Median Treatment Duration Research Articles

Duration of antimicrobial treatment for uncomplicated streptococcal bacteraemia: another example of shorter is better

ObjectivesDuration of treatment for uncomplicated streptococcal bacteraemia is unknown. The study aims to assess clinical outcomes of patients with uncomplicated streptococcal bacteraemia receiving a short course (5-10 days) of antimicrobial treatment compared to those receiving the traditional, longer duration (11-18 days). MethodsThis retrospective study was conducted at the Lausanne University Hospital, Switzerland and included episodes of uncomplicated streptococcal bacteraemia among adult patients from 2015 to 2023. Clinical failure was defined as mortality, recurrence of bacteraemia by the same streptococcal species and development in bone and joint infection within 120 days. ResultsDuring the study period, 336 episodes of uncomplicated streptococcal bacteraemia were included. The median duration of antimicrobial treatment was 10 days (interquartile range: 7-14); 184 (55%) and 152 (45%) episodes received a short (5-10 days) and long (11-18 days) duration of antimicrobial treatment, respectively. Forty-three (13%) episodes had clinical failure; 120-day mortality was 11% (36 episodes); recurrence of bacteraemia by the same streptococcal species was observed in 8 episodes (2%). No difference in clinical failure was observed between episodes receiving short and long courses of antimicrobial treatment (10% versus 16%; P 0.143). The Cox multivariable regression model found that a Charlson comorbidity index >4 (aHR 4.87, 95% CI 3.08-7.71), and septic shock (1.67, 1.04-2.67) were associated with clinical failure; a short course of antimicrobial treatment was not associated with clinical failure (0.90, 0.57-1.12). ConclusionsThis study has shown that a short duration of antimicrobial treatment for cases of streptococcal bacteraemia is effective and safe.

Analysis of the efficacy of adjusting the dose of imatinib with therapeutic drug monitoring in adjuvant treatment after complete resection of gastrointestinal stromal tumors

Objective: To explore the efficacy of adjusting the dose of imatinib dose in the context of therapeutic drug monitoring (TDM) in patients with gastrointestinal stromal tumors (GISTs) who are receiving adjuvant therapy after complete resection of their tumors. Methods: This was a descriptive study. Inclusion criteria were (1) complete surgical resection with a pathological diagnosis of GIST, (2) postoperative adjuvant therapy with imatinib and dosage adjustment, (3) multiple TDM of imatinib, and (4) complete clinical, pathological, and follow-up data. The data of 70 patients with GISTs treated at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 and December 2023 were collected retrospectively. The study cohort comprised 15 (21.4%) men and 55 (78.6%) women of median age 60 years (range: 25-82). Of the eligible patients, 49 (70.0%) were at high-risk, 14 (20.0%) at intermediate-risk, six (8.6%) at low-risk, and one (1.4%) at very low risk. Patients were followed up by the gastrointestinal stromal tumor clinic every 2-3 months and their plasma concentrations of imatinib were checked. The dose was adjusted to 300 mg/d or 200 mg/d depending on whether they had had ≥ grade III adverse reactions, and whether the first plasma concentration of imatinib was ≥ 1,500 μg/L or between the expected range of 760 μg/L-1,100 μg/L. Studied indicators included adverse reactions, quality of life before and after dose adjustment, and overall survival and recurrence-free survival (RFS) after dose adjustment. Results: Before dose adjustment, all 70 patients received 400 mg of imatinib daily, with initial TDM values of 1,900 ± 568 μg/L, for a median duration of 8.3 months. After dose adjustment, 60 patients received 300 mg daily, with a TDM of 1,216 ± 350 μg/L, whereas 10 received 200 mg daily, with a TDM of 1,023 ± 269 μg/L. The median duration of treatment after dose adjustment was 23.4 months. Compared with those whose dosages were not adjusted, the incidence of bone marrow suppression was significantly lower (74.3% [52/70] vs. 51.4% [36/70], χ2=9.202, P=0.010); as were the incidences of edema (95.7% [67/70] vs. 50.0% [35/70], χ2=40.526, P<0.001); skin reactions (70.0% [49/70] vs. 32.9% [23/70), χ2=22.495, P<0.001); and gastrointestinal reactions (38.6% [27/70] vs. 10.0% [7/70], χ2=15.899, P<0.001) in those whose dosages were adjusted. The average total scores for physical health before and after dose adjustment were 76 ± 5 and 88 ± 4, respectively; whereas the mental health scores were 75 ± 6 and 89 ± 4, respectively. The median follow-up period was 36 months (range 6-126). During the first 3 years of follow-up, five high-risk patients with non-gastric GISTs developed recurrences. The 3-year overall survival rate was 100%, and the 3-year RFS rate was 92.8%, high-risk patients having a 3-year RFS rate of 89.8%. Conclusion: The adverse reactions and quality of life of GIST patients with severe adverse reactions to adjuvant imatinib therapy after complete resection can be mitigated by appropriately reducing the dosage of imatinib under the guidance of TDM.

Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study.

Vepdegestrant (ARV-471) is an oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. This phase 1 study (NCT05463952) investigated safety, pharmacokinetics, and antitumor activity of vepdegestrant in Japanese patients with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer at the 200-mg once daily (QD) recommended phase 3 dose. Eligible patients had ER+/HER2- advanced breast cancer resistant to standard therapy, with no standard therapy available, or had received two or more prior endocrine therapies in any setting. The primary endpoint was dose-limiting toxicities (DLTs) in cycle 1; secondary endpoints included safety, pharmacokinetics, and antitumor activity. Six female patients (median age, 58 [range: 47-62] years) were treated. For advanced disease, three (50.0%) patients received three or more prior regimens and five (83.3%) patients received prior cyclin-dependent kinase 4/6 inhibitors. At data cutoff, median treatment duration was 9.8 (range: 6-28) weeks; two patients remained on treatment. No DLTs were observed. Four (66.7%) patients experienced adverse events; none led to dose reduction or discontinuation. Four (66.7%) patients had treatment-related adverse events; all were grade 1 except anemia (grade 2). Geometric mean maximum plasma concentration and 24-h area under the plasma concentration-time curve of vepdegestrant were 630.9 ng/mL and 10,400 ng∙hr/mL after a single dose and 1056 ng/mL and 18,310 ng∙hr/mL after multiple doses. Two (33.3%) patients demonstrated stable disease at week 24. Vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer with no notable differences in pharmacokinetics from Western patients. ClinicalTrials.gov: NCT05463952 (date of registration: July 19, 2022).

Aetiology, Treatment and Outcomes of Pericarditis: Long-Term Data from a Longitudinal Retrospective Single-Centre Cohort.

Background. Pericarditis has a heterogeneous clinical spectrum and rate of relapse. Data on aetiology, real-life treatment strategies, and long-term course from contemporary pericarditis cohorts are lacking. Methods. Pericarditis patients referred to the Cardioimmunology Outpatient Clinic at Padua University Hospital in 2001-2020 were retrospectively included. Kaplan-Meier method was used for recurrence-free survival probability estimation. The appropriateness of treatment was assessed based on the European Society of Cardiology guidelines. Results. One-hundred forty-four patients (57% males, mean age 50 years) followed up for 18 months (IQR 7-45) were included; of those, 52% had acute, 35% recurrent, 8% incessant, and 5% chronic pericarditis; 9% had cardiac tamponade at diagnosis. Time to pericardial effusion resolution was 53 days (IQR 16-124); median medical treatment duration was 87 days (IQR 48-148). Treatment was readjusted following the ESC guidelines for nonsteroidal anti-inflammatory drugs in 29% of the cases, steroids in 12%, and colchicine in 25%. Eleven (8%) patients were treated with anti-IL1 agents. Recurrence-free survival probability was 86% at 1st-year follow-up, and 23 patients (16%) had at least one recurrence, with a mean of two relapses per patient. Compared to patients without recurrences, they had a higher frequency of cardiac tamponade (27% vs. 6%, p = 0.006) and left bundle branch block (14% vs. 1%, p = 0.034). Out of the 144 patients, 5 (3%) were diagnosed as having constrictive pericarditis at first evaluation at our clinic, underwent successful pericardiectomy, and are currently alive and asymptomatic. Conclusions. When treated following a guideline-based approach, pericarditis has a favourable evolution. A relevant quote of cases benefits from the treatment readjustment of previously prescribed medical therapy when not in line with ESC recommendations. Cases relapsing despite treatment readjustment should receive anti-IL1 therapies.

