Multicenter Non-interventional Study Research Articles

Investigating coping and stigma in people living with HIV through narrative medicine in the Italian multicentre non-interventional study DIAMANTE

Antiretroviral therapy (ART) significantly reduced Human Immunodeficiency Virus (HIV) morbidity and mortality; nevertheless, stigma still characterises the living with this condition. This study explored patients’ coping experience by integrating narrative medicine (NM) in a non-interventional clinical trial. From June 2018 to September 2020 the study involved 18 centres across Italy; enrolled patients were both D/C/F/TAF naïve and previously ART-treated. Narratives were collected at enrolment (V1) and last visit (V4) and then independently analysed by three NM specialist researchers through content analysis. One-hundred and fourteen patients completed both V1 and V4 narratives. Supportive relationships with clinicians and undetectable viral load facilitated coping. Conversely, lack of disclosure of HIV-positive status, HIV metaphors, and unwillingness to narrate the life before the diagnosis indicated internalised stigma. This is the first non-interventional study to include narratives as patient reported outcomes (PROs). Improving HIV awareness and reducing the sense of guilt experienced by patients helps to overcome stigma and foster coping.

A clinical decision support system to predict the efficacy for EGFR-TKIs based on artificial neural network.

The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) was affected by numerous factors. In the study, we developed and validated an artificial neural network (ANN) system based on clinical characteristics and next-generation sequencing (NGS) to support clinical decisions. A multicenter retrospective non-interventional study was conducted. 240 patients from three hospitals with advanced non-small cell lung cancer (NSCLC) and EGFR mutation were tested by NGS before the first treatment. All patients received formal EGFR-TKIs treatment. Five different models were individually trained to predict the efficacy of EGFR-TKIs based on one medical center with 188 patients. Two independent cohorts from other medical centers were collected for external validation. Compared with logistic regression, four machine learning methods showed better predicting abilities for EGFR-TKIs. The inclusion of NGS tests improved the predictive power of models. ANN performed best on the dataset with mutations TP53, RB1, PIK3CA, EGFR mutation sites, and tumor mutation burden (TMB). The prediction accuracy, recall and AUC were 0.82, 0.82, and 0.82, respectively in our final model. In the external validation set, ANN still showed good performance and differentiated patients with poor outcomes. Finally, a clinical decision support software based on ANN was developed and provided a visualization interface for clinicians. This study provides an approach to assess the efficacy of NSCLC patients with first-line EGFR-TKI treatment. Software is developed to support clinical decisions.

Changes in serotype distribution of <i>Streptococcus pneumonia</i> circulating among children in the Russian Federation after 13-valent pneumococcal conjugate vaccine introduction.

During a prospective multicenter non-interventional observational study, a comparative assessment was made of the serotype structure of pneumococci circulating among healthy children under the age of 5 years and children of the same age group with signs of respiratory infections in the periods 2016-2018 and 2020-2022. Data on the serotype structure of pneumococci in the period from 2016-2018 were obtained from our previous works. In 2020-2022 the study included 2066 healthy children and 603 children with respiratory infections. Streptococcus pneumoniae and their DNA were detected in nasopharyngeal swabs by classical culture and molecular methods. Typing was carried out by molecular methods. On the territory of the Russian Federation, pneumococci belonging to the serotypes included in the 13-valent vaccine are being forced out of circulation and replaced by non-vaccine serotypes. Before the introduction of mass antipneumococcal vaccination (until 2015), the 13-valent conjugate vaccine covered from 66.2% to 92% of pneumococci, after the start of mass anti-pneumococcal vaccination in the period 2016-2018, coverage decreased to 57.3%. Between 2020 and 2022, coverage was less than 40%. The main “non-vaccine” serotypes/serogroups circulating in the Russian Federation are 15AF, 11AD, 23A, 9LN and 16F.

MELODY (Methods for Localization of Different Types of Breast Lesions): A prospective non-interventional multicenter cohort study to evaluate different imaging-guided methods for localization of malignant breast lesions (EUBREAST-4/iBRA-NET).

