Background Therapy Research Articles

Sotatercept (Winrevair)

Canada’s Drug Agency (CDA-AMC) recommends that sotatercept (Winrevair) should be reimbursed by public drug plans for the treatment of patients with WHO Group 1 pulmonary arterial hypertension (PAH) if certain conditions are met. Winrevair should only be covered as add-on therapy in patients with confirmed WHO Group 1 PAH based on guidelines-approved diagnostic procedure including right-heart catheterization (RHC). Winrevair should only be reimbursed as an add-on therapy in patients who are not at low risk, currently treated with optimal background therapy for at least 3 months, and if the cost of Winrevair is reduced.

Eculizumab in refractory myasthenia gravis: a real-world single-center experience.

Immunosuppressive treatment is effective in most Myasthenia gravis patients, but 10-15% of patients areconsidered refractory due to inadequate response or intolerance to therapy. Eculizumab, a humanized monoclonalantibody directed against C5 complement protein, was approved in Italy to treat Ab-AchR generalized refractoryMG (rMG) in October 2022. We aim to describe a real-world Italian experience in a population of refractory myasthenia gravis patients with oneyear follow up. A retrospective data analysis was conducted on patients with refractory generalized MG treated with eculizumabbetween November 2022 and May 2024. Clinical assessment through specific scales (MG ADL - QMG - MGFA -PIS), rescue, and background therapy was recorded after one, three, six, and twelve months. 21 rMG patients were treated with eculizumab with a medium follow up of 10.4 months and 14 patients had at leastone year follow up. A clinically meaningful reduction in total MG-ADL and QMG scores was achieved in the firstmonth. It was maintained throughout the first, third, sixth, and twelfth month along with concomitant reduction ofimmunosuppressive treatments. A drastic reduction of myasthenic exacerbations and crisis was observed duringfollow up and intravenous immunoglobulin treatment was discontinued in all patients except one. The total dailydose of prednisone was significantly reduced. This single-center real-world study confirmes safety and effectiveness of eculizumab. Eculizumab improved rapidlyall clinical outcome measures, leading to discontinuation of intravenous immunoglobulin treatment and remarkable immunosuppressant-sparing benefits.

Immunogenicity of adalimumab reference product and adalimumab-adbm in patients with rheumatoid arthritis, Crohn’s disease and chronic plaque psoriasis: a pooled analysis of the VOLTAIRE trials

ObjectiveThis post hoc analysis compared the immunogenicity of the biosimilar adalimumab-adbm (Cyltezo) with the adalimumab reference product (RP; Humira) across indications, including rheumatoid arthritis (RA), Crohn’s disease (CD) and plaque psoriasis (PsO), and by patient sex in the VOLTAIRE trials programme.MethodsIn each active-comparator randomised controlled trial (RCT), immunogenicity was assessed at various time points by the proportion of patients with antidrug antibodies (ADAs) and neutralising antibodies (nAbs), using acid dissociation followed by electrochemiluminescence assay. Assay sensitivity was 50 ng/mL, and drug tolerance was ≥30 µg/mL (free drug) at the low positive control level.ResultsMinor differences in immunogenicity parameters (ADAs, ADA titres and nAbs) were evident between adalimumab-adbm and adalimumab RP across these three immune-mediated inflammatory diseases (IMIDs). The proportion of ADA-positive and nAb-positive patients increased from baseline over time in all three RCTs, as expected, and was similar in the RA and CD RCTs but with higher numbers of ADA-positive and nAb-positive patients reported in the PsO trial. Subgroup analysis by patient sex showed the same trend.ConclusionsDifferences among the RCTs may partially be explained by concomitant background therapy (methotrexate) in the RA trial, stable doses of azathioprine, 6-mercaptopurine or methotrexate in 36% of patients with CD and absence of background therapy in the PsO RCT. The analyses further confirm the biosimilarity of adalimumab-adbm with the adalimumab RP across IMIDs and provide supporting evidence that adalimumab-adbm is an interchangeable biosimilar with consistent clinical results in patients originally treated with the RP.Trial registration numbersVOLTAIRE-RA (NCT02137226; EudraCT 2012-002945-40); VOLTAIRE-CD (NCT02871635; EudraCT 2016-000612-14); VOLTAIRE-PsO (NCT02850965; EudraCT 2016-000613-79).

ARCADIA trials: Can nemolizumab be a valid alternative to the therapies currently available?