EGS SO24 - Endoscopic Vacuum Therapy for Oesophageal Perforation and Anastomotic Leaks

Abstract Background Oesophageal perforations and oesophago-gastric (OG) anastomotic leaks are challenging conditions, associated with significant morbidity and mortality. In recent years, endoscopic vacuum (EndoVac) therapy has emerged as a novel, alternative intervention for source control and to promote healing. Introduced to our unit in 2019, this cohort study presents our experience with EndoVac management of both post operative OG anastomotic leaks and primary oesophageal ruptures. Method Retrospective analysis of patient electronic records was conducted for all patients who received EndoVac management between the study period of October 2019 to June 2023. Pertinent outcome variables included length of vacuum therapy, number of changes, length of admission, in hospital and 90 day mortality rates. Results 37 patients were identified within the study period. The average age of this study cohort was 68 years with a mode ASA of III. The most common indication for EndoVac therapy was anastomotic leak (56%), followed by oesophageal perforation (31%). Defect resolution was achieved in 72% of patients. The median duration of treatment was 26 days (range 2-157), whilst the median number of changes was 7 (range 2-31). The overall in hospital complication (Clavien Dindo I-V) rate was 34%. The 90-day mortality rate was 22% whilst the morbidity rate was 13% in the form of anastomotic stricturing requiring serial dilatations. Conclusion EndoVac therapy is an effective minimally invasive treatment for post operative OG anastomotic leaks and oesophageal ruptures. With ongoing expansion in it’s use in our unit and throughout the UK, further work is required to assess the long-term outcomes and develop guidelines around its use in both oesophageal leaks and perorations.

Longitudinal assessment of thyroid function in dogs with hypoadrenocorticism: Clinical outcomes and prevalence of autoantibodies.

Knowledge about primary hypoadrenocorticism coexisting with immune-mediated thyroiditis (Schmidt's syndrome) in dogs is limited. To evaluate thyroid function in dogs with naturally occurring hypoadrenocorticism before and during treatment. Sixty-six client-owned dogs. Measurement of canine thyroid stimulating hormone (cTSH), total thyroxine (T4), free thyroxine, and autoantibodies against thyroglobulin, T4, and total triiodothyronine. Thirty-eight dogs were assessed before and 28 during treatment. Follow-up data were available for 24/38 and 17/28 dogs, with median follow-up duration of 3.8 years (range, <1.0-8.8 years) and 4 years (range, 1.1 weeks to 10.5 years), respectively. Canine thyroid stimulating hormone was above the reference range at the time of diagnosis of hypoadrenocorticism in 10 of 38 dogs but decreased into the reference range in 7 for which follow-up data was available. Hypothyroidism was confirmed in 5 dogs at a median age of 11 years (range, 7-15 years). In 4 dogs, the condition was diagnosed after a median treatment duration of 5.75 years (range, 2.6-10 years), while in 1 dog, the diagnosis was made concurrently. One dog had detectable thyroid autoantibodies. Hypothyroidism occurs as a rare concurrent condition in dogs with hypoadrenocorticism, potentially at any phase of treatment. Close monitoring of cTSH levels in these dogs could be beneficial, as early changes might indicate the onset of hypothyroidism. The low prevalence of detectable thyroid autoantibodies suggests that nonimmune mechanisms might contribute to thyroid dysfunction.

Survival, treatment duration and costs of patients with prostate cancer treated with triptorelin in Italy: a study of administrative databases.

Several data support the efficacy/effectiveness, safety and favorable impact on quality of life of triptorelin treatment in patients with prostate cancer. However, little evidence is available concerning triptorelin use in the long term. We analyzed data on triptorelin treatment in patients with prostate cancer in an integrated Italian administrative database, covering around 6 million health-assisted subjects throughout the country. Patients with at least one prescription for triptorelin in the period 2010-2020 and with no evidence of metastasis were included and followed up until 2021. Overall survival (OS) and duration of treatment were analyzed using Kaplan-Meier curves, starting from the date of first prescription. The cohort included a total of 3,411 patients (mean age: 76.8 ± 8.7 years), of whom 1,326 (38.9%) were treated with triptorelin only and 2,085 (61.1%) with triptorelin combined with an anti-androgen. Overall, 847 (24.8%) patients with prostate cancer died and 1,037 (30.4%) had a treatment switch during the follow-up period, and both the median OS and median duration of treatment were not reached in both groups. The mean annual total cost per patient was estimated as 5,574 €, with almost half of the costs related to medication expenses (2,737 €). We found a long survival and duration of triptorelin treatment in this population of Italian patients with prostate cancer. This study with a long follow-up period further highlights the usefulness of healthcare utilization databases to integrate results obtained from clinical studies with those from everyday clinical practice.

