Treatment Discontinuation Research Articles

Two-year cumulative live-birth rates and maximum number of transfer cycles in women aged ≥ 40 years

This retrospective study aimed to clarify the cumulative live-birth rates (CLBRs) and cost per live-birth (LB) to evaluate the validity of frozen–thawed embryo transfer without preimplantation genetic testing for aneuploidy (PGT-A) in women aged ≥ 40 years. The study included 1,011 patients aged ≥ 40 years who underwent their first oocyte retrieval at our hospital between January 2010 and September 2017. They were followed up for up to two years or until either treatment discontinuation or a pregnancy that resulted in a live birth. The 2-year CLBRs were 55.6%, 39.0%, 31.3%, 19.1%, 10.6%, 4.4%, and 0% for patients aged 40, 41, 42, 43, 44, 45, and > 46 years, respectively. In approximately 80% of LB cases, patients aged 40–42 years and 43–44 years became pregnant by the fourth and second transfers, respectively. Costs per LB were $30,207, $49,034, $66,345, $102,759, and $195,862 for patients aged 40, 41, 42, 43, and 44, respectively. Cost per LB for each number of transfers reached $300,000 and $ 450,000 for the third transfer at 42 and 43 years of age, respectively. For cost-effectiveness, up to two ET cycles are recommended for patients aged 42–43, and none for patients aged ≥ 44 years.

Adverse drug reactions following treatment of latent tuberculosis infection: a linked national tuberculosis surveillance with claims database.

Few real-world studies explored factors associated with latent tuberculosis infection (LTBI) treatment-related adverse drug reactions (ADRs). This study evaluate ADRs that lead to the discontinuation of LTBI treatment and identify the associated factors, including age groups and drug regimens. Using the Korean national tuberculosis registry and HHC investigation database linked to the National Health Insurance Service claims database, we examined treatment discontinuation due to ADRs among HHCs on LTBI treatment from January 2015 to December 2018. Multivariable logistic regression analysis was conducted to examine factors associated with ADRs, including demographics, LTBI treatment, comorbidities, and steroid use. Among 11,913 participants initiated LTBI treatment, 633 participants (5.3%) discontinued treatment due to ADRs. The primary contributors to discontinuation were adverse skin reactions (2.0%) and abnormal liver function (1.9%). Risk associated with ADRs and abnormal liver function showed age-related increase, except for the age group 66-75 (adjusted odds ratio [AOR] 3.82, 95% confidence interval [CI] 2.31-6.31) which reported lower OR to that of age group 36-65 (AOR 4.38, 95% CI 3.09-6.21). Three months isoniazid/rifampin and 4 months rifampin exhibited a lower odds of ADRs and abnormal liver function when compared to 6-9 months isoniazid. We discovered the real-world prevalence of LTBI treatment discontinuation due to ADRs among HHCs. Our findings suggest a notably increased odds of ADRs resulting in discontinuation with age of 76 years or above, emphasizing careful attention when prescribing LTBI treatment in this population. Further studies are warranted to validate these results.

Clinical Outcome Patterns of Use of Radium-223 in Patients with Metastatic Castration-Resistant Prostate Cancer

