First-line Treatment Research Articles

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial

Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214. Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

Antibiotic practice and stewardship in the management of neutropenic fever: a survey of US institutions.

To describe neutropenic fever management practices among healthcare institutions. Survey. Members of the Society for Healthcare Epidemiology of America Research Network (SRN) representing healthcare institutions within the United States. An electronic survey was distributed to SRN representatives, with questions pertaining to demographics, antimicrobial prophylaxis, supportive care, and neutropenic fever management. The survey was distributed from fall 2022 through spring 2023. 40 complete responses were recorded (54.8% response rate), with respondent institutions accounting for approximately 15.7% of 2021 US hematologic malignancy hospitalizations and 14.9% of 2020 US bone marrow transplantations. Most entities have institutional guidelines for neutropenic fever management (35, 87.5%) and prophylaxis (31, 77.5%), and first-line treatment included IV antipseudomonal antibiotics (35, 87.5% cephalosporin; 5, 12.5% penicillin; 0, 0% carbapenem).We observed significant heterogeneity in treatment course decisions, with roughly half (18, 45.0%) of respondents continuing antibiotics until neutrophil recovery, while the remainder having criteria for de-escalation prior to neutrophil recovery. Respondents were more willing to de-escalate prior to neutrophil recovery in patients with identified clinical (27, 67.5% with pneumonia) or microbiological (30, 75.0% with bacteremia) sources after dedicated treatment courses. We found substantial variation in the practice of de-escalation of empiric antibiotics relative to neutrophil recovery, highlighting a need for more robust evidence for and adoption of this practice. No respondents use carbapenems as first-line therapy, comparing favorably to prior survey studies conducted in other countries.

Comparison of efficacy of eltrombopag combined with immunosuppression in the treatment of severe aplastic anemia and very severe aplastic anemia: real-world data and evidence.

Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.

Immunotherapy and Overall Survival Among Patients With Advanced Non–Small Cell Lung Cancer and Obesity

The association between obesity and response to cancer treatment and survival remains unclear, with conflicting findings from various studies. The optimal choice between conventional chemotherapy and immunotherapy for first-line treatment remains uncertain in patients with obesity who potentially have an inadequate therapeutic response to immunotherapy. To investigate whether body mass index (BMI) modifies the association of immunotherapy or conventional therapy with overall survival in patients with advanced non-small cell lung cancer (aNSCLC). A retrospective cohort study, using administrative claims data obtained from advanced treatment centers in Japan, was conducted between December 1, 2015, and January 31, 2023. Participants included individuals aged 18 years or older with aNSCLC who received immunotherapy, using immune checkpoint inhibitor (ICI) treatment or conventional chemotherapy. Immune checkpoint inhibitor therapy as first-line chemotherapy was compared with conventional chemotherapy, identified through patient medical records. The main outcome was overall survival. Survival analysis covered a 3-year follow-up period after the first-line chemotherapy. A total of 31 257 patients with aNSCLC were identified. Of these, 12 816 patients received ICI therapy (mean [SD] age, 70.2 [9.1] years; 10 287 [80.3%] men) and 18 441 patients received conventional chemotherapy (mean [SD] age, 70.2 [8.9] years; 14 139 [76.7%] men). Among patients with BMI less than 28, ICI therapy was associated with a significantly lower hazard of mortality (eg, BMI 24: hazard ratio [HR], 0.81; 95% CI, 0.75-0.87) compared with those who underwent conventional chemotherapy. However, no such association was observed among patients with BMI 28 or greater (eg, BMI 28: HR, 0.90; 95% CI, 0.81-1.00). The findings of this retrospective cohort study suggest that BMI modifies the association of ICI therapy compared with conventional chemotherapy with overall survival in patients with aNSCLC. A lack of association between ICI therapy and improved survival in patients with aNSCLC and overweight or obesity compared with conventional chemotherapy was observed. This suggests that ICI therapy may not be the optimal first-line therapy for patients with overweight or obesity and the use of conventional chemotherapy should also be considered in such patients.