INNV-07. IVOSIDENIB AND BEVACIZUMAB IN HEAVILY PRETREATED PATIENTS WITH IDH1 MUTANT GLIOMAS

Abstract Isocitrate dehydrogenase 1 (IDH1) inhibitors are transforming the treatment of patients with non-enhancing IDH1 mutant gliomas that have only undergone surgical resection. Questions remain on the utility of IDH1 inhibitors in patients that have received prior therapies such as radiation therapy (RT) and chemotherapy (e.g. temozolomide (TMZ)) and have progressive disease. We evaluated the safety and efficacy of ivosidenib, an oral IDH1 inhibitor, in combination with bevacizumab (BEV), a monoclonal antibody targeting VEGF-A, in IDH1 mutant glioma patients that were heavily pretreated. Fourteen patients received combination ivosidenib and bevacizumab starting between February 2021 to July 2023. In our small cohort, patient age range was 26 to 73 years with seven female patients and seven male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=10) and oligodendroglioma, IDH1 mutant (n=4). At the time of IDH1 therapy initiation, the majority of patients (n=10) had a grade 3 tumor. All patients (n=14) had canonical IDH1 mutation (p.Arg132His) and had enhancing disease. Therapies initiated prior to ivosidenib therapy included: prior RT (n=12), prior TMZ (n=14) and prior BEV (n=10). The median number of progressions prior to initiation of ivosidenib combination therapy was 3 (range 2 to 6). All patients received ivosidenib dosed at 500 mg daily with bevacizumab doses varying from 5 to 15 mg/kg IV dosed every 2 to 3 weeks. Combination therapy was well tolerated with minimal patients experiencing toxicities requiring dose interruptions; diarrhea (n=2), creatine phosphokinase elevations (n=1), QTc prolongation (n=1), and thrombocytopenia (n=1). The median treatment duration on ivosidenib combination therapy was 4.42 months (range 0.69 to 11.4 months). In this cohort, the combination of ivosidenib and bevacizumab was well tolerated. More information is needed on the benefit of ivosidenib in combination with other therapies and in heavily pretreated patients with IDH1 mutant gliomas.

CTNI-22. DABRAFENIB (D) AND TRAMETINIB (T) EITHER IN COMBINATION OR AS MONOTHERAPY IN PEDIATRIC PATIENTS HARBORINGBRAF ALTERATIONS IN GLIOMAS OR OTHER RARE TUMORS: FINDINGS FROM AN EARLY ACCESS PROGRAM (EAP)

Abstract BACKGROUND In 2022, dabrafenib and trametinib (D+T) combination received an accelerated US FDA approval for use in adult and pediatric patients with BRAF V600E–mutated unresectable or metastatic solid tumors with no viable alternative therapy. However, to provide global access to therapy in countries where the suitable formulations and/or indications are not yet approved, EAPs are established. We report on patient data from an EAP for pediatric patients with BRAF V600-mutated gliomas or other rare tumors with BRAF alterations such as BRAF fusions, seeking clinical benefit from therapy with dabrafenib and/or trametinib. METHODS We analyzed data from the global EAP, where pediatric patients with BRAF alterations in solid tumors including gliomas or other rare tumors received D+T combination or monotherapy. Key eligibility criteria included: age &amp;lt;18 years, absence of approved indications, presence of BRAF V600E/K mutation or other BRAF alterations, and exhaustion of standard therapies. Requests were processed through a global system from November 2016 to December 12, 2022 (cutoff date). Key data on patient characteristics and median treatment duration (mDoT) were collected and will be presented. RESULTS Overall, 482 patients with solid or hematological malignancies were included, of which 35.1%, 31.7%, and 33.2% received combination therapy and dabrafenib and trametinib monotherapies, respectively. Across the treatment cohorts, median age was 4.2-6.6 years, and 49.4%-52.9% were males. Most patients had low-grade (72%) or high-grade (4.6%) gliomas, followed by Langerhans cell histiocytosis (17.8%) and other tumors (5.6%). The estimated mDoT for liquid and solid formulations were, respectively, 14.6 months and 10.1 months in combination therapy, 16.5 months and 12.8 months in dabrafenib monotherapy, and 8.8 months and 7.4 months in trametinib monotherapy. CONCLUSIONS EAP data represent a valuable real-world resource in understanding patient characteristics in rare tumors (pediatric gliomas). A significant number of treatment requests indicate substantial unmet need, and significant mDoT across age categories was suggestive of benefit to pediatric patients on therapy.

INNV-27. TEMOZOLOMIDE FOR PATIENTS WITH AGGRESSIVE PITUITARY TUMORS: A CASE SERIES

Abstract BACKGROUND Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors. METHODS We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide. RESULTS Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2). CONCLUSION In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.