ARCADIA 1 and ARCADIA 2 were two randomized, placebo-controlled phase 3 trials showing the effectiveness of nemolizumab with concomitant use of low-to-medium potency topical corticosteroids, and/or with or without topical calcineurin inhibitors, in adults and adolescents with moderate-to-severe atopic dermatitis. Coprimary endpoints were met in the nemolizumab plus background therapy groups in both trials, with significant differences versus placebo.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry

Abstract Background/Introduction No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. Purpose This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Methods The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. Results We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. Conclusions Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH) study

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval. Purpose To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily. Methods Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort. Results The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P<0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P<0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p<0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P<0.05) with Imatinib that reached plateau before TPR. Conclusions Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.

Elegibility for Sacubitril/Valsartan in italian clinical practice: insights from the OPTIMA-HF registry

Abstract Background/Introduction Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Among them, angiotensin receptor blocker/neprylisin inhibitor (ARNi) are the foundation of neuro-hormonal blockade in patients with HFrEF, however the degree to which gaps in this medication use and dosing persist in outpatient practice is unclear. Purpose To assess the proportion of patients with HFrEF who are eligible for ARNi based on the PARADIGM-HF trial criteria and the association between eligibility and baseline characteristics. Methods The OPTIMA-HF (Optimization of Therapy in the Italian Management of Heart Failure) registry included outpatients in Italy with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/ARNI, beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Outpatients with HFrEF from 29 ambulatory cardiology practices and university hospitals in the OPTIMA-HF registry recruited between January 2022 and September 2023 were included. Of 1291 patients, 1018 (79%) met the PARADIGM-HF criteria and 949 of them (93%) were on ARNi. Of the enrolled patients, 342 (27%) were not on ARNi, however only 129 (38%) did not met the PARADIGM-HF inclusion criteria for ARNi prescription. Reasons for not meeting PARADIGM-HF criteria were no beta-blocker background therapy (22%), hyperkalemia (4%), hypotension (15%), chronic kidney disease (65%) and hyperkalemia (79%). In a logistic regression model not being on ARNi was associated with older age, chronic kidney disease, not being on cardiac resynchronization therapy, lower systolic blood pressure, lower BMI, and higher PAPs (Figure), representing the picture of a more fragile patient net of compliance with the PARADIGM-HF criteria. Conclusions Among outpatients with HFrEF in the OPTIMA-HF Registry, 79% met the PARADIGM-HF criteria. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Clinical characteristics and treatment patterns of new users of dapagliflozin for heart failure with reduced ejection fraction: an observational study programme across 12 countries (EVOLUTION HF)

Abstract Background Clinical trials have shown that dapagliflozin, a sodium–glucose cotransporter-2 inhibitor (SGLT-2i), reduces cardiovascular mortality and worsening heart failure (HF). Adoption of new therapies has historically been slow despite robust evidence. Furthermore, treatment profiles of patients in real-world settings are scarce. Purpose EVOLUTION HF is a multinational study programme that aims to describe clinical characteristics and treatment patterns among patients initiating dapagliflozin for HF with reduced ejection fraction (HFrEF) in routine clinical practice. Methods The EVOLUTION HF primary data study programme consists of prospective, observational, descriptive studies of new users of dapagliflozin for HFrEF in 12 countries (Italy, Portugal, UK and the Central and Eastern Europe and Baltic [CEEBA] region [Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovenia]). Patients with type 1 diabetes or prior SGLT-2i treatment were excluded. Clinical characteristics were obtained from electronic health records. A total of 2170/2555 (85%) patients were enrolled from November 2021 to November 2023; 1736 patient profiles were assessed using descriptive statistics in this interim analysis. Results In total, 256, 228, 125 and 1127 new dapagliflozin users were analysed from Italy, Portugal, the UK and the CEEBA region, respectively (Table 1). Across the 12 countries, mean patient age in the studies was 65–70 years. Patients were predominantly male (67–76%) and generally had HF with an ischaemic aetiology (35–56%) and New York Heart Association functional class II (52–85%). Mean left ventricular ejection fraction in the studies was 29–32% and estimated glomerular filtration rate was 61–77 mL/min/1.73m². Hypertension and atrial fibrillation were common comorbidities. Mean time between HF diagnosis and dapagliflozin initiation in the studies was 23–52 months. Background therapy included angiotensin receptor-neprilysin inhibitors (36–72%), angiotensin receptor blockers (4–12%) and angiotensin-converting enzyme inhibitors (9–33%). At 6 and 12 months after dapagliflozin initiation, respectively, treatment discontinuation rates across the CEEBA region were 5.22% (59/1131) and 4.66% (50/1072). Conclusions The EVOLUTION HF primary data study programme provides novel insights into clinical characteristics and treatment patterns in patients with HFrEF initiating dapagliflozin in real-world practice across a broad European population. At dapagliflozin initiation, a large proportion of patients were receiving other HF therapeutics, suggesting dapagliflozin is one of the later therapies to be initiated. Indeed, this study identified a substantial delay (23–52 months) in dapagliflozin initiation following HF diagnosis. Treatment discontinuation rates following dapagliflozin initiation were also low, reinforcing the findings of the EVOLUTION HF secondary data studies.