TPS626 Background: In the last decades, the proportion of breast cancer patients receiving breast-conserving surgery has increased, reaching 70-80% in developed countries. In case of non-palpable lesions, surgical excision requires some form of breast localization. While wire-guided localization has long been considered gold standard, it carries several limitations, including logistical difficulties, the potential for displacement and patient discomfort, and re-excision rates reaching 21%. Other techniques (radioactive seed or radio-occult lesion localization, intraoperative ultrasound, magnetic, radiofrequency and radar localization) have been developed with the aim of overcoming these disadvantages. However, comparative data on the rates of successful lesion removal, negative margins and re-operations are limited. In the majority of studies, the patient’s perspective with regard to discomfort and pain level has not been evaluated. The aim of MELODY is to evaluate different imaging-guided localization methods with regard to oncological safety, patient-reported outcomes, and surgeon and radiologist satisfaction. Methods: The EUBREAST and the iBRA-NET have initiated the MELODY study to assess breast localization techniques and devices from several perspectives (NCT05559411, http://melody.eubreast.com ). MELODY is a prospective intergroup cohort study which enrolls female and male pts. requiring breast-conserving surgery and imaging-guided localization for invasive breast cancer or DCIS. Multiple or bilateral lesions and neoadjuvant chemotherapy are allowed. Primary outcomes are: 1) Intended target lesion and/or marker removal, independent of margin status on final histopathology, and 2) Negative resection margin rates at first surgery. Secondary outcomes are, among others: rates of second surgery and secondary mastectomy, Resection Ratio (defined as actual resection volume divided by the calculated optimum specimen volume), duration of surgery, marker dislocation rates, rates of marker placement or localization failure, comparison of patient-reported outcomes, rates of “lost markers” and diagnostician/radiologist’s and surgeon’s satisfaction as well as the health economic evaluation of the different techniques. Target accrual: 7,416 patients. Enrollment started in January 2023. The study will be conducted in 20 countries and is supported by the Oncoplastic Breast Consortium (OPBC), AWOgyn, AGO-B and SENATURK. Clinical trial information: NCT05559411 .

A disease registry study to prospectively observe treatment patterns and outcomes in patients with HER2+ unresectable locally advanced or metastatic breast cancer (aBC): Interim results of the ESTHER study (NCT02393924).

e13039 Background: Over the last decade the standard-of-care treatment for patients with HER2+ aBC has included anti-HER2 therapies often combined with chemotherapy. These approaches have shown efficacy in clinical trials which have recruited patients in restricted populations defined by lines of therapy and previous treatments. There are few data regarding the long-term outcomes of patients treated with these regimens, including those with brain metastases. We conducted a prospective, multicentre non-interventional study to observe anti-cancer treatment regimens and clinical outcomes in patients with HER2 positive aBC. Methods: Adult patients diagnosed with HER2-positive aBC within the last 6 months were included. No specific treatment approach or course was mandated by the protocol. Source data was taken from the patient’s chart and other medical records, then reported by means of an electronic data collection system. Data regarding treatment received, efficacy (progression-free and overall survival (PFS), response rates (RR) and development of CNS metastases) and safety (including cardiac toxicity) were captured. Results: Between February 2015 and April 2018, 311 eligible patients were recruited with median age 57 years (24-96). At diagnosis of aBC the most common distant metastatic sites were bone (n = 145;47%), liver (n=117;38%), lung (n=100;32%) and brain (n=21;7%). First line treatment was with pertuzumab (P)/trastuzumab(T)/chemotherapy (n=212;68%), T/chemotherapy (n=45;14%), other T combinations without P (n=19;6%), Trastuzumab Emtansine regimens without T or P (n=16;5%) (19; 5% other combinations). Patients’ status as of cut-off date for this analysis (28th Feb 2022, median follow-up 44.1 months) is shown. The median PFS of patients treated in the 1st, 2nd and 3rd lines was 26.7 months, 10.7 months and 8.6 months. At the time of this analysis an additional 60 patients (19%) had developed brain metastases during first line. The number of patients starting 2nd, 3rd and 4th line treatment with brain metastases were 28 (22%), 17 (40%), 7 (37%) respectively. Conclusions: In routine clinical practice, as reflected by this registry, at least 40% of patients who initiate first line therapy for advanced breast cancer do not proceed to 3rd line therapy, and brain metastases become increasingly common. These findings have implications for selection of optimal 2nd and 3rd line treatment. Clinical trial information: ISRCTN02393924 . [Table: see text]

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study

PurposeChronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients’ quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems.MethodsThis retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion.ResultsThe patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years’ observation. The most common diagnostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC.ConclusionRCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems.