INNV-37. REAL-WORLD OUTCOMES AMONG HIGH GRADE IDH1-MUTANT GLIOMA PATIENTS TREATED WITH AN IDH INHIBITOR

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) inhibitors are transforming the treatment of patients with non-enhancing grade 2 IDH-mutant gliomas. Uncertainty remains on the utility of IDH-inhibitors in high-grade IDH-mutant glioma patients that had prior therapies and have progressive disease. METHODS From October 2020 to December 2023, we identified high-grade IDH1-mutant patients treated with off-label ivosidenib, a mutant IDH1 inhibitor. We report their clinical and imaging characteristics. RESULTS In our cohort (n=18), the patient age range was 29-68 years with male predominance (n=11). Diagnoses included astrocytoma grades 3 (n=9) or 4 (n=2), and oligodendroglioma grade 3 (n=7). The median number of progressions prior to ivosidenib initiation was 2 (range 1-7). Fifteen patients had prior surgical resection, three had biopsy. Prior treatment exposures included radiation therapy (n=15), temozolomide (n=18), lomustine (n=5), bevacizumab (n=3), etoposide (n=1), optune (n=1) and a clinical trial (n=1). Mean time from diagnosis to ivosidenib treatment was 9.6 years (95% CI, 6.7 to 16.4 years). Karnofsky performance-status score upon initiation was 80 (n=6) or 90 (n=12). Thirteen patients had &amp;gt;1 cm enhancing disease, five had non-enhancing disease. Ivosidenib was initiated due to enhancing disease progression (n=11), non-enhancing disease progression (n=4), a combination of both (n=2) or temozolomide intolerance (n=1). Best radiographic responses per RANO criteria were partial response (n=2), minor response (n=3), stable disease (n=7), and progressive disease (n=6). Nine patients continue ivosidenib without disease progression, with a median treatment duration of 27.5 months (95% CI, 18.0 to 33.0 months). All had FLAIR stabilization/improvement and 45% (n=4) had improved enhancing disease. Nine patients discontinued ivosidenib due to progression, with a median treatment duration of 7 months (95% CI, 3 to 9 months). CONCLUSIONS These data suggest that treatment with an IDH inhibitor can provide disease control for some high-grade IDH-mutant glioma patients who had prior therapies and progressive disease. Future studies are needed to investigate this patients population.

Cannabinoids for obstructive sleep apnea: A systematic review.

Cannabinoids have emerged as a potential treatment for obstructive sleep apnea (OSA). This systematic review aimed to summarize the efficacy and safety of cannabinoids to treat OSA. Databases including Ovid MEDLINE, EMBASE, Scopus, PsycINFO, and International Pharmaceutical Abstracts were searched; experimental and observational studies were eligible for inclusion. One-hundred seventy unique records were screened, and nine studies included: five full-text studies and four published abstracts. The five full-text studies were judged for quality appraisal: two studies deemed at low risk for bias, one study deemed to have some concerns for bias, and two studies deemed to have high risk for bias. Seven of nine total studies were experimental designs and evaluated dronabinol, and the other two studies were observational designs evaluating cannabis. The range of cannabinoid therapy duration spanned from 1 to 6 weeks, and the median duration was 3 weeks. Eight of nine total studies reported statistically significant, positive OSA outcomes due to cannabinoid therapy including reductions in the apnea hypopnea index and improvements in patient-reported daytime sleepiness scales. Between 70% and 80% of study participants reported neuropsychiatric and gastrointestinal adverse events attributable to cannabinoids. The American Academy of Sleep Medicine does not recommend using cannabinoids to treat OSA due to a lack of long-term safety and efficacy data. This systematic review found similar limitations, with the median cannabinoid treatment duration being only 3 weeks. Adequately powered experimental trials over longer time frames are necessary to more completely assess the long-term efficacy and safety of cannabinoids in the treatment of OSA and its effects on common comorbid conditions, such as obesity and cardiovascular disease.

Darolutamide in Japanese patients with metastatic hormone-sensitive prostate cancer: Phase 3 ARASENS subgroup analysis.

In the global ARASENS study (NCT02799602), darolutamide plus androgen-deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57-0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants. Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival. The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50-1.64), despite 85% of patients in the placebo group receiving subsequent life-prolonging therapy. Darolutamide prolonged time to castration-resistant prostate cancer (HR 0.31; 95% CI 0.17-0.55). Treatment-emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population. In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients.