Predictive biomarkers for low-dose IL-2 therapy efficacy in systemic lupus erythematosus: a clinical analysis

BackgroundLow-dose IL-2 (Ld-IL2) has shown favorable therapeutic effects in systemic lupus erythematosus (SLE) therapy. However, previous clinical trials reported an SLE Responder Index-4 (SRI-4) response rate of 65.52%-68%, with approximately half failing to achieve the primary endpoint by week 24. Our study aims to determine the real-world use of Ld-IL2 and to identify determinants of its effectiveness in SLE.MethodsWe pooled data from 342 SLE patients undergoing sequential Ld-IL2 treatment, with 314 persisting for over 3 months were included in effectiveness and prediction analyses. All patients were categorized into responder (n = 136) and non-responder group (n = 178) according to SRI-4. Lupus Low Disease Activity State (LLDAS) was also analyzed to validate our results.ResultsRash, lower complement 3 (C3), and renal involvement including urine protein, urine occult blood and urine casts emerged as prominent predictors of achieving SRI-4. Adjusting for baseline values using the ratio of change to baseline revealed significant differences in CD4 + T cell immune profiles between responders and non-responders. ROC analysis confirmed a satisfactory performance of rash, renal involvement, percentage change of CD4 + T cells, and C3 in predicting SRI-4, yielding an AUC of 0.933. LLDAS analysis showed that hematological involvements and lower CLA + Treg were potent predictive markers in LLDAS attainment. Conversely, renal involvement failed to have significant association in achieving LLDAS. The analysis of background therapy in SLE patients showed that MMF was more likely to reach the SRI-4 response with the combination of Ld-IL2.ConclusionsThese findings uncovered the predictors of Ld-IL2 treatment efficacy in SLE patients and provided guidance to physicians for rational utilization.

Transit-guided radiation therapy: a novel patient monitoring approach

Background and purposeTransit-Guided Radiation Therapy (TGRT) is a novel technique that uses the transit portal images (TPIs) acquired with Electronic Portal Image Devices (EPID) to quantify patient position errors during the treatment. It has been validated using anthropomorphic phantoms but a validation in a clinical setting was lacking. A pilot clinical study is presented to confirm our previous results. Materials and methodsA prospective study was conducted between June and December 2022 with patients who received whole-brain or breast radiotherapy treatments. The selected treatments were composed of radiation fields using skin-flash, where the body contour projected a sharp edge on the EPID which has been used as a surrogate of the true patient position. Daily imaging procedures were applied as scheduled before running the one- and two-parameter model (1PM and 2PM) of the TGRT formalism on the acquired TPIs to independently estimate the patient position errors. Results43 patients and 1015 TPIs have been assessed. The 2PM showed a better correlation with the true position errors (R2 = 0.76 vs. 0.73), a lower detection threshold (0.77 mm vs. 1.24 mm), and a lower overcorrection risk above the detection threshold (7.0 % vs. 11.1 %) than the 1PM. Overall, the 2PM would have significantly reduced the true position errors by a factor of 0.58 (0.49 – 1.27) (p < 0.0001). ConclusionThe TGRT technique has confirmed the ability to reduce the position errors in a clinical setting, demonstrating the potential to enhance the patient position monitoring without increasing treatment time or patient dose.