Hysterectomy versus chemotherapy for low-risk non-metastatic gestational trophoblastic neoplasia (GTN): A cost-effectiveness analysis

ObjectiveDetermine the cost-effectiveness for hysterectomy versus standard of care single agent chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). MethodsA cost-effectiveness analysis was conducted comparing single agent chemotherapy with hysterectomy using decision analysis and Markov modeling from a healthcare payer perspective in Canada. The base case was a 40-year-old patient with low-risk non-metastatic GTN that completed childbearing. Outcomes were life years (LYs), quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and adjusted 2022 costs (CAD). Discounting was 1.5% annually and the time horizon was the patient's lifetime. Model validation included face validity, deterministic sensitivity analyses, and scenario analysis. ResultsMean costs for chemotherapy and hysterectomy arms were $34,507 and $17,363, respectively, while effectiveness measure were 30.37 QALYs and 31.04 LYs versus 30.14 QALYs and 30.82 Lys, respectively. The ICER was $74,526 (USD $54,516) per QALY. Thresholds favoring hysterectomy effectiveness were 30-day hysterectomy mortality below 0.2% and recurrence risk during surveillance above 9.2% (low-risk) and 33.4% (high-risk). Scenario analyses for Dactinomycin and Methotrexate led to similar results. Sensitivity analysis using tornado analysis found the cost to be most influenced by single agent chemotherapy cost and risk of resistance, number of weeks of chemotherapy, and probability of postoperative mortality. ConclusionCompared to hysterectomy, single agent chemotherapy as a first-line treatment costs $74,526 for each additional QALY gained. Given that this cost falls below the accepted $100,000 willingness-to-pay threshold and waitlist limitations within public healthcare systems, these results support the continued use of chemotherapy as standard of care approach for low-risk GTN.

ITALIAN REGISTRY ON RARE UROLOGICAL TUMORS (MEET-URO-23): THE FIRST ANALYSIS ON COLLECTING DUCT CARCINOMA OF THE KIDNEY

IntroductionRare genitourinary tumors are lacking of randomized and observational data. We aimed to describe the clinical characteristics and outcomes of patients with collecting duct carcinoma (CDC) through the Meet-URO 23/I-RARE database. Materials and methodsWe performed a multicentric retrospective-prospective study within the Meet-URO network, enrolling patients from March 2021 (retrospectively up from 2011) until March 2023. The primary objective was to describe the clinical characteristics of patients with CDC, the secondary objectives were to assess the oncological outcomes in terms of relapse-free survival (RFS), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) to treatment. Results37 patients with CDC were enrolled. Four patients underwent only surgery, 33 received first-line systemic therapy. Median OS was 22.1 months (95%CI 8.9-31.9). Median RFS for patients with localized disease at onset (n = 30) was 3.7 months (95%CI 1.9-12.8), median PFS for first-line treatment was 3.3 months (95%CI 2.7-9.9), with an ORR of 27%. Female sex and good performance status (PS) were associated with longer PFS (p = 0.072 and p < 0.01, respectively) and OS (p = 0.030 and p = 0.141, respectively). ConclusionsPatients with CDC had dismal prognosis, with scarce benefit from the available treatments. Female sex and good PS seemed to be associated with better prognosis. Micro-AbstractAim. The Meet-URO 23/I-RARE is a multicentric retrospective-prospective study on patients with rare genitourinary cancer.Methods. The objectives were to describe the characteristics and outcomes of patients with collecting duct carcinoma (CDC) and assess the oncological outcomes.Results. The median overall survival (OS) of the 37 patients was 22.1 months. Median relapse-free survival after surgery was 3.7 months; median progression-free survival (PFS) for first-line treatment (n=33) was 3.3 months. Female sex seemed to have longer OS (p=0.030), good performance status (PS) patients appeared to have better PFS (p<0.01).Conclusions. Although showing dismal prognosis, with scarce benefit from treatments, female sex and good PS showed better outcomes.

Plasmonic nanophotothermal therapy: Destruction of 500 mm3 subcutaneous human basal cell carcinoma with gold nanoparticles and near infrared laser.