Introduction: Radium-223 dichloride (radium-223) is a bone-targeting radioisotope therapy that aids in the survival of patients with metastatic castration-resistant prostate cancer (mCRPC) to bones. This study aimed to describe the clinical characteristics and outcomes of patients with mCRPC treated with radium-223 in a real-world setting. Methods: This was a retrospective study of patients with mCRPC treated with radium-223 between 2016 and 2020 at the London Health Sciences Centre in London, Canada. The baseline characteristics between the patients receiving 1–3 and 4–6 treatment cycles were compared using a two-sample t-test and Chi-square test. ANOVA was used to determine if there was a difference in each diagnostic variable per treatment cycle. Kaplan–Meier curves were generated to estimate progression-free survival (PFS) and overall survival in the patients treated with different numbers of cycles. Results: Fifty eligible patients were identified. The median age was 71 years (IQR: 66–76). Most patients (62%) received radium-223 beyond the third-line treatment. The mean number of radium-223 treatments was four. While 60% of the patients received 4–6 injections, 40% received 1–3 injections. Fifty-eight percent (58%) of the patients demonstrated a clinical benefit, with the remainder expressing either disease progression (28%) or stable disease (10%). The patients treated with 4–6 cycles had a delay to disease progression compared to those given 1–3 cycles of radium-223 (F5,35 = 10.52, p < 0.001). A higher alkaline phosphatase level prior to treatment was associated with a longer PFS (z33 = 2.362, p = 0.018). Treatment-related hospitalization for skeletal-related events was noted in 8% of the patients, and 14% required treatment discontinuation due to hematologic toxicity. Conclusions: This study confirms the safety of radium-223 in patients with mCRPC in a real-world setting. The radium-223 treatment was associated with a clinical benefit in the majority of the patients, particularly in those with higher pre-treatment serum alkaline phosphatase levels. Further studies to identify the predictive biomarkers are warranted to better guide the contemporary use of radium-223.

Real-World Experience of Erenumab in Patients with Migraine in Germany: The SPECTRE Study.

To provide real-world insights into migraine patient population in Germany treated with erenumab, focusing on the prescription patterns and reasons for the initial dosage choice. SPECTRE was an observational, non-interventional, multicenter, open-label, single-arm study in patients treated with erenumab according to approved local dose and guidelines. The study enrolled adult patients (n = 571; Germany: 105 sites) with migraine who had received erenumab for not more than 3months before the start of the study. The mean (standard deviation) patient age was 45.0 (12.3) years, and most patients were female (89.0%), Caucasian (97.6%), and non-smokers (85.1%). The starting dose of erenumab was 70mg in 68.5% of patients and 140mg in 31.5%. The proportion of patients with 140mg as the starting dose was the highest (43.5%) in those aged 30-40years. The most common reason for starting a higher dose of erenumab 140mg was severity of migraine (47.4%). During the observational period, the proportion of patients taking erenumab 140mg increased to 64.6% (visit 5; V5) after 12months. Due to attrition of patients towards the end of the study (V9: 90 participants), data at V9 must be interpreted with caution. At least one dose change was performed in 45.3% of patients (i.e., erenumab 70 to 140mg or 140 to 70mg), 21.2% of patients attempted at least once to discontinue treatment (i.e., period with erenumab discontinuation and no other antibody treatment for migraine prevention), and 15.3% discontinued erenumab treatment, mainly because of no or insufficient treatment response (13.5%). The mean time until the first omission attempt was 332.3 (range 37-633) days. Constipation (12.1%) was the most frequently reported adverse event, in line with the summary of product characteristics (SmPC) of erenumab. Most patients with migraine were prescribed erenumab 70mg as the starting dose. No new safety signals were observed for erenumab versus the previous trials.

Menopausal hormone therapy for breast cancer survivors.

The global incidence of breast cancer continues to increase and increasing efficacy of treatments has improved overall prognosis and survival with a resulting requisite focus on improving quality of life after cancer. Treatment inevitably results in symptoms of menopause and these symptoms may be more severe after cancer treatment compared to natural menopause and may pose a potential risk of early treatment discontinuation. Consequently, the global burden of successfully managing these symptoms is significant. There is a discordance between randomized and observational data regarding the risk of systemic menopausal hormone therapy and breast cancer recurrence; hormone receptor status is significant to recurrence risk in this setting. The systemic absorption of local oestrogen is not a consistent surrogate marker for cancer recurrence and clinical data has not demonstrated a consistent increase in the risk of cancer recurrence with local therapy. Nonhormonal treatments remain first-line management of menopause symptoms in breast cancer survivors to minimize the risk of cancer recurrence. However, severe symptoms not responding to nonhormonal interventions require a multidisciplinary, patient-centred approach to discuss the evidence base for hormonal treatments.

Efficacy of Biofeedback Therapy for Giggle Incontinence in Children: How Many Sessions Are Required?