Effect of modified constraint-induced movement therapy along with bimanual massed practice on upper extremity functions in tetraplegics: a pilot study

Background and objectiveConstraint-induced movement therapy is a widely used rehabilitation program in the stroke population, but its application in spinal cord injury is limited. The objective of the study is to determine the feasibility of modified constraint-induced movement therapy (mCIMT) in incomplete tetraplegia exhibiting upper limb weakness and activities of daily living (ADLs) difficulty.MethodThis is a quasi-experimental one-group pilot study, consisting of 12 subjects diagnosed with incomplete tetraplegia. They received 2-h sessions of modified constraint-induced movement therapy of the weaker hand along with a 1-h session of bimanual massed practice, 5 days a week for 3 weeks. Apart from this, they were asked to do 3 h of constrained-induced movement therapy daily 5 days a week for 3 weeks at their home as a part of a home exercise program. Box and block test (BBT) and Spinal Cord Independence Measure version III (SCIM-III) were taken as the primary measure, and manual function test (MFT) and capabilities for upper extremity (CUE) were used as secondary measures to access hand functions and ADLs. Subjects were examined during pre-intervention and post-intervention.ResultsAfter 3 weeks of intervention, the mean change of the score for the trained hand showed significant changes in the scores of the box and block test (p = 0.03), manual function test (p = 0.02), SCIM-III (p = 0.03), and CUE (p = 0.02).ConclusionThis preliminary study revealed that modified CIMT may be a feasible and effective alternative for hand rehabilitation in incomplete tetraplegia.

Association between inappropriate empirical antimicrobial therapy and mortality in gram-negative bloodstream infections in patients with febrile neutropenia and hematological malignancy

Background and objectiveInappropriate initial antimicrobial therapy has been associated with high mortality in patients with gram-negative bacilli bloodstream infections during febrile neutropenia following chemotherapy for hematological malignancies. The aim of this study is to determine this association in our hospital. MethodsA single center, retrospective, cohort study of bloodstream infection due to gram-negative bacilli and febrile neutropenia was conducted. Clinical characteristics, microbiological etiology, antimicrobial resistance profile, empirical and targeted antibiotic therapy, intensive care unit admission, persistent bacteremia and mortality were analyzed. ResultsOf the 171 episodes of bloodstream infection due to gram-negative bacilli, empirical antimicrobial therapy was inappropriate in 43 episodes (25.1 %). There was a significant difference in mortality at 7 and 30 days between patients who received appropriate versus inappropriate empirical treatment (4.6 % versus 13.9 %, p = 0.04; 15.6 % versus 32.5 %, p = 0.016). Inappropriate empirical treatment (RR, 2.97 [95 % CI, 1.01–8.74]), shock at the time of febrile neutropenia diagnosis (RR, 6.5 [95 % CI, 1.83–23.05]) carbapenem-resistant microorganism (RR, 3.73 [95 % CI, 1.14–12.24]) and persistent bacteremia (RR, 84.6 [95 % CI, 11.3–629.4]) were associated with an increased mortality at 7 and 30 days. In the multivariate analysis, shock (RR, 4.85 [95 % CI, 2.10–11.65]) and persistent bacteremia was independently associated with increased 30-day mortality, but inappropriate empirical antimicrobial therapy was not an independent prognostic determinant (RR, 1.66 [0.53–4.82]). ConclusionShock at the time of febrile neutropenia diagnosis contributes to mortality in patients with gram-negative bacilli bloodstream infection, in this scenario, appropriate empirical antimicrobial therapy should be encouraged.

Evaluating changes in body composition, bone mass, and metabolic profile in an animal model undergoing transfeminine hormone therapy and physical exercise

Background & AimsGender-affirming hormone therapy (GAHT) is essential for transgender individuals seeking body modifications. For transfeminine people assigned male at birth, GAHT typically involves a combination of antiandrogens and estrogens. Despite its importance, the scientific literature presents inconsistencies regarding the effects of these hormones on nutritional status, body composition, and biochemical markers. This study aims to evaluate the impact of estradiol enanthate and dihydroxyprogesterone acetophenide (E2EN/DHPA) hormonal treatment, in conjunction with resistive physical exercise, on body composition and metabolic profiles. MethodsTwenty-eight male rats were divided into three groups: MO (control group, n=8), receiving sesame oil vehicle; MH (n=11), receiving E2EN/DHPA; and MEH (n=9), receiving E2EN/DHPA along with physical exercise. The hormonal treatment was administered every ten days for two months, while the exercise regimen involved stair climbing with progressively increasing weights, performed five times weekly for seven weeks. Evaluated parameters included body mass index (BMI), body composition (fat and lean mass), bone mineral density (BMD), and lipid profile (triglycerides, HDL-C, LDL-C). ResultsThe rats that received E2EN/DHPA showed significant changes in body composition and BMI, regardless of exercise. The MH group had increased body fat, while both the MH and MEH groups had decreased bone area and mineral content. However, BMD remained the same across all groups. Elevated triglyceride levels were observed, and the MEH group also had reduced LDL-C levels. HDL-C levels did not show significant variation. ConclusionThe study's findings show similarities to changes seen in transfeminine individuals undergoing GAHT with estrogen and antiandrogens. These changes include decreased muscle mass, increased body fat, preserved bone mineral density, and elevated triglycerides. The study also found that resistance exercise positively impacted lipid profiles, particularly in reducing LDL-C. These results highlight the need for further research and comparative trials on hormone therapy regimens.