Non-inferiority trial in veal calves on the efficacy of oxytetracycline and florfenicol treatment for pneumonia guided by quick thoracic ultrasound

Purchase dependent calf rearing systems, such as the white veal industry, systematically rely on antimicrobial mass medication (metaphylaxis) to counter respiratory tract infections. Despite mounting criticism, the industry fears that without metaphylaxis, mortality would drastically increase. This randomized clinical trial aimed to compare the efficacy of a quick thoracic ultrasonography (qTUS) individualized treatment length between oxytetracycline (OTC) and florfenicol (FF). Regression of maximum consolidation depth < 1cm was used as a criterion for cure and to stop antimicrobial treatment. Additionally, the study assessed the associations of consolidation depth at treatment initiation with cure and treatment duration. The trial involved 320 veal calves, randomly assigned into one of 2 groups: one receiving OTC (n = 160) and the other FF (n = 160) on d 1 (2-d metaphylaxis). Clinical scoring and qTUS were done on d 1 and every 48 h for a 10-d period. After d 1, only calves with consolidations ≥ 1cm were given further treatment. On each time point, maximum consolidation depth was used to categorize calves into 4 qTUS categories: healthy (no consolidation), mild pneumonia (consolidation < 1cm), moderate pneumonia (consolidation 1-3cm) and severe pneumonia (consolidation ≥ 3cm). Cure, treatment duration and the number of antimicrobial dosages (NAD) were compared between treatment groups. In addition, pathogen identification and antimicrobial susceptibility testing was performed on isolates from non-endoscopic broncho alveolar lavage fluid. On d 1, 30.0% (96/320) of the calves had consolidation ≥ 1cm, which increased to 50.9% (162/318) by d 9. After single metaphylactic treatment, cure was 20.9% (9/43) and 20.9% (9/43) in the OTC and FF group, respectively. Calves with severe pneumonia had lower odds to be cured after first treatment than calves with moderate pneumonia (Odds ratio (OR) = 0.17; 95% Confidence interval (CI): 0.04 - 0.63). By d 9, final cure of the initial cases was 27.9% in both the OTC- and FF-group. both groups, cure was similar at all observation points (P > 0.05). Overall, final cure of all calves with either moderate or severe pneumonia during the trial was 41.2% (52/102) and 19.0% (12/63), respectively (P = 0.004). Median treatment duration was 4 d (Interquartile range (IQR) = 2-6; Minimum (Min) = 2; Maximum (Max) = 8) and was similar in both treatment groups (P = 0.59). Treatment duration for calves with moderate pneumonia (Med = 6; IQR = 4-6; Min = 2; Max = 8) was lower than the median treatment duration of calves with severe pneumonia (Med = 8; IQR = 4-8; Min = 2; Max = 8) (P = 0.004). When compared with calves with mild pneumonia on d 1, calves with moderate (P = 0.01) and severe pneumonia (P < 0.001) had significantly longer treatment durations. In this study, cure was low and not different between both antimicrobials. Categorizing calves based on consolidation depth appears useful as both cure and treatment duration were different for the mild, moderate and severe group.

Epidemiological and virological characteristics of people living with HIV on antiretroviral treatment for more than 6 months in virological failure in Brazzaville, Republic of Congo

Introduction. Virological failure is one of the main causes of failing to treat, and better management of HIV infection requires understanding and controlling the factors that contribute to this phenomenon. The main objective was to characterize the patients of the active file of the Brazzaville Outpatient Treatment Center in virological failure to identify predictive factors leading to virological failure. Methods. Conducted between June and December 2020, this was a cross-sectional study. Patients enrolled were HIV-1-infected patients from the Brazzaville Outpatient Treatment Center receiving a potent combination therapy for at least 6 months but experiencing virological failure. Viral load was measured using the automated Abbott Real-time HIV-1 m2000rt System. Sociodemographic and clinical data were collected from a computerized patient record software called Santia. For the identification of the independent predictors of virological failure, statistical analysis was performed. Results. A total of 109 patients with virological failure were recruited. The median age of the patients was 45 years (interquartile range: 37–52 years) and women were more represented (74%). More than half of the patients had World Health Organization stage IV HIV and the median duration of antiretroviral treatment was 96 months. The most followed treatment regimen was AZT+3TC+EFV (or nevirapine) with 48%, while the median viral load was 12985 copies ml−1. Conclusion. In our study, we did not identify any sociodemographic or clinical variables predictive of virological failure. However, we felt that it would be desirable to carry out a study with temporal follow-up and the possibility of sequencing in order to identify the different circulating genotypes and resistance mutations.

Sodium Zirconium Cyclosilicate for Renin-Angiotensin-Aldosterone System Inhibitor Optimization in Patients with Heart Failure with Reduced Ejection Fraction: A Retrospective Analysis.