A Multi-Centre Non-Interventional Study to Assess the Tolerability and Effectiveness of Extended-Release Tacrolimus (LCPT) in De Novo Liver Transplant Patients.

Available tacrolimus formulations exhibit substantial inter- and intra-individual variability in absorption and metabolism. The present non-interventional cohort study aimed to assess the tolerability and effectiveness of the once-daily tacrolimus formulation, LCPT, in hepatic allograft recipients in real life. This study was conducted in Austria and the Czech Republic between July 2016 and August 2019. Patients aged ≥ 18 years old received LCPT per the approved label and local clinical routine. All the participants provided informed consent. Patients newly treated with tacrolimus (de novo) directly after transplantation were observed for six months. The relevant clinical variables were tacrolimus trough level (TL), total daily dose (TDD), number of dose adjustments, kidney and liver function, and tolerability. Of the 70 analyzed patients, 72.9% were male and 85.7% were aged < 65 years old. The mean (SD) time to achieve tacrolimus target TL was 6.4 (4.6) days after 4.4 (4.0) dose adjustments; thereafter, TL remained stable throughout observation at approximately 8 ng/mL. The LCPT TDD at initiation was 8 mg and decreased by a median of 41.4% to 5 mg at 6 months. Liver function continuously improved, and kidney function remained stable. LCPT was well tolerated with 24 adverse events in eight patients (17 related to immunosuppression, mostly mild renal insufficiency, and hematological adverse events); two serious unrelated adverse events were reported (atrial flutter and liver dysfunction). TL was rapidly attained with few dose adaptations after LCPT initiation in de novo liver transplant patients. Liver function rapidly improved, whereas kidney function remained normal. LCPT was well-tolerated in this population.

Abstract P3-02-05: Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer

Abstract BACKGROUND: Metastatic breast cancer (MBC) is incurable, with the primary goal of treatment being to extend survival while preserving quality of life. Treatment options available to patients (pts) with human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) may vary between countries, in terms of both the drugs used and the sequence in which they are used. There is limited data available on the clinical characteristics and outcomes in pts with unresectable locally advanced (LA) BC. This study aimed to capture real-world data on treatment patterns and clinical outcomes in HER2+ unresectable LABC and MBC. METHODS: SAMANTHA (NCT02913456) is an ongoing, prospective, multicentre non-interventional study designed to observe pts with HER2+ unresectable LABC or MBC for a period of up to 8 years on study. The primary objectives are progression-free survival (PFS), assessed according to standard medical practice, and the treatment received. Secondary objectives included overall survival (OS), duration of response and safety. This pre-planned interim analysis reports baseline characteristics, treatment regimens received, first-line (1L) PFS by advanced BC status and the incidence of adverse events (AEs). RESULTS: The study enrolled 647 pts from five European (EU) countries (Nov 2016-Nov 2019); 629 received 1L treatment and were included in data analysis. At data cut-off date (16 Nov 2021), median follow-up on study was 30.4 months (mo; range: 0.1; 60.0); 342 (54%) pts discontinued 1L treatments, of whom 170 (50%) pts received 2L treatments, 74 pts died, 49 pts were lost to follow-up, 35 pts withdrew consent and 14 pts withdrew due to physician decision. The full analysis set (FAS) included 222 (35%) LABC pts and 407 (65%) MBC pts [Table]. Pertuzumab/trastuzumab based regimens were given as 1L in the majority of pts [462 (73 %)]. The FAS Median (m) PFS in 1L was 41.3 mo (95% CI: 36.1, 54.1) for LABC and 23.5 mo (95% CI: 20.6, 27.6) for MBC. Median OS was not reached. In the FAS, any AEs were reported in 352 (56%) pts; of these 212 (34%) had a grade 3 or higher AE. Serious (S) AEs were reported in 135 (22%) pts; of whom, 36 (6%) pts had treatment related SAEs. CONCLUSIONS: This interim analysis of SAMANTHA provides a snapshot of LABC/MBC treatment practices in five EU countries, where pertuzumab/trastuzumab based regimens appear to be the most used 1L treatment options, which aligns with the recommended standard of care. The mPFS is consistent with previous literature although higher than what was reported in the pivotal clinical trial CLEOPATRA. Given the good outcome observed in 1L and the current follow-up period of 30.4 mo, the data are not yet mature enough to provide complete insights into the treatment sequencing patterns and the clinical outcomes associated with these treatments. Acknowledgments: The study is sponsored by F. Hoffmann-La Roche Ltd. Table: Demographics and baseline disease characteristics of patients by status of advanced BC Citation Format: Marija Balic, Luis Costa, Joseline Ojaimi, Cristina Marinela Oprean, José L. Passos Coelho, Isabel Pazos, Fabio Puglisi, Thibaut Sanglier, Giuseppa Scandurra, Michael Schenker, Laurentia A. Wahyudi, Georgi Zhbantov, Constanta Timcheva. Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-05.