Giggle incontinence (GI) is characterized by the sudden and involuntary expulsion of urine coinciding with episodes of laughter. The underlying pathophysiology of this condition remains unclear, and various treatment approaches are employed. The objective of this study is to assess the effectiveness of biofeedback (BF) therapy in treating GI and ascertain the requisite number of therapy sessions needed for efficacy. Medical records of children treated with BF therapy for GI between November 2022 and November 2023 were retrospectively analyzed. The success of treatment was assessed after four and eight sessions, as well as following three maintenance sessions. Treatment outcomes were evaluated using the scoring system recommended by the International Children's Continence Society (ICCS), which categorizes responses into three levels: no response (Score 0), partial response (Score 1), and complete response (Score 2). Thirteen patients were initially diagnosed with GI. Of these, 10 patients were included in the study as three discontinued treatments. The cohort comprised an equal gender distribution with five females (50.0%) and five males (50.0%). The mean age of patients was 8.9 ± 3.3 (range 5-16) years. Two out of ten patients had a history of previous treatment for overactive bladder, while three had received treatment for primary monosymptomatic nocturnal enuresis. Following the completion of all BF sessions, the rate of complete response was observed at 80.0% (n = 8), while the partial response rate accounted for 10.0% (n = 1). Statistical analysis revealed significant differences in response scores after four and eight sessions (p < 0.01) as well as between the results after eight sessions and the completion of maintenance sessions (p < 0.01). BF therapy demonstrates a high success rate in managing GI. Completion of at least eight BF therapy sessions enhances the probability of a successful outcome in the treatment of GI. Additionally, it has been observed that maintenance sessions contribute to the increased efficacy of the treatment.

A case report of benzodiazepine withdrawal delirium due to accidental discontinuation of benzodiazepines in cancer perioperative period.

Benzodiazepines are known for their possible risk of delirium, especially when administered to older adults or during the perioperative period. However, the risk of sudden discontinuation of benzodiazepines and subsequent withdrawal delirium seems to be underappreciated and not properly recognized in cancer treatment, even among healthcare workers. A man in his late 70s was diagnosed with rectal cancer and had a history of taking etizolam and alprazolam for over 15 years. After hospitalization for cancer, these benzodiazepines were discontinued abruptly 2 days before the surgery, due to concerns about benzodiazepine-related delirium. After half a day, severe benzodiazepine withdrawal symptoms, such as disorientation, agitation, tachycardia, diaphoresis, and muscle twitching, appeared. The patient was diagnosed with delirium associated with benzodiazepine withdrawal, and his symptoms subsided soon after re-administration of benzodiazepines. Despite development of mild postoperative delirium, the operation was performed safely. The rapid and abrupt discontinuation of benzodiazepines before cancer surgery could impose a high risk of benzodiazepine withdrawal delirium in patients, which makes the management of psychiatric symptoms in the perioperative period more complex and difficult. We believe that it is necessary to highlight the risks of withdrawal delirium and abrupt benzodiazepine discontinuation in cancer treatment. Moreover, re-education on this topic is essential for healthcare workers.

Prospective single-arm multicenter interventional study of surgical resection for liver metastasis from gastric cancer; 3-year overall and recurrence-free survival

ObjectivePotential benefit of surgical resection for liver metastasis from gastric cancer (LMGC) remains controversial because most previous studies were retrospective. We evaluated the outcomes of surgical resection following chemotherapy for LMGC in a prospective single-arm multicenter interventional study. MethodsPatients with synchronous or metachronous LMGC received 2–4 cycles of standard chemotherapy and proceeded to surgical resection if restaging showed a non-progressive disease with a chance of R0 resection. The primary endpoint was 3-year OS of R0 patients, with RFS as secondary. Prognostic factors for R0 patients were evaluated by multivariable Cox regression analysis. ResultsSeventy patients were enrolled between 2011 and 2019. Two patients were ineligible, and 20 discontinued treatment before surgery. Of the 48 patients eventually undergoing surgery, 43 accomplished R0 resection of the primary and/or metastatic GC, while 1 ended in R2 resection and 4 were considered ineligible. Median and 3-year OS for R0 patients were 39.8 months (95 % confidence interval [CI], 26.9 to not reached) and 58.1 % (95 % CI, 43.1–71.8), respectively, while median and 3-year RFS were 14.9 months (95 % CI 7.9–34.0) and 34.9 % (95 % CI 22.2–50.1), respectively. On multivariable analysis, both multiple liver metastases and positive nodal status (pN1–3) were negatively associated with OS (multiple liver metastases: hazard ratio [HR] 2.71 (95 % CI, 1.16–6.35), P = 0.022; pN1–3: HR 9.11 (95 % CI, 1.22–68.2), P = 0.031). ConclusionR0 resection following chemotherapy for LMGC yielded promising survival, with multiple liver metastases and positive nodal status being significant indicators of poor prognosis. Clinical trial registration number: UMIN 000011445 (https://www.umin.ac.jp/ctr/).