Multilesional basal cell carcinoma (BCC) are spread on sun exposed skin areas, including arms, face and back. The first-line treatment remains the surgical resection or Mohs surgery. Despite its high complexity, Mohs surgery is well practiced in USA and Germany and presents very good results both in esthetic and in carcinology point of view. Large lesions more than 2cm remain challenging to remove by topical cream used in photodynamic therapy (PDT). If these larger lesions are not treated in less than 1 month, they could grow deeply in the skin, thus enhancing the risk of reoccurrence and the severity of the disease. Despite this model herein studied, that is non melanoma skin cancer is a good prognostic cancer, the therapy aims to be applied to more aggressive melanoma skin cancers. Total regression of large cutaneous lesions less than 1 month with no reoccurrence. Tumor induction on murine model bearing a 500 mm3 subcutaneous lesion. Increasing dose of gold nanoparticles at fixed initial concentration C0=0.3mg/mL, infused into the tumor then exposition of the region of interest to NIR medical laser to assess the therapy. One or two intratumoral administration(s) were compared to surgery and control, that is no treatment, laser alone or nanoparticles alone. Gold nanoparticles alone or the NIR laser alone did not induce the tumor regression. The combination of laser and nanoparticles called plasmonic nanophotothermal therapy induced apoptosis. Derma and hypoderm do not show any visible gold nanoparticles and demonstrated a good cicatrization process. Plasmonic nanophotothermal therapy using two doses of gold nanoparticles was the only protocol that proved its efficacy on large lesions in 14 days, that is 500 mm3 on a murine model bearing human basal cell carcinoma.

Antibody-drug conjugates combined with immunotherapy: a potential game changer in the treatment of upper tract urothelial carcinoma

Currently, treatment strategies for upper tract urothelial carcinoma (UTUC) are changing rapidly. However, there are many limitations in the implementation of new surgical methods and systemic treatment options, which cannot reverse the current status quo of UTUC treatment. In recent years, antibody-drug conjugates have shown great potential in the field of cancer treatment, which can activate the immune system and enhance the effect of immunotherapy while accurately killing targeted tumor cells. The results of multiple clinical trials, including the EV-302 study, have confirmed that combination therapy can improve the survival rate of patients with advanced urothelial cancer, and may replace chemotherapy as the first-line treatment for advanced urothelial cancer. However, there are still a series of challenges in the application of combination therapy in UTUC, such as low level of evidence, adverse reactions, and drug resistance. In the future, it is necessary to focus on clinical trials of UTUC combination therapy, further optimize antibody drug conjugates and immunotherapy drugs to adapt to the disease characteristics of UTUC, and further study the molecular biology characteristics of UTUC to meet this series of challenges.

Tocilizumab in the treatment of steroid refractory immune-related hepatotoxicity: a case series and review of the literature.

With the widespread use of immune checkpoint inhibitors, management of immune-related adverse effects specific to these treatments became an important research era in patient management. Among these, immune-related hepatotoxicity (IRH) is an adverse event that can be fatal. While the first-line treatment of IRH is well established, there is still no consensus regarding the management approach for steroid-refractory, severe IRH. Here, we report four patients with metastatic melanoma who developed IRH during antiprogrammed cell death protein-1 plus anticytotoxic T-lymphocyte-associated protein-4 combination therapy and review of the literature. All of our patients were steroid-refractory and were successfully treated with tocilizumab. Given the rapid improvement in liver enzymes and patient's clinical status with tocilizumab, this treatment should be prioritized in steroid-refractory IRH.

Treatment with chemotherapy plus brentuximab vedotin in anaplastic large cell lymphoma and pregnancy: A case report

Introduction: Brentuximab vedotin (BV) is a CD-30 directed antibody and microtubule inhibitor conjugate indicated for the treatment of multiple types of lymphoma, including anaplastic large cell lymphoma (ALCL). Consensus-based guidelines recommend BV with cyclophosphamide, doxorubicin, and prednisone (CHP) as first-line treatment in a patient with ALCL. Alternative treatment options for ALCL can be limited due to patient-specific factors. Lymphomas account for approximately 11% of cancers in pregnancy. Brentuximab vedotin has not been studied in pregnancy; therefore, making the use of an antibody drug conjugate in this patient the first documented use in pregnancy. Case Report: A 26-year-old female was diagnosed with anaplastic large cell lymphoma at 14 weeks gestation. The patient has a past medical history of ALCL in 2004 at eight years old and a prior miscarriage. Consensus-based guidelines recommend BV with cyclophosphamide, doxorubicin, and prednisone (CHP) as first-line treatment in a patient with ALCL. Treatment with BV plus CHP was initiated at 15 weeks gestation for a total of 6 cycles during the antepartum period. At 33 weeks gestation, the patient delivered a 4-pound infant male without complications, birth defects, or health disparities. Two additional cycles of BV and CHP were administered during the postpartum period. Complete remission has been achieved in this patient. Conclusion: The outcomes in this case indicate the potential safety of BV in patients after the first trimester of pregnancy.