Prospective Observational Evaluation of Fixed Combination Calcipotriol/Betamethasone Aerosol Foam (Enstilar®) in the Management of Psoriasis with Scalp Involvement in Everyday Clinical Practice (the CAPITIS Study)

Background and aim: Clinical trials have demonstrated the efficacy of fixed-dose combination calcipotriol/betamethasone (Cal/BD) aerosol foam for the treatment of patients with scalp psoriasis. However, data on the real-world effectiveness of Cal/BD aerosol foam in this subgroup of patients are lacking. Therefore, this study investigated the effectiveness and tolerability of 4 weeks’ treatment with Cal/BD aerosol foam in patients with scalp psoriasis in everyday clinical practice. Methods: This prospective, non-interventional multicenter study involved 217 adults with scalp psoriasis who were treated with Cal/BD aerosol foam for 4 weeks. Primary endpoints included the proportion of patients with <10% of the scalp area affected (Scalp-BSA) plus a Scalp-PGA of “mild” after 4 weeks, as well as the proportion of patients with an absolute PSSI ≤2 points after 4 weeks. Secondary endpoints included patient reported changes in erythema, itching, flaking, and thickness at baseline, 3 days, 1 week, 2 weeks, and 4 weeks. Results: After 4 weeks, 53.4% of patients treated with Cal/BD aerosol foam had achieved a Scalp-BSA of <10% and a mild Scalp-PGA. Furthermore, 47.6% of patients achieved a PSSI ≤2. Improvements in pruritus and other symptoms (induration, erythema, and scaling) were seen already within 3 days. The proportion of patients who reported that scalp psoriasis had no influence on their quality of life (Dermatology Quality of Life Index 0/1 points) increased from 3.2% at baseline to 47.9% at study end. Patient satisfaction with treatment was high (Treatment Satisfaction Questionnaire-9 scores of 74.5 ± 27.1 for effectiveness, 72.0 ± 25.2 for ease of use, and 77.8 ± 24.2 for general satisfaction). Overall, 97.4% of HCPs assessed the tolerability of Cal/BD aerosol foam as good/very good with no new safety concerns. Conclusion: This study demonstrated the effectiveness, rapid onset of action, good tolerability, and good safety profile of the Cal/BD aerosol foam in patients with scalp psoriasis treated in a real-world setting.

Approaches to the diagnosis and treatment of patients with stage III—IV non-small cell lung cancer in Russia. Preliminary results of a prospective multicenter non-interventional observational study KARL

Approaches to the diagnosis and treatment of patients with stage III—IV non-small cell lung cancer in Russia. Preliminary results of a prospective multicenter non-interventional observational study KARL

REFLECT: prospective multicenter non-interventional study evaluating the effectiveness and safety of Sandoz rituximab (SDZ-RTX; Rixathon®) in combination with CHOP for the treatment of patients with previously untreated CD20-positive diffuse large B-cell lymphoma.