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect.

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

Quality of care for secondary cardiovascular disease prevention in 2009–2017: population-wide cohort study of antiplatelet therapy use in Scotland

BackgroundAntiplatelet therapy (APT) can substantially reduce the risk of further vascular events in individuals with established atherosclerotic cardiovascular disease (ASCVD). However, knowledge regarding the extent and determinants of APT use...

Factors influencing the discontinuation of biologic therapies in patients with ulcerative colitis

BackgroundThe therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients.MethodsThis retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups.ResultsOf the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075).ConclusionThe study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy.

Update Motility Disorders: Gastro-Oesophageal Reflux Disease – Diagnostic and Conservative Approach

Background: Gastro-oesophageal reflux disease (GORD) is extremely common, with at least 1 in 10 people in the general population reporting heartburn and acid regurgitation on a weekly basis. GORD can also be associated with a variety of atypical symptoms, including chest pain, chronic cough, and laryngopharyngeal symptoms. The causes of GORD are multifactorial, and the severity of symptoms is influenced by peripheral and central factors, including psychosocial stress and anxiety. Therefore, for a variety of reasons, no single investigation provides a definitive diagnosis, and standard treatment with acid suppressants is not always effective. Summary: This review introduces the Lyon Consensus, now in its second iteration, a classification system that provides a “conclusive” positive or negative diagnosis of GORD by integrating the results of endoscopy, ambulatory reflux monitoring, and high-resolution manometry. Different algorithms are applied to patients with high and low pre-test probability of a causal relationship between reflux episodes and patient symptoms. The results of these studies identify patients with “actionable” results that require escalation, revision, or discontinuation of GORD treatment. Guidance is provided on the range of conservative treatments available for GORD, including dietary and lifestyle advice, antacids and alginates, and drugs that suppress acid secretion. Key Messages: GORD is a common disorder; however, the causes of reflux and symptoms can be complex. As a result, the diagnosis can be missed, and management is sometimes challenging, especially for patients with atypical symptoms. The Lyon classification establishes a conclusive diagnosis of GORD, based on results of endoscopic and physiological investigation. Typical symptoms usually respond to empiric use of alginate-antacid preparations and acid suppression; however, the management of treatment refractory symptoms is tailored to the individual.

A Multicenter, Open-Label Study to Evaluate the Long-term Safety and Efficacy of Adjunctive Brexpiprazole 2 mg Daily in Japanese Patients with Major Depressive Disorder.

