTS: 63% of the enrolled parents adhered to the program until the end. The families who cancelled the program did not differ concerning the severity of ADHD symptoms, but they did more often show an impaired familial and social background, and their children received pharmacological treatment more often. Three-fourths of the children who completed the program had received pharmacological treatment at the beginning of the program. The children had more severe ADHD symptoms than a clinical control group. During the intervention, ADHD symptoms as well as psychosocial functioning improved with large effect sizes of d>0.9. Additionally, comorbid oppositional and emotional symptoms decreased. CONCLUSIONS: These results indicate that guided self-help programs for families with children with ADHD are effective, also as an addition to pharmacological treatment.

Efficacy of Pyrotinib With/Without Trastuzumab in Treatment-Refractory, HER2-Positive Metastatic Colorectal Cancer: Result From a Prospective Observational Study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target in metastatic colorectal cancer (mCRC). This study was to evaluate the efficacy and safety of pyrotinib alone or pyrotinib with trastuzumab in patients with HER2-positive mCRC. PATIENTS AND METHODS: In this prospective observational study, patients with HER2 positive, Ras Sarcoma Viral Oncogene Homolog (RAS) wild type mCRC who received at least one standard treatment of palliative chemotherapy were enrolled. Patients were treated with oral pyrotinib alone or pyrotinib with trastuzumab. The primary endpoint was progression free survival (PFS), and the secondary endpoints were overall survival (OS), confirmed objective response rate (ORR), and safety. This trial is registered with chitcr.org, number ChiCTR2100046381. RESULTS: From February 15, 2021, to January 10, 2023, 32 patients were enrolled in this study. Twenty (62.5%) patients were treated with pyrotinib, while 12 (37.5%) received pyrotinib and trastuzumab. As of June 24, 2023, with a median follow-up of 11.0 months, the median PFS was 5.7 months (95%CI 4.5-10.2), while OS was not evaluable (NE), ORR and disease control rate (DCR were 34.4% and 87.5%. Patients' PFS in the pyrotinib plus trastuzumab subgroup and pyrotinib monotherapy group were 8.6 and 5.5 months, OS was not evaluable (NE) and 10.9 months, ORR was 50.0% and 25.0%, respectively. Most treatment-related adverse events (TRAEs) were grade 1-2, diarrhea was the most frequent TRAE (81.3%, 26/32). Grade 3 TRAEs occurred in 11 patients: 9 for diarrhea, 1 for nausea, and 1 for oral mucositis. CONCLUSION: Pyrotinib with or without trastuzumab showed promising anti-tumor activity and acceptable toxicities in treatment-refractory, HER2-positive mCRC.

Conservative management of early-onset severe preeclampsia: comparison between randomized and observational studies a systematic review.

OBJECTIVE: To compare maternal and perinatal outcomes between randomized trials and observational studies in which conservative management was performed for more than 48 h in patients with early-onset severe preeclampsia. METHODOLOGY: We searched PubMed, LILACS, Cochrane and Google Scholar. The studies were divided in two groups: randomized and observational studies, from 1990 to 2018 that included patients with severe preeclampsia before 34 weeks of gestation with pregnancy prolongation ≥48 h but that did not include fetal growth restriction or HELLP syndrome at the beginning. The main variables recorded were maternal and perinatal complications. MAIN RESULTS: Forty-four studies met the inclusion criteria, and 5 of these were randomized. The average pregnancy prolongation was 9 days, with no difference between groups. Maternal complications were significantly more common in observational studies, RR = 0.71, 95% CI (0.54-0.93), p = .009. Perinatal complications were also significantly more common in observational studies (RR = 0.89, 95% CI (0.80-0.98), p = .01) at the expense of stillbirth and neonatal deaths. The percentages of cesarean sections were significantly higher in randomized studies, RR = 1.54, 95% CI (1.46-1.64). There were 2 maternal deaths, both in observational studies. CONCLUSION: Observational studies in which conservative management of early-onset preeclampsia is performed and do not include patients with fetal growth restriction or patients with HELLP syndrome and where at least 2 days of pregnancy prolongation is achieved are associated with significantly more maternal and perinatal complications.