Statin use is associated with less ST-elevation versus non-ST-elevation myocardial infarction in a nationwide study

Background and aimsStatin therapy reduces myocardial infarction rate but whether it is associated with a shift of ST-elevation myocardial infarction (STEMI) towards non-ST-elevation myocardial infarction (non-STEMI) remains unknown. Thus, we tested the hypothesis that statin use is associated with less STEMI relative to non-STEMI in first-time myocardial infarction. MethodsIn a nationwide study, including 66896 patients with first-time myocardial infarction between 2010 and 2021, we obtained multivariable risk estimates for STEMI versus non-STEMI according to any statin use, cumulated statin use, and daily statin dose. Furthermore, we obtained hazard ratios for 60-day mortality (5545 deaths) following myocardial infarction according to type of infarction. ResultsOdds ratios for STEMI versus non-STEMI were 0.81 (95% CI:0.77-0.85) and 1.07 (1.01-1.13) in current and previous statin users compared to never statin users. Cumulated statin exposure yielded odds ratios of 0.96 (0.87-1.07) for <2 statin-years, 0.87(0.79-0.95) for 2-4.9 statin-years, 0.80 (0.74-0.87) for 5-10 statin-years, and 0.75(0.70-0.80) for >10 statin-years compared to never users. Corresponding odds ratios for statin dose intensity were 0.89 (0.84-0.95) for low-intensity, 0.77 (0.73-0.82) for moderate-intensity, and 0.70 (0.63-0.77) for high-intensity. Results were similar in multiple sensitivity analyses and using a cohort design. The hazard ratio for 60-day mortality after first-time STEMI versus non-STEMI was 2.24 (2.13-2.37). ConclusionsIn this nationwide study, prior statin use is associated with less STEMI relative to non-STEMI in a dose dependent manner. This indicates that statin therapy, in addition to reducing myocardial infarction event rates, also result in a less severe presentation of myocardial infarctions.

Comparing robust proton versus online adaptive photon radiotherapy for short-course treatment of rectal cancer

Background and purposeImage-guided proton beam therapy (IG-PBT) and cone-beam CT (CBCT)-based online adaptive photon radiotherapy (oART) have potentials to restrict radiation toxicity. They are both hypothesised to reduce therapy limiting bowel toxicity in the multimodality treatment of locally advanced rectal cancer (LARC). This study aimed to quantify the difference in relevant dose-volume metrics for these modalities. Material and MethodsSix-degrees-of-freedom IG-PBT and oART short-course radiotherapy (SCRT) were simulated for 18 LARC patients. Relative biological effectiveness (RBE) was 1.1 for IG-PBT. Delivered dose was evaluated using post-CBCTs. Target coverage was considered robust if average dose to 99 % of the clinical target volume was ≥ 95 % of the prescription. Organ at risk (OAR) doses were compared using dose-volume histograms and severe bowel toxicity estimated using dose–response modelling. ResultsTarget coverage was robust in all patients for oART and all but one patient for IG-PBT. For the main OARs, IG-PBT increased the volume exposed to ≥ 15 Gy (RBE), but reduced volumes exposed to lower doses. Both low- and high-dose exposure to bowel loops were significantly different between the modalities (median (interquartile range) IG-PBT-V8.9Gy(RBE) = 92 cm3 (51–156), oART-V8.9Gy(RBE) = 166 cm3 (107–234), p < 0.001; IG-PBT-V23Gy(RBE) = 62 cm3 (25–106), oART-V23Gy(RBE) = 38 cm3 (18–75), p < 0.001), translating into similar total grade ≥ 3 bowel toxicity risk. ConclusionIG-PBT and oART delivered comparable and satisfying target coverage in SCRT for LARC with similar estimated risk of severe bowel toxicity. Volumes of OAR exposed to 15 Gy (RBE) or more were reduced by oART, while IG-PBT reduced the volumes receiving doses below this level.