Inadequate response to antidepressant monotherapy is common among patients with major depressive disorder (MDD). The efficacy and safety of adjunctive brexpiprazole 2 mg/day has recently been confirmed during the 6-week, randomized, placebo-controlled phase 2/3 (BLESS) study, which evaluated brexpiprazole at 1 mg/day and 2 mg/day versus placebo as adjunctive therapy to antidepressant therapies in 740 Japanese patients with MDD and an inadequate response to antidepressant monotherapy. This study evaluated the long-term safety and efficacy of adjunctive fixed-dose brexpiprazole 2 mg/day in Japanese patients with MDD. An open-label, 52-week study enrolled rollover patients who completed the 6-week, double-blind, randomized, placebo-controlled phase 2/3 BLESS study (NCT03697603), and de novo patients aged ≥ 65 years. Patients were titrated to fixed-dose brexpiprazole 2 mg/day from Week 1. Safety assessments included treatment-emergent adverse events (TEAEs; primary outcome) and clinical and laboratory variables. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale(MADRS), Clinical Global Impression-Improvement (CGI-I) scale, Hamilton Depression Rating Scale (HAM-D) 17-item total score, and Sheehan Disability Scale (SDS) score. In total, 247 patients [rollover, n = 216; de novo (previously unexposed), n = 31] were included in the safety/efficacy populations, and 138 (rollover, n = 132; de novo, n = 6; 55.9%) completed the study. Common TEAEs (incidence ≥ 10%) were weight gain [33.2% (n = 82)], akathisia [23.5% (n = 58)], nasopharyngitis [21.1% (n = 52)], and somnolence [10.5% (n = 26)]. TEAEs leading to treatment discontinuation occurred in 26.7% of patients receiving brexpiprazole and 58.1% of de novo patients. The mean (SD) increase in body weight from baseline to Week 52 [observed cases (OC)] was 4.2 (6.5) kg (n = 138); 44.5% (n = 110) had weight gain ≥ 7% at any postbaseline visit. There were no cases of tardive dyskinesia and no AEs related to suicide/suicide attempts. One death occurred (unknown cause), which was unrelated to study treatment. Improvements in the MADRS total score were observed from baseline over the course of the 52-week study [mean (SD) change at Week 52 (OC): - 7.3 (8.7)] for all patients receiving brexpiprazole. The overall MADRS response rate and remission rate in patients receiving brexpiprazole was 41.3% (n = 57) and 34.8% (n = 48), respectively, at Week 52 (OC). Improvements in CGI-S, HAM-D 17 item total score, and SDS mean scores were also observed from baseline over the 52-week study, with a mean (SD) change from baseline at Week 52 (OC) of - 0.8 (1.0), - 5.9 (6.3), and - 1.0 (2.2), respectively, indicating a sustained improvement in symptoms with long-term brexpiprazole treatment. This is the first study to evaluate the safety profile of brexpiprazole 2 mg/day in Japanese patients with MDD, including older adults, which is similar to previous reports, with no new safety risks, and continued efficacy over 52 weeks. ClinicalTrials.gov (NCT03737474; registered on 29 July 2018).

When end of treatment situations challenge patient-centered care: a discussion paper proposing new theoretical insights.

According to the Institute of Medicine patient-centered medicine is one of the six crucial dimensions of health care quality. Although the patient-centered care model is widely recognized for its ethical underpinnings and effectiveness, its practical implementation still raises challenges, especially in end-of-treatment situations. This discussion paper offers an overview of the challenges facing the physician-patient relationship in end-of-treatment situations. We developed three clinical vignettes and made some theoretical considerations about ethical issues related to the decision-making process leading to the end of treatment. We identified two main challenges that end-of-treatment situations pose to patient-centered care: (1) when the patient's autonomy challenges the best clinical treatment; and (2) when the proposed treatment (discontinuation of treatment) challenges the patient's preferences. Patient-centered care supports personalized decision-making, in which the physician's approach varies according to the patient's situation and individuality. The idea of beneficence may change during care, because of acceptance of the patient's principles or a change in the primary goal of care.