REFLECT is the first prospective study of Sandoz biosimilar rituximab (SDZ-RTX) in patients with diffuse large B-cell lymphoma (DLBCL). To evaluate the 2-year effectiveness and safety of SDZ-RTX as first-line treatment for DLBCL. Real-world, multicenter, open-label, single-arm, non-interventional, post-approval study of SDZ-RTX in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with treatment-naïve CD20‑positive DLBCL. Treatment-naïve, CD20-positive adult patients (⩾18 years) with DLBCL eligible for therapy with R-CHOP were treated with SDZ-RTX-CHOP every 2 or 3 weeks for 6-8 cycles. The effectiveness of SDZ-RTX was measured by the complete response (CR) rate at the end of R-CHOP treatment, as assessed by the treating physician. Progression-free survival (PFS) was assessed at 24 months. A total of 169 patients [52.1% female, median (range) age 70 (24-94) years] with DLBCL were included in the full analysis set. At baseline, 19.5% and 24.3% of patients had Ann Arbor disease stage III or IV, respectively, and most patients (80.5%) had Eastern Cooperative Oncology Group Performance Status of 0 or 1. A total of 100 (59.2%) patients completed the 24-month observation period. In total, 110 [65.1%; 95% confidence interval (CI): 57.4-72.3] patients achieved CR as best response and 50 (29.6%; 95% CI: 22.8-37.1) patients achieved partial response. Overall best response rate was 94.7% (95% CI: 90.1-97.5). One-year PFS was 84.9% (95% CI: 78.2-89.6), while 2-year PFS was 78.5% (95% CI: 70.9-84.4); median PFS was not reached within the observational period. A total of 143 (84.6%) patients experienced ⩾1 adverse event, 53 (31.4%) of which were suspected to be related to study drug. This real-world, 2-year study reconfirms that first-line treatment of CD20-positive DLBCL with R-CHOP using SDZ-RTX is effective and well tolerated. N/A.

Obesity is associated with myelin oligodendrocyte glycoprotein antibody-associated disease in acute optic neuritis

Optic neuritis (ON) is a frequent presentation at onset of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The pathophysiology underlying these diseases, especially MOGAD, is still being elucidated. While obesity has been reported to potentially be a risk factor for MS, this has not been explored in NMOSD or MOGAD. We aimed to investigate a possible association between obesity (body mass index [BMI] > 30 kg/m2) in patients with MOGAD, aquaporin 4-IgG positive NMOSD (AQP4-IgG+ NMOSD) or MS. In this multicenter non-interventional retrospective study, data was collected from patients with a first ever demyelinating attack of ON subsequently diagnosed with MOGAD (n = 44), AQP4-IgG+ NMOSD (n = 49) or MS (n = 90) between 2005 and 2020. The following data was collected: age, sex, ethnicity, BMI (documented before corticosteroid treatment), and the ON etiology after diagnostic work-up. A mixed model analysis was performed to assess the potential of obesity or BMI to predict MOGAD-ON, and to distinguish MOGAD-ON from AQP4-IgG+ NMOSD-ON and MS-ON. Main outcome measures included BMI in patients with acute ON and subsequent diagnosis of MOGAD, AQP4-IgG+ NMOSD or MS. A higher BMI was significantly associated with a diagnosis of MOGAD-ON (p < 0.001); in MOGAD patients the mean BMI was 31.6 kg/m2 (standard deviation (SD) 7.2), while the mean BMI was 24.7 kg/m2 (SD 5.3) in AQP4-IgG+ NMOSD patients, and 26.9 kg/m2 (SD 6.2) in MS patients. Mixed-effects multinomial logistic regression, adjusted for age and sex, with obesity as a binary variable, revealed that obesity was associated with a higher odds ratio (OR) of a subsequent MOGAD diagnosis (OR 5.466, 95% CI [2.039, 14.650], p = 0.001) in contradistinction with AQP4-IgG+ NMOSD. This study suggests an association between obesity and MOGAD. Our findings require further exploration, but could have significant pathophysiologic implications if confirmed in larger prospective studies.

Real-world treatment patterns, patient-reported outcomes, and effectiveness of flexibledosing etanercept in patients with plaque psoriasis in Greece.

Etanercept is approved for continuous or intermittent use and flexible dosing in plaque psoriasis (PsO). The objectives of this study were to investigate real-world treatment patterns with etanercept in Greek adults with moderate-to-severe PsO. This non-interventional multicenter study included a retrospective-to-prospective (RP) cohort, previously treated with etanercept for ≥24 months and followed for an additional 6 months, and a biologic-naïve, prospective-only (PO) cohort, followed for 6 months after treatment initiation. Parameters assessed included Psoriasis Area and Severity Index (PASI), percentage of body surface area (BSA) affected, Dermatology Life Quality Index (DLQI), and adverse events (AEs). This study enrolled 123 patients (RP, n = 56; PO, n = 67), who mostly adhered to continuous treatment (RP, 68%; PO, 95%). The two cohorts had similar mean baseline-to-endpoint decreases in PASI (-9.5 vs -10.1) and BSA (-11.9 vs -12.3). The PO-CTP population had a mean DLQI baseline-to-endpoint score decrease of -5.8, which was statistically significant and clinically meaningful. Treatment-emergent AE rates were 58.9% (RP) versus 26.9% (PO). These real-world data suggest a similar effectiveness of continuous and intermittent etanercept treatment in Greek patients with PsO.

Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 5th Interim Analysis of the Study RISA, with Special Consideration of Treatment Discontinuations

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet clearance and decreased megakaryopoiesis. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist, which is proved to be effective and safe in the treatment of ITP. Here we present data from the 5th interim analysis of the RISA study, specially considering the reasons for treatment discontinuation and possible links to the safety profile of EPAG. Methods: RISA is a prospective multicenter non-interventional study in Germany. It started in December 2015, and it will continue until December 2023. Statistical analysis is solely descriptive. Results: Data cutoff for this 5th interim analysis was 11th Feb 2022. 313 patients with persistent or chronic primary ITP (pITP) were enrolled. 302 of them received at least one dose of EPAG and completed at least one post baseline visit. Mean duration of participation was 74.1 months. Mean±SD age was 62.8±17.4 years. 54.8% of the patients were female. Mean±SD duration of ITP at baseline was 5.4±7.5 years. Comorbidity was present in 245 (81.1%) patients. Mean±SD number of concomitant diseases was 2.9±3.0. 99 (32.8%) patients completed the entire treatment period of 24 months, which includes all scheduled visits before data cutoff. Median treatment duration was 14 months (minimum 1 day, maximum 6.1 years). Treatment with EPAG was carried out at a median dosage of 50 mg daily. Median platelet counts increased from baseline 34.0x109/L (N=292) to 91.5x109/L (N=262) within one month. From then and until the end of the two-year observation period, platelet counts remained stable above 90x109/L. The proportion of patients whose platelet count was at least 50x109/L increased from 30.1% at baseline to 74.4% after one month and to 85.6% after twelve months. The number of bleeding events per patient-year decreased, from 1.35 at baseline to 0.59 and 0.16 after one and two years, respectively. 128 (42%) patients discontinued treatment, 51 (40%) of them before day 92. Reasons for discontinuation (multiple answers possible) were insufficient effectiveness in 55 (43%) cases, adverse events (AE) in 36 (28%) cases, death in 20 (16%) cases, non-compliance in 16 (13%) cases, lost to follow up in 10 (8%) cases, cessation of therapy due to complete response in 15 (12%) cases and other reasons in 10 (8%) cases. Across the data set, most frequent AE classified as non-serious adverse drug reactions (nsADR) were fatigue (5.3%), thrombocytopenia (3.3%), thrombocytosis (2.3%), diarrhea (3.0%) and dizziness (2.0%). The most common AE leading to discontinuation of treatment and classified as nsADR were thrombocytosis (1.3%), diarrhea (1.7%), fatigue (1.0%) and arthralgia (1.0%). The most frequent serious AE that led to treatment discontinuation and was rated as serious adverse drug reaction was pulmonary embolism, which occurred in 2 (0.7%) patients. Comorbidity was present in 109 (85.2%) of all patients who discontinued treatment. In this subgroup, the mean±SD number of concomitant diseases was 3.4±3.3. Conclusions: We were able to confirm that EPAG therapy in ITP effectively increases platelet counts and reduces the risk of bleeding. For methodological reasons, we were unable to calculate the actual overall response rate. However, based on the proportion of total patients who were shown to discontinue treatment due to insufficient effectiveness (18%), one could assume that all other patients responded to EPAG at least temporarily. This would result in an overall response rate of 82%. This seems to be consistent with the results of the open extension study EXTEND [Wong RSM et al. Blood 2017; 130: 2527-36], in which a similarly high overall response rate (86%) was found. In general, treatment with EPAG was well tolerated, with no new safety signals from our data set. In view of the high discontinuation rate, it should be borne in mind that about one in eight (12%) of these patients responded so well to EPAG therapy that this was taken as an opportunity for a discontinuation attempt. Other factors that may have contributed to treatment discontinuation included age and comorbidity of patients. Notably, the percentage and number of comorbidities in the discontinuation subgroup were even higher than in the overall study population. However, since this is a non-interventional observational study, results are descriptive and need to be interpreted with caution.

Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle

Sepsis is defined as a dysregulated host response to infection leading to organs failure. Among them, sepsis induces skeletal muscle (SM) alterations that contribute to acquired-weakness in critically ill patients. Proteomics and metabolomics could unravel biological mechanisms in sepsis-related organ dysfunction. Our objective was to characterize a distinctive signature of septic shock in human SM by using an integrative multi-omics approach. Muscle biopsies were obtained as part of a multicenter non-interventional prospective study. Study population included patients in septic shock (S group, with intra-abdominal source of sepsis) and two critically ill control populations: cardiogenic shock (C group) and brain dead (BD group). The proteins and metabolites were extracted and analyzed by High-Performance Liquid Chromatography-coupled to tandem Mass Spectrometry, respectively. Fifty patients were included, 19 for the S group (53% male, 64 ± 17 years, SAPS II 45 ± 14), 12 for the C group (75% male, 63 ± 4 years, SAPS II 43 ± 15), 19 for the BD group (63% male, 58 ± 10 years, SAPS II 58 ± 9). Biopsies were performed in median 3 days [interquartile range 1–4]) after intensive care unit admission. Respectively 31 patients and 40 patients were included in the proteomics and metabolomics analyses of 2264 proteins and 259 annotated metabolites. Enrichment analysis revealed that mitochondrial pathways were significantly decreased in the S group at protein level: oxidative phosphorylation (adjusted p = 0.008); branched chained amino acids degradation (adjusted p = 0.005); citrate cycle (adjusted p = 0.005); ketone body metabolism (adjusted p = 0.003) or fatty acid degradation (adjusted p = 0.008). Metabolic reprogramming was also suggested (i) by the differential abundance of the peroxisome proliferator-activated receptors signaling pathway (adjusted p = 0.007), and (ii) by the accumulation of fatty acids like octanedioic acid dimethyl or hydroxydecanoic. Increased polyamines and depletion of mitochondrial thioredoxin or mitochondrial peroxiredoxin indicated a high level of oxidative stress in the S group. Coordinated alterations in the proteomic and metabolomic profiles reveal a septic shock signature in SM, highlighting a global impairment of mitochondria-related metabolic pathways, the depletion of antioxidant capacities, and a metabolic shift towards lipid accumulation.ClinicalTrial registration: NCT02789995. Date of first registration 03/06/2016.

&lt;i&gt;BRCA&lt;/i&gt;-associated ovarian cancer: a review of the current literature

Ovarian cancer is a heterogeneous disease and is the leading cause of mortality among all gynecological malignancies. The disease is characterized by a high frequency of germline and somatic mutations in BRCA1/2 suppressor genes, which, according to various sources, occur in 10–27 % of all ovarian cancer cases. Determination of mutations in BRCA1 / 2 genes is a mandatory diagnostic criteria and includes performing next generation sequencing. Knowledge of the disease mutational status is important not only in the case of determining treatment plan, but also in the case of prevention of the other malignant neoplasms. The purpose of this review is to summarize the current data on the disease characteristics, diagnosis and treatment of BRCA-associated ovarian cancer. Also, the article presents data from a non-interventional multicenter OvATAR study to assess the prevalence of germline and somatic mutations in BRCA1 / 2 genes in the Russian patient population.

Epidemiology and natural history of non-metastatic castration-resistant prostate cancer in Russia

Aim. To study the clinical and demographic profile of patients with non-metatstatic castration-resistant prostate cancer (nmCRPC) and clinical approaches to the treatment of nmCRPC in the context of daily medical practice before and after progression M1 stage.Materials and methods. The multicenter non-interventional epidemiological study were included 200 patients with a documented diagnosis of nmCRPC from 2019 to 2020. Each patient visited twice: start and after 6 months. Of the 200 patients included, 9 were excluded from the analysis presented in this article: 1 patient had no information on inclusi- on criteria, 1 patient did not meet the inclusion criteria, 7 patients did not attend visit 2. Thus, data are presented for 191 patients.Results and conclusion. The median age was 74.3 years (range 55 to 91). 72 % (137/191) had a disability group. The most common comorbidities were hypertension (n = 115) and hypercholesterolemia (n = 56). The median time from the diagnosis of prostate cancer to the development of castration resistance (diagnosis of nmCRPC) was 75 months. Prostate specific antigen (PSA) nadir (0.37 ng/ml on average) was achieved after 15 months of prostate cancer therapy (median time to reach PSA nadir). At the same time, PSA doubling time in most cases (47.6 %; 91/191) was less than 6 months, 18.8 % of persons (36/191) had PSA doubling time for more than 10 months.