C-REGS 2 - Design and methodology of a high-quality comparative effectiveness observational trial.

The main aim of this study is to systematically record Cerebrolysin treatment modalities and concomitant medication, according to local standards, in patients with moderate to severe neurological deficits after acute ischemic stroke and to assess the impact of these parameters on therapy outcome during early rehabilitation (day 21) and on day 90. An open observational treatment design based on the principles of high-quality comparative effectiveness research (HQCER) has been chosen to capture the therapies as applied in real-world clinical practice. HQCER opens a new horizon for strengthening the validity of the results from observational trials, thereby enhancing the associated level of evidence. Rigorous pre-specification of analytical procedures and tight risk-based centralized monitoring were additional measures to improve the impact of the observational approach. The value for real-world studies has become obvious, and such studies based on comparative effectiveness designs supplement the classical study designs by enabling the inclusion of larger proband numbers and more statistical reliability for practical use.

Influence of Anatomic Conditions on Efficacy and Safety of Combined Intermediate Cervical Plexus Block and Perivascular Infiltration of Internal Carotid Artery in Carotid Endarterectomy: A Prospective Observational Trial.

Ultrasound-guided intermediate cervical plexus blockade with perivascular infiltration of the carotid artery bifurcation perivacular block (PVB) is a reliable technique for regional anesthesia in carotid endarterectomy (CEA). We investigated the effect of the carotid bifurcation level (CBL) on PVB efficacy and safety in patients undergoing CEA. This prospective observational cohort study included 447 consecutive CEA patients who received PVB over a 6-y period. Vascular and neurologic puncture-related complications were recorded. The CBL was localized at the low level (C4 and C5 vertebra, low-level [LL] group) in 381 (85.2%) patients and at the high level (C2 and C3 vertebra, high-level [HL] group) in 66 (14.8%) patients. Local anesthetic supplementation by surgeons was necessary in 64 (14.3%) patients in the LL group and 38 (59.4%) patients in the HL group (p < 0.001) and was associated with a higher rate of central neurologic complications in the HL group (p = 0.031). Therefore, the efficacy of the PVB may be influenced by the CBL.

PSA decay during salvage radiotherapy for prostate cancer as a predictor of disease outcome - 5 year follow-up of a prospective observational study.

BACKGROUND AND PURPOSE: Biochemical recurrence after prostatectomy is commonly treated with salvage radiotherapy (SRT). In this prospective observational study we investigated the PSA decay rate, determined by predefined serial PSA measurements during SRT, as a predictor for treatment outcome. MATERIALS AND METHODS: Between 2013 and 2016, 214 patients were included in the study. The prescribed dose to the prostate bed was 70 Gy in 35 fractions (7 weeks) without hormonal treatment. PSA was measured weekly during SRT. Assuming first order kinetics, a PSA decay-rate constant (k) was calculated for 196 eligible patients. The ability of k to predict disease progression was compared with known clinical prediction parameters using Cox regression, logistic regression and ROC analyses. Disease progression was defined as continuously rising PSA after SRT, PSA increase by ≥0.2 ng/ml above nadir after SRT, hormonal treatment or clinical progression. RESULTS: After a median follow up of 4.7 years the estimated failure-free survival at 5 years was 56%. The PSA decay-rate constant (k) was found to be the strongest predictor of disease progression in both uni-and multivariable analyses. CONCLUSION: The addition of k to established clinical variables significantly improves the possibility to predict treatment outcome after SRT and could be used to personalize future therapies.

The Prospective Huntington At-Risk Observational Study (PHAROS): The Emotional Well-Being, Safety and Feasibility of Long-Term Research Participation.