Buprenorphine/Naloxone vs Methadone for the Treatment of Opioid Use Disorder

Previous studies on the comparative effectiveness between buprenorphine and methadone provided limited evidence on differences in treatment effects across key subgroups and were drawn from populations who use primarily heroin or prescription opioids, although fentanyl use is increasing across North America. To assess the risk of treatment discontinuation and mortality among individuals receiving buprenorphine/naloxone vs methadone for the treatment of opioid use disorder. Population-based retrospective cohort study using linked health administrative databases in British Columbia, Canada. The study included treatment recipients between January 1, 2010, and March 17, 2020, who were 18 years or older and not incarcerated, pregnant, or receiving palliative cancer care at initiation. Receipt of buprenorphine/naloxone or methadone among incident (first-time) users and prevalent new users (including first and subsequent treatment attempts). Hazard ratios (HRs) with 95% compatibility (confidence) intervals were estimated for treatment discontinuation (lasting ≥5 days for methadone and ≥6 days for buprenorphine/naloxone) and all-cause mortality within 24 months using discrete-time survival models for comparisons of medications as assigned at initiation regardless of treatment adherence ("initiator") and received according to dosing guidelines (approximating per-protocol analysis). A total of 30 891 incident users (39% receiving buprenorphine/naloxone; 66% male; median age, 33 [25th-75th, 26-43] years) were included in the initiator analysis and 25 614 in the per-protocol analysis. Incident users of buprenorphine/naloxone had a higher risk of treatment discontinuation compared with methadone in initiator analyses (88.8% vs 81.5% discontinued at 24 months; adjusted HR, 1.58 [95% CI, 1.53-1.63]), with limited change in estimates when evaluated at optimal dose in per-protocol analysis (42.1% vs 30.7%; adjusted HR, 1.67 [95% CI, 1.58-1.76]). Per-protocol analyses of mortality while receiving treatment exhibited ambiguous results among incident users (0.08% vs 0.13% mortality at 24 months; adjusted HR, 0.57 [95% CI, 0.24-1.35]) and among prevalent users (0.08% vs 0.09%; adjusted HR, 0.97 [95% CI, 0.54-1.73]). Results were consistent after the introduction of fentanyl and across patient subgroups and sensitivity analyses. Receipt of methadone was associated with a lower risk of treatment discontinuation compared with buprenorphine/naloxone. The risk of mortality while receiving treatment was similar for buprenorphine/naloxone and methadone, although the CI estimate for the hazard ratio was wide.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

Real-world outcomes in patients with brain metastases secondary to HR+/HER2- MBC treated with abemaciclib and local intracranial therapy.

Real-world data are limited for patients with brain metastases secondary to metastatic breast cancer (MBC) and treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study describes real-world outcomes in patients with hormone receptor-positive, human epidermal growth factor 2-negative (HR+/HER2-) MBC with brain metastases diagnosis before abemaciclib initiation. A nationwide electronic health record-derived de-identified MBC database (January 2011-December 2021) was assessed retrospectively. Patients with HR+/HER2- MBC who were treated with abemaciclib (monotherapy or in combination) following diagnosis of brain metastases were included. Real-world best response reflected clinician-documented response assessment of the brain imaging (intracranial) and change in disease burden following radiographic imaging (extracranial); these were reported descriptively. Time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and overall survival (rwOS) were assessed using Kaplan-Meier methods from abemaciclib initiation (index date). Among 82 included patients (mean age 57.0 years; 98.8% female), 22.0% and 19.5% received CDK4/6i and chemotherapy before abemaciclib initiation, respectively, and the majority (80.5%) received radiation/local surgery to the brain before abemaciclib initiation. Patients mostly received abemaciclib as monotherapy (n = 6) or in combination with endocrine therapy (n = 68). Median TTD was 7.1 (95% CI 4.6-11.3) months, rwPFS was 9.2 (95% CI 6.0-11.6) months, and rwOS was 20.8 (95% CI 13.9-26.0) months. Intracranial and extracranial objective response rates, as determined by treating physicians, were 45.1% (n = 23/51) and 56.7% (n = 34/60), respectively. Intracranial and extracranial clinical benefit rates were 62.7% (n = 32/51) and 70.0% (n = 42/60), respectively. In this real-world study of patients diagnosed with brain metastases and initiating abemaciclib, most patients received radiation/local surgery to the brain before abemaciclib initiation. Although the outcomes in this real-world study are encouraging, it is unclear if the benefit was due to local therapy, abemaciclib, or the combination, and causality cannot be inferred. Further prospective clinical studies are needed to confirm the clinical benefit of this approach.

Comparison of abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer: A multicenter study.