Complex case of multiple sclerosis with multiple demyelinating locations

Multiple sclerosis (MS) is a chronic inflammatory disorder with an unpredictable progression that affects the central nervous system and has significant emotional, social, and professional implications. The therapeutic approach is multifactorial and requires complex management coordinated by a specialized, multidisciplinary team over the long term. Current non-pharmacological treatment strategies under study, which may improve the course of the disease, focus on the gut microbiome and include the administration of probiotics and fecal transplantation. This study presents a case of secondary progressive multiple sclerosis in a young patient, with rapidly progressive evolution despite ongoing background therapy. The study analyzed literature data regarding both medical rehabilitation programs used in secondary progressive multiple sclerosis and other therapeutic strategies that can improve the quality of life. Medical rehabilitation has no proven impact on disease progression but can enhance the quality of life for patients with multiple sclerosis through spasticity management, improved mental health, increased mobility, and muscle strength. These therapeutic strategies can improve involvement in professional activities and participation in social and family life for patients with multiple sclerosis.

Early Addition of Selexipag to Double Therapy for Pulmonary Arterial Hypertension

A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied. To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i. This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023. TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT. Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up. A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90). This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

Effect of leech therapy in dermatophytosis: A randomized standard controlled trial

Background and purposeIn Unani medicine leech therapy is used as analgesic and resolvent purposes. The saliva of leech contains various biological substances like Hirudin, hyaluronidase, vasodilators, anesthetics, antibacterial, fibrinases, collagenase etc. To compare the efficacy of Leech therapy with local antifungal clotrimazole (1 %) cream in dermatophytosis on long term basis. Material and methodsA randomized, standard controlled, open labeled, clinical study was conducted on 40 patients of dermatophytosis, aged 18–60 years, and were randomly assigned into two groups; 20 patients in test group and 20 in control group. Patients were diagnosed clinically and confirmed through KOH examination. Complete haemogram, bleeding and clotting times, random blood sugar, HIV I & II, and HBsAg tests were carried out before starting the therapy, while haemogram was repeated after completion of treatment too. In test group, five sittings of leech therapy were applied, with intervals of one week. The control group was given clotrimazole (1 %) cream for topical application twice daily, continuously for a period of 28 days. Post-treatment follow-ups were done on 35th day in person, and then over the phone on 45th, 60th, and 90th days. Data were collected using Signs and Symptoms Severity Score for study, and Visual Analogue Scale (VAS). After completion of trial, appropriate tests were applied for statistical analysis of data. ResultsThe study shows, in most of the parameters, statically significant therapeutic effect in both the groups (p<0.001). No patients of either group reported any adverse event throughout the trial. Conclusionit appeared that leech therapy can contribute significantly in treating dermatophytosis (Qūbā) without any adverse effect, and with prolonged efficacy compared to standard treatment.

MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

Perception and knowledge of general practitioners on COPD management according to the GOLD23 document and reimbursement criteria for drugs prescription: an e-Delphi study

Background COPD management and therapy have been periodically revised to support a more patient-specific approach. Several concerns remain in primary care, such as the proper choice of initial treatment, medication adherence, and missing values for spirometry investigations. These concerns may be exacerbated by inconsistencies between the GOLD23 report and reimbursement criteria, as per the Italian NOTA99, especially for what concerns the assessment of disease severity and related treatment choice. We therefore examined the perception and knowledge of general practitioners (GPs) on COPD management and treatment. Methods We conducted an exploratory e-Delphi study among 600 GPs. The study examined the COPD-related GP's access to spirometry evaluations in primary care clinics; knowledge on early recognition of COPD and related clinical concerns; perception of the clinical application of the NOTA99; the place in therapy of the triple LABA/LAMA/ICS combination. Results Among 466 participating GPs (response rate: 70.3%; mean age 52, SD: 14.2; mean years of experience: 21.3, SD: 15) had a good level of knowledge about the GOLD 2023 document and the reimbursement criteria for COPD medications. Nevertheless, a low (34%) direct access to spirometry was reported, along with absence of consensus on the proper choice of initial treatment (especially of use of LABA/LAMA combination), and the re-evaluation of free-triple therapy LABA/LAMA/ICS through specialist’s referral. Conclusions This study captured the domains on which further training for GPs might be implemented to improve the management and treatment of COPD. An extension of this e-Delphi to a larger GPs’ panel might further confirm these findings.