BACKGROUND: There is limited understanding of the feasibility of conducting long-term research among undiagnosed (pre-symptomatic) adults at risk to develop Huntington disease (HD), while protecting their emotional well-being and safety. OBJECTIVE: To assess pre-specified events pertaining to emotional well-being, safety, and feasibility among healthy consenting adults at risk for developing HD who have chosen not to undergo genetic testing. METHODS: PHAROS research participants prospectively reported the occurrence of events pertaining to psychological distress (psychiatric evaluations, depression, suicidality) and feasibility (maintaining confidentiality, study attrition). PHAROS enrolled 1001 participants. RESULTS: Events pertaining to psychological distress were reported by 35% of participants. The most common events included heightened suicide risk (26%), new onset depression (12%), and new mental health evaluation (9%); all occurred significantly more frequently among participants with expanded trinucleotide CAG repeats (≥37). Five deaths occurred, none related to suicide. Forty-one percent of participants reported self-disclosure of their HD at-risk status, and 15% reported that someone else (usually a family member) had done so. Confidentiality of CAG test results was maintained by investigators. The withdrawal rate was largely uniform over the study period and did not differ significantly by gender or CAG status. CONCLUSIONS: The potentially vulnerable research participants in PHAROS showed good emotional tolerability and safety. Individual CAG data were not disclosed, and confidentiality about disclosure of at-risk HD status was well maintained by others (family, friends, etc.). Long-term research participation of adults at risk for HD who choose not to undergo pre-symptomatic DNA testing is well tolerated, safe and feasible.

A prospective observational treatment study of aerococcal urinary tract infection.

OBJECTIVES: Aerococcus urinae and Aerococcus sanguinicola cause urinary tract infections (UTIs) and antibiotic treatment recommendations are solely based on in vitro findings and limited clinical experience. Our objective was to investigate the effectiveness of different treatment strategies in aerococcal UTI through a prospective observational study. METHODS: Urine samples with aerococci were identified and patients were enrolled. The aerococci were subjected to Etests. Information on clinical symptoms, and the treatment given, was collected. Patients were interviewed after the conclusion of treatment to assess clinical cure and a control urine culture assessed the microbiological cure. RESULTS: Of 31,629 urine samples, 144 grew aerococci and fulfilled the inclusion criteria. 91 patients gave consent and the 72 patients with UTI were assessed for treatment outcome. 53 patients had A. urinae UTI, while 19 had A. sanguinicola UTI. Nitrofurantoin was most commonly prescribed, achieving clinical and microbiological success in 71/76% of cases of A. urinae UTI, and 42/50% of cases of A. sanguinicola UTI. Pivmecillinam achieved success in patients with A. urinae cystitis and ciprofloxacin in patients with pyelonephritis. CONCLUSIONS: Our results support that nitrofurantoin is a valid option for the treatment of cystitis caused by A. urinae.

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

Predictivity of clinical, laboratory and imaging findings in diagnostic definition of palpable thyroid nodules. A multicenter prospective study.

PURPOSE: To assess the role of clinical, biochemical, and morphological parameters, as added to cytology, for improving pre-surgical diagnosis of palpable thyroid nodules. METHODS: Patients with a palpable thyroid nodule were eligible if surgical intervention was indicated after a positive or suspicious for malignancy FNAC (TIR 4-5 according to the 2007 Italian SIAPEC-IAP classification), or two inconclusive FNAC at a ≥3 months interval, or a negative FNAC associated with one or more risk factor. Reference standard was histological malignancy diagnosis. Likelihood ratios of malignancy, sensitivity, specificity, negative (NPV), and positive predictive value (PPV) were described. Multiple correspondence analysis (MCA) and logistic regression were applied. RESULTS: Cancer was found in 433/902 (48%) patients. Considering TIR4-5 only as positive cytology, specificity, and PPV were high (94 and 91%) but sensitivity and NPV were low (61 and 72%); conversely, including TIR3 among positive, sensitivity and NPV were higher (88 and 82%) while specificity and PPV decreased (52 and 63%). Ultrasonographic size ≥3 cm was independently associated with benignity among TIR2 cases (OR of malignancy 0.37, 95% CI 0.18-0.78). In TIR3 cases the hard consistency of small nodules was associated with malignity (OR: 3.51, 95% CI 1.84-6.70, p < 0.001), while size alone, irrespective of consistency, was not diagnostically informative. No other significant association was found in TIR2 and TIR3. CONCLUSIONS: The combination of cytology with clinical and ultrasonographic parameters may improve diagnostic definition of palpable thyroid nodules. However, the need for innovative diagnostic tools is still high.