First-line Treatment Option Research Articles

Comparing the Efficacy of Combined Intralesional Triamcinolone Acetonide With Topical Calcipotriol Versus Intralesional Triamcinolone Acetonide Monotherapy in Scalp and Beard Alopecia Areata: Results From a Randomized Single-Blinded Clinical Trial.

Intralesional (IL) steroids are the first-line treatment option for localized alopecia areata (AA). The present study aimed to compare the efficacy of topical calcipotriol with IL triamcinolone acetonide versus IL triamcinolone acetonide alone in AA. This randomized single-blinded clinical trial was conducted in a dermatology outpatient department. Both groups A and B received IL triamcinolone acetonide injections every 4 weeks for 12 weeks. Group A also received twice-daily topical calcipotriol. Follow-up was done every 4 weeks till 12 weeks. The primary outcome parameter was hair density assessment using a hair regrowth scale (RGS). Other parameters were the presence or absence of poor clinical response (less than 50% hair density), regrowth patterns, dermoscopy features, and adverse effects. Seventy-three (179 patches) patients completed the study. RGS and patches with more than 50% terminal hair regrowth significantly improved in both the groups beginning in the fourth week and going forward (P-value: .001, .001). The two treatment groups exhibited no statistically significant difference in terminal hair density (P values: .930, .616, .178). However, subgroup analysis showed a statistically significant difference in scalp patches of group A compared to group B in the 12th week of the study (P = .018) but not in beard patches (P-value: .527). Group A exhibited more irritation with a reduced incidence of atrophy. The addition of topical calcipotriol to IL steroid showed increased efficacy in scalp patches of AA but not in beard patches. Also, the incidence of atrophy was lower in the combination group.

CXCR4 promotes tumor stemness maintenance and CDK4/6 inhibitors resistance in ER-positive breast cancer

BackgroundCDK4/6 inhibitors have significantly improved the survival of patients with HR-positive/HER2-negative breast cancer, becoming a first-line treatment option. However, the development of resistance to these inhibitors is inevitable. To address this challenge, novel strategies are required to overcome resistance, necessitating a deeper understanding of its mechanisms. Recent research has identified several dysregulated genes in CDK4/6 inhibitors-resistant breast cancer, but the underlying mechanism is complex due to tumor heterogeneity and warrants further investigation.MethodsRNA sequencing and KEGG pathway analysis was carried out to identify the mainly dysregulated genes in CDK4/6 inhibitors-resistant breast cancer cells. The effects of CXCR4 knockdown and overexpression via siRNAs and plasmids transfection were examined by mammosphere formation, RT-qPCR, flow cytometry, MTT and colony formation assays. The regulation mechanisms were analyzed by RT-qPCR, western blotting and immunofluorescence experiments. Mouse xenografts were used to analyze the role of CXCR4 in regulation palbociclib sensitivity in vivo. Additionally, we collected the clinical samples and performed immunohistochemistry to analyze the clinical significance of CXCR4.ResultsIn our study, we focused on cancer stem cells, a critical contributor to cancer metastasis and therapy resistance, and detected an upregulation of stemness in our established palbociclib-resistant ER-positive breast cancer cells. Additionally, our research pinpointed CXCR4 as a pivotal gene responsible for maintaining cancer stemness and promoting palbociclib resistance. Mechanistically, CXCR4 activates the WNT5A/β-catenin signaling pathway by enhancing the expression of WNT5A and β-catenin, facilitating the nuclear translocation of β-catenin protein. Targeting CXCR4 using siRNAs or small molecular inhibitors effectively reduces cancer stemness and reverses palbociclib resistance both in vitro and in vivo. Clinical sample analysis further underscores the overactivation of the CXCR4/WNT5A/β-catenin axis in palbociclib-resistant breast cancer, suggesting CXCR4 as a potential biomarker for predicting resistance to CDK4/6 inhibitors.ConclusionsCollectively, our study demonstrates that CXCR4 overexpression plays a vital role in maintaining breast cancer stemness and promoting resistance to CDK4/6 inhibitors through the activation of the WNT5A/β-catenin pathway. Targeting CXCR4 may offer a promising therapeutic approach for advanced CDK4/6 inhibitor-resistant ER-positive breast cancer.

Very Early Health Technology Assessment for Potential Predictive Biomarkers in the Treatment of Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI)-containing treatment is currently prescribed as first-line treatment for all patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, only 30-45% of patients show no progression within 12 months after treatment start. Various biomarkers are being studied to save costly and potentially harmful treatment in non-responders. We evaluated the cost-effectiveness of implementing a hypothetical predictive biomarker for ICI-containing treatment response compared with standard of care (e.g., no implemented biomarker) for pembrolizumab-containing treatment in patients with advanced NSCLC in the Netherlands. Standard-of-care-based and predictive-biomarker-based strategies were compared using Markov models for three first-line pembrolizumab-containing treatments depending on a patient's tumor programmed cell death ligand-1 (PD-L1) expression and histology. A Dutch healthcare system perspective was adopted. Assuming a receiver operating characteristic-area under the curve of 1.0 in identifying responders, alternative treatments were offered for non-responders in the predictive-biomarker-based strategy. Parameters and assumptions were based on real-world data from surveys, literature using a targeted search, expert opinion, and registries. Outcomes included differences in costs, survival (life years (LYs)), and survival corrected for health-