In this retrospective analysis, we evaluate the effectiveness of the potassium (K+) binder sodium zirconium cyclosilicate (SZC) in maintaining normokalemia and facilitating the initiation, optimization, and maintenance of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). A total of 44 patients with HFrEF and a history of hyperkalemia who were receiving SZC to enable the prescription of RAASi were identified from two district general hospital sites. Retrospective analysis was performed to determine biochemical response, alterations in pharmacotherapy, and subsequent HF outcomes following initiation of SZC. Mean K+ was reduced by 0.9mmol/L within 1month of initiation of SZC; mean K+ after 12months of treatment was 4.8mmol/L with a median (interquartile range) duration of treatment of 13 (8.4-15.1) months. Following SZC treatment, 100% of patients received an angiotensin receptor-neprilysin inhibitor (18% increase) and 93% received a mineralocorticoid receptor antagonist (41% increase), with 59% and 37% achieving guideline-recommended dosing, respectively. Ninety-one percent of patients were able to receive triple or quadruple therapy with the addition of a beta-blocker and a sodium glucose co-transporter2 inhibitor. Reduced rates of hospitalization for HF (HHF) were observed with 12 episodes per 100 patient-years recorded (reduced from 21) in addition to improvements in mean left ventricular ejection fraction (29-36%) and median N-terminal pro-B-type natriuretic peptide (3458-2055ng/L, 45% median reduction). Renal function (creatinine clearance increased from 48.4 to 49.3ml/min) and systolic blood pressure (decreased from 124 to 122mmHg) were similar following optimization, and no tolerability issues were identified. Extended real-world treatment with the K+ binder SZC was effective at maintaining normokalemia, and was associated with a greater uptake of RAASi, a reduced rate of HHF, and improvements in cardiac biomarkers in patients with HFrEF.

Evaluation of Clinical and Laboratory Findings of Sinusitis Complications in Children

Abstract Objective This retrospective study evaluates the demographic characteristics, clinical symptoms, laboratory results, treatment approaches, and outcomes of children with complications arising from bacterial sinusitis. Methods Fifty-four pediatric inpatients with sinusitis complications admitted between September 2013 and October 2022 were included in the study. These patients were categorized into two groups: those with preseptal cellulitis (group 1) and those with orbital–intracranial complications (group 2). Results The median age of the patients was 10.8 years, and 61.1% were males. Maxillary sinusitis (n = 40.74%) was the most common type of sinus involvement. Half of the patients exhibited preseptal cellulitis. The median age of our patients with intracranial complications was 13.7 years, while the median age of patients with orbital complications was 8 years. The predominant orbital–intracranial complication was meningitis, which accounted for 41% of the cases. All patients with a subdural abscess (n = 6) presented with frontal sinusitis, while all cases of cavernous sinus thrombosis (n = 3) involved the sphenoidal sinus. Surgical intervention was undertaken in 37% of cases. Streptococcus pneumoniae was the most frequently isolated microorganism. The median duration of hospital stay was 14 days, with a total median treatment duration of 21 days. There were no fatalities, although neurological sequelae were observed in 7.4% of patients (n = 4). Conclusion Preseptal cellulitis and meningitis remain the most common complications of sinusitis in children. Adolescents with sinusitis should be monitored closely for intracranial complications. The prevalence of S. pneumoniae as the most frequently detected pathogen underscores the importance of vaccination.

Endogenous reactivation cases identified by whole genome sequencing of Mycobacterium tuberculosis: Exploration of possible causes in Latvian tuberculosis patients

BackgroundThe recurrence of tuberculosis (TB) continues to place a significant burden on patients and TB programs worldwide. Repeated TB episodes can develop either due to endogenous reactivation of previously treated TB or exogenous reinfection with a distinct strain of Mycobacterium tuberculosis (Mtb). Determining the precise cause of the recurrent TB episodes and identifying reasons for endogenous reactivation of previously successfully treated patients is crucial for introducing effective TB control measures. MethodsHere, we aimed to provide a retrospective individual analysis of the clinical data of pulmonary TB patients with assumed endogenous infection reactivation based on WGS results to identify the reasons for reactivation. Patient medical files were reviewed to describe the provoking factors for endogenous reactivation. ResultsIn total, 25 patients with assumed endogenous TB reactivation were included in the study group, and 30 patients with one TB episode during the study period were included in the control group. There were no statistically significant differences identified between studied patient groups in patients age (t(53) = −1.53, p = 0.13), body mass index (t(53) = 0.82, p = 0.42), area of residency (χ2(1;55) = 0.015, p = 0.9), employment status (χ2(1;55) = 0.076, p = 0.78) and presence of comorbidities (χ2(1;55) = 3.67, p = 0.78). Study group patients had statistically significantly more frequently positive sputum smear microscopy results (χ2(1;55) = 8.72, p = 0.0031), longer time to sputum smear (t(31) = −2.2, p = 0.036) and sputum culture conversion (W (55) = 198.5, p = 0.0029). Smoking was statistically significantly (χ2(1;55) = 5.77, p = 0.016) more frequently represented among study group patients. The median treatment duration for drug susceptible TB was 6 months in both in the control group (IQR 6–6) and among study group patients (IQR 6–7.75). The median treatment duration for multidrug-resistant TB was 20 months (IQR 17–23) in the control group and 19 months (IQR 16–19) in the study group patients. ConclusionPositive SSM for acid-fast bacteria, delayed time to sputum smear and sputum culture conversion, smoking, and incomplete therapy in the study group patients with multidrug-resistant TB should be considered as potential reasons for reactivation in recurrent TB patient group in our study.

Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib.

Sotorasib was the first drug approved for adults with Kirsten rat sarcoma G12C-mutated locally advanced/metastatic non-small cell lung cancer (NSCLC) who received prior systemic therapy in the US. This study aimed to provide initial real-world evidence on patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs (HCC) associated with sotorasib in US clinical practice. A retrospective observational study was conducted using the Optum Clinformatics® Data Mart US claims database spanning January 2016 to March 2023. The study population included adults with a diagnosis of lung cancer (diagnosis (Dx) date), claims for sotorasib on/post-Dx date (index date), Continuous enrollment for medical/pharmacy benefits from 180 days pre-Dx date to≥30 days post-index date was required. Patients receiving treatments for small-cell lung cancer (SCLC) pre-index were excluded. Outcomes were analyzed for patients receiving sotorasib as second or subsequent line (2L+) treatment and included adherence [proportion of days covered (PDC)], treatment duration, time to next treatment (TTNT), HCRU, and HCC during sotorasib treatment. Among 169 patients with lung cancer that met all inclusion criteria, 140 patients received sotorasib as 2L+ treatment (mean age: 71 years; 67.1% females). Mean PDC for sotorasib was 94.9%. Kaplan-Meier median treatment duration was 4.3 months. Median TTNT in patients with subsequent treatment (n=31) was 6.8 months. During sotorasib treatment, patients had a mean 3.87 outpatient, 0.09 inpatient, and 0.11 emergency visits per month. Mean monthly HCC during sotorasib treatment were US$23,063 versus $25,541 during the 180-day pre-index period. Patients in the US receiving sotorasib as 2L+ therapy for NSCLC in real-world clinical practice showed high adherence, TTNT comparable to progression-free survival observed in clinical trials, and HCC similar to those immediately prior to treatment demonstrating real-world benefits with no additional impact on healthcare resources with sotorasib.

Cardiovascular events in CML patients treated with nilotinib: validation of the HFA-ICOS baseline risk score

Abstract Background The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, a potent 2nd generation TKI, showed higher rates of major molecular response than imatinib, however was associated with higher rates of cardiovascular (CV) toxicity. Objectives To describe the CV events associated with nilotinib in a real-world CML population and assess the predictive value of the HFA-ICOS baseline risk score in clinical practice. Methods The HFA-ICOS baseline risk was calculated (low, medium, high /very high) for patients with CML treated with nilotinib between 2006 and 2021. The incidence of all CV events, ischaemic events and Major CV Adverse Events (MACE) were reviewed and compared among the different risk groups. Results A total of two hundred and twenty-nine eligible patients were included in the analysis. The incidence of CV events, ischaemic events, and MACE, while on nilotinib, were 20.9% (95% CI: 15.7% to 26.2%), 12.7% (95% CI: 8.4% to 16.9%), and 12.2% (95% CI: 7.9% to 16.5%) respectively, following a median duration of treatment with nilotinib of 34.4 months for the entire cohort. Patients with a higher HFA-ICOS baseline risk score had higher rates of all CV events (low: 11.2%, medium: 28.2% [HR: 2.8, 95% CI: 1.2 to 6.2], high/very high: 32.4% [HR: 3.5, 95% CI: 1.8 to 6.8]), ischaemic events (low: 5.2%, medium: 17.9% [HR: 3.7, 95% CI: 1.2 to 10.9] , high/very high: 21.6% [HR: 3.7, 95% CI: 1.4 to 9.7]) and MACE (low: 7.8% , medium: 10.3% [HR:1.2, 95% CI: 0.38 to 4.1], high/very high: 20.2% [HR: 2.2, 95% CI: 0.9 to 5.3]). The predictive tool presented an 89% NPV, and an area under the ROC curve: 0.65 for all CV events, an NPV of 95% and AUC 0.68 for ischaemic events and NPV 92% and AUC 0.62 for MACE. Conclusions The HFA-ICOS risk stratification tool has been shown to be an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk categories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients, as it also underscores the potential for further improvement in the overall discriminatory ability of the model.