We aimed to assess the differential efficacy and safety of androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, and apalutamide, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a real-world practice setting. We retrospectively reviewed the records of consequent 668 patients with mHSPC treated with ARPI plus androgen deprivation therapy between September 2015 and December 2023. Based on the LATITUDE criteria, the comparison among abiraterone, enzalutamide, and apalutamide was exclusively conducted in high-risk patients. Prostate-specific antigen (PSA) responses such as the achievement of 95% and 99% PSA decline, overall survival (OS), cancer-specific survival (CSS), time to castration-resistant prostate cancer (CRPC), and the incidence of adverse events (AEs) were compared. All two-group comparisons relied on propensity score matching (PSM) to minimize the effect on possible confounders. In total, 297 patients with high-risk mHSPC treated with abiraterone, 127 with enzalutamide, and 142 with apalutamide were compared. There were no differences in time to CRPC (p = 0.13), OS (p = 0.7), and CSS (p = 0.5) among the three ARPIs. No differences were observed in the achievement rates for 95% PSA decline at 3 months among the three ARPIs, while abiraterone was significantly better in 99% PSA decline achievement compared to apalutamide (72% vs. 57%, p = 0.003). The aforementioned oncologic outcomes were sustained even when performing PSM analyzes. Although skin rash for APA (34%) was the highest incidence of AEs, there were no differences in the rates of severe AEs across the three ARPIs. Enzalutamide resulted in the lowest treatment discontinuation rates (10%) other than disease progression compared to the other regimens. Abiraterone, enzalutamide, and apalutamide have comparable oncologic outcomes in terms of OS, CSS, and time to CRPC in patients with high-risk mHSPC. Our data on differential treatment discontinuation rates, PSA response, and AE profiles can help guide clinical decision-making.

SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors (DART): Non-Epithelial Ovarian Cancer.

The role of dual checkpoint inhibition in advanced rare/ultra-rare non-epithelial ovarian cancers (NEOCs) is yet to be explored. DART is a prospective, multicenter (1,016 US sites), multi-cohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4) (1mg/kg every 6 weeks) and nivolumab (anti-PD-1) (240mg every 2 weeks) in adults with advanced NEOCs who lack beneficial standard therapy. Primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; stable disease (SD) ≥6 months plus ORR], and toxicity. Seventeen patients (median age: 64; number of prior therapies ranged from 0-8 with no immunotherapy exposure; 8 granulosa, 6 carcinosarcomas, 1 Sertoli-Leydig, 1 yolk sac, 1 Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n=2/8; 1 CR, 1 PR) and CBR, 50% (n=4/8); PFS of 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months (95% confidence intervals (CI) 1.7-11.2 months); median OS, 42.5 months (95% CI 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3-4 adverse events. Ipilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n=2/8) of patients experiencing either CR or PR lasting over 4 years.​.

30-Month Impact of Medications for Opioid Use Disorder on Acute Care Utilization in Rural Communities.

To assess both the short- and longer-term impact of offering medications for opioid use disorder (MOUD, ie, methadone, buprenorphine, or naltrexone) on rates of all-cause emergency department (ED) visits and acute inpatient admissions (IP) over a 30-month period among Medicaid enrollees with opioid use disorder (OUD) residing in rural communities. A quasi-experimental retrospective analysis of longitudinal Medicaid claims data among continuously enrolled adult patients with OUD residing in 71 predominantly rural counties in the United States between 2018 and 2020. A cohort of patients receiving MOUD treatment was compared against a contemporaneous propensity score-matched comparison group consisting of those who received no MOUD during the period. The sample included 5370 patients with OUD in each group. At the index period (ie, the month in which any MOUD was used for the first time), buprenorphine was the most commonly used MOUD (82% of the MOUD treatment group). By the eighth month since the index period, MOUD use dropped below 60% among the MOUD treatment group. Over the 30-month post-MOUD period, MOUD treatment was associated with 24% (112 vs 148 per 1000 per month) and 52% (21 vs 44) lower rates of ED visit and IP admission rates, respectively (P < 0.001), relative to the comparison group. Moreover, the reductions persisted well after the 18th month period. Receipt of MOUD was associated with both immediate- and long-term lower rates in acute care utilization rates among adult Medicaid beneficiaries with OUD residing in rural communities despite significant treatment discontinuation.