Efficacy of first-line immune checkpoint inhibitor and anti-angiogenic agent combination therapy for Kirsten rat sarcoma viral antigen-mutant advanced non-small-cell lung cancer: a systematic review and network meta-analysis.

Recent advancements in advanced non-small-cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first-line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first-line treatment for KRAS-mutant NSCLC. We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression-free survival (PFS) and overall survival (OS). A random-effects network meta-analysis was conducted to perform direct and indirect comparisons among treatment groups. Six RCTs were eligible for inclusion. In the network meta-analysis for KRAS-mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22-0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47-0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49-0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34-0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48-0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56-0.92). Regarding OS in wild-type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50-1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63-0.99). The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS-mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first-line treatment.

Updates in chronic graft-versus-host disease: novel treatments and best practices in the current era.

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplant. The development of cGVHD involves a complex, multistep process that is characterized by early inflammation and tissue injury, followed by chronic inflammation, aberrant tissue repair, and fibrosis. Systemic corticosteroids remain the first line of treatment for cGVHD. New treatments for patients with cGVHD for whom treatment has failed or who develop steroid-dependent cGVHD are now available; these include ibrutinib, ruxolitinib, and belumosudil. Treatment selection may be based on the patient's individual needs, graft-versus-host disease organ involvement, and comorbidities. However, as therapeutic options for patients without a treatment response or with only a partial response remain an unmet need, new agents are under investigation. Furthermore, patients with cGVHD can develop multiorgan involvement and frequently require specialized care. A multidisciplinary team approach that focuses on the individual's needs and quality of life is strongly encouraged.

Coronary angiography following transcatheter aortic valve replacement: Insights from the SWEDEHEART registry.

Transcatheter aortic valve replacement (TAVR) is the most common treatment in patients with symptomatic severe aortic stenosis (AS). As concomitant coronary artery disease is common in AS patients, access to the coronary arteries following TAVR is of increasing importance. This study evaluated the incidence and risk factors for unplanned coronary angiography following TAVR and, using fluoroscopic time as a surrogate, analyzed the complexity of coronary artery cannulation. All patients who underwent TAVR in Sweden between 2008 and 2022 were identified using the SWEDEHEART registry. The cumulative incidence of coronary angiography after TAVR was analyzed with mortality as a competing risk. Angiography and PCI complexity were analyzed using fluoroscopic time and compared across different transcatheter heart valve designs. Out of 9806 patients, 566 subsequently required coronary angiography. The incidence was highest for three-vessel and/or left main disease. Younger age, the extent of prior coronary artery disease, and peripheral vascular disease were associated with an increased risk of coronary angiography. Fluoroscopy time was increased in TAVR patients compared to the control group with the longest fluoroscopy times observed in cases involving supra-annular and self-expanding valves. The incidence of coronary angiography following TAVR is still low. Younger patients and patients with concomitant coronary artery disease have a higher risk. Procedural time is longer in patients with a previous THV replacement. As TAVR is emerging as the first-line treatment in patients with longer life expectancy, facilitating coronary access is an important factor when considering which THV device to implant.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs.

Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination. To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs. All anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR). We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding. Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.

Role of genetic variations and protein expression of β-Microsemino protein in intrauterine insemination outcome of unexplained infertile men: A case-control study

Background: Intrauterine insemination (IUI) is often the first-line treatment for unexplained infertility. β-Microsemino protein (MSMB) is an abundant protein in seminal plasma that has an inhibitory effect on spontaneous acrosome reaction. Objective: The present study aimed to evaluate MSMB gene variations and protein expression on IUI success rate in unexplained infertile men. Materials and Methods: A case-control study was performed on 100 unexplained infertile Iranian men referred to the Royan Institute, Tehran, Iran for IUI (50 men with IUI positive result [IUI+], and 50 men with IUI negative result [IUI-]). Couples with female infertility factors (such as hormonal disorders, infrequent menstrual period, abnormality in uterus, fallopian tubes, or ovaries) and men with infections of the male accessory glands, hypogonadotropic hypogonadism, clinical varicocele, retractile testis, genital trauma, drug use, or concurrent hormonal treatment Y chromosome microdeletions, and abnormal karyotype were excluded from the study. The polymerase chain reaction sequencing was performed for the promoter and the coding regions of MSMB functional domains. To study the protein expression, the total protein of sperm was extracted, and sandwich enzyme-linked immunosorbent assay was performed. Results: 4 variations were detected (rs12770171, rs10993994, rs2075894, and rs4517463). None of them showed significant differences between the IUI+ and IUI-groups. The mean value of protein expression did not show any differences between the groups. Conclusion: In conclusion, there is no association between genetic variations of promoter and coding regions of MSMB functional domains as well as its expression with IUI success in unexplained infertile men. Key words: MSMB, Beta microseminoprotein, Infertility, Male infertility.

Nordic inflammatory bowel disease treatment strategy trial: protocol for the NORDTREAT randomised controlled biomarker-strategy trial

IntroductionThe absence of reliable prognostic markers poses a challenge to the management of inflammatory bowel disease (IBD). Patients with aggressive disease may not receive sufficient treatment with conventional ‘step-up’ therapy,...

Novel Advances in Cell-Free Therapy for Premature Ovarian Failure (POF): A Comprehensive Review

Premature ovarian failure (POF), is a condition characterized by the early decline of ovulation function. POF is a complex disorder that can be caused by various factors, and the idiopathic form represents a significant proportion of POF patients. Hormone replacement therapy (HRT) is currently considered the first-line treatment for POF. This review aims to provide a comprehensive overview of recent advancements in platelet-rich plasma (PRP), in vitro activation (IVA), stem cell (SC) therapy, exosome therapy, microRNAs, and mitochondrial targeting therapies as a promising cell-free therapeutic approach in reproductive medicine. PLT-Exos, a new generation of cells, has been used to treat POF for more than a decade and has been shown to attenuate oocyte morphology and promote the differentiation of theca cells through the upregulation of PI3K/Akt and Bcl2, as well as the downregulation of the Smad and Bax signaling pathways. This review summarizes the current state of the art in the field of PLT-Exos and discusses the advantages and limitations of their potential clinical applications.

European Study of Cerebral Aspergillosis treated with Isavuconazole: an EFISG study.

Cerebral aspergillosis (CA) is associated with high mortality. According to ECIL-6 and ESCMID guidelines, the recommended first-line treatment for all forms of aspergillosis is voriconazole or isavuconazole. However, little is known about the efficacy and safety of isavuconazole in CA. We conducted a European multi-centre retrospective study of patients treated with isavuconazole for proven or probable CA between 2014 and 2022 and compared the outcomes to those of weighted control groups from the previously published French national cohort of CA, the Cerebral Aspergillosis Lesional Study. Forty patients from 10 countries were included. The main underlying conditions were hematological malignancies (53%) and solid organ transplantation (20%). Isavuconazole was administered as a first-line treatment to 10 patients, primarily in combination therapy, resulting in control of CA in 70% of these cases. Thirty patients received isavuconazole after a median of 65 days on another therapy, mostly because of side effects (50%) or therapeutic failure (23%) of the previous treatment. Predominantly given as monotherapy, it achieved control of CA in 73% of the patients. Seventeen patients (43%) undergone neurosurgery. When measured, isavuconazole levels were low in cerebrospinal fluid but adequate in serum and brain tissue. Isavuconazole toxicity led to treatment interruption in 7.5% of the patients. Twelve-week mortality was 18%. Comparison with the CEREALS cohort showed a comparable survival in patients receiving isavuconazole or voriconazole as a first line treatment. Isavuconazole appears to be a well-tolerated treatment. Mortality of CA treated with isavuconazole is similar to that reported with voriconazole.

The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study

AimsThis investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022.MethodsData from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment.ResultsFirst-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively.ConclusionsCompared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.