Effect of different antidiabetic medications on atherosclerotic cardiovascular disease (ASCVD) risk score among patients with type-2 diabetes mellitus: A multicenter non-interventional observational study

ObjectiveThe aim of this study was to compare the clinical outcomes associated with different combinations of oral diabetic drugs among patients with type 2 diabetes mellitus.MethodA prospective multicenter longitudinal, noninterventional observation study design was applied. At baseline (0 month), clinical parameters including glucose profile, renal function, lipid profile and risk assessment for cardiovascular risks were calculated. Mean Weighted difference (MWD) with heterogeneity and effect z was calculated to determine the risk reduction at the end of the study.ResultsA total of 1,657 were enrolled to different cohorts with response rate of 75.5%. The distribution of patients was based on prescribed drug. A total of 513 (30.9%) in G1 (metformin alone), 217 (13.09%) in G2 (metformin with Glimepiride), 231 (12.85%) in G3 (Metformin with Gliclazide), 384 (23.17%) in G4 (metformin with Sitagliptin) and 312 (18.89%) in G5 (Metformin with Saxagliptin). There was no significant different in all clinical and social variables at baseline. The Intergroup analysis showed significant differences with all the primary outcome variables except BMI (p = 0.217) and eGFR (p = 0.782) among patients using sulphonylurea (SU) combination (G2 & G3). Findings also showed significant high frequency of emergency visit and hospitalization in G1 (78.16% & 30.8%) as compared to SU (70.1% & 28.3%, p = 0.001) and DPP-4 (56.6% & 20.4%, p = 0.001). The overall reported effect was z = 2.58, p = 0.001 for ASCVD risk reduction assessment.ConclusionThe study concluded that significant effect of Dipeptidyl peptidase-4 inhibitor on reduction of hospitalization, lipid profile and also ASCVD risk score of type-II diabetes mellitus patients regardless of clinical comorbidities. Also, sulfonylurea combinations have showed significant reduction in LDL and triglycerides values.

Safety of combining dabrafenib plus trametinib in elderly BRAF V600 mutation-positive advanced melanoma patients: real-world data analysis of Spanish patients (ELDERLYMEL).

Efficacy and safety of dabrafenib and trametinib in metastatic melanoma have been demonstrated in two-phase III and one-phase I/II clinical trials. However, patients at least 75 years old (y.o.) were largely underrepresented. Additionally, the safety profile of dabrafenib and trametinib based on age is unknown. ELDERLYMEL is a retrospective noninterventional multicenter study, describing the effectiveness and safety of at least 75 y.o. patients compared with less than 75 y.o. patients with advanced BRAF V600-mutated melanoma treated with dabrafenib plus trametinib or dabrafenib monotherapy. A total of 159 patients were included, 130 less than 75 y.o. and 29 at least 75 y.o. Clinical features were similar between the groups, except in the number of comorbidities, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and BRAF V600-mutation type. Five patients per group received dabrafenib monotherapy. There were no differences in adverse events (AEs) rate or grade between the groups. However, AE profiles were different between the groups, being pyrexia infrequent in patients at least 75 y.o. (13.8% vs. 42.3%; P = 0.005). Dabrafenib and trametinib dose intensities were lower in at least 75 y.o. patients ( P = 0.018 and P = 0.020), but there were no differences in effectiveness between the groups. Finally, in a multivariate analysis, sex (female) was the only variable independently associated with an increased risk of AE grade ≥3. Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity. Additionally, we describe a different safety profile depending on age and sex.

Obesity and Impaired Metabolic Health Increase Risk of COVID-19-Related Mortality in Young and Middle-Aged Adults to the Level Observed in Older People: The LEOSS Registry.

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18–55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55–27.3)] as older (56–75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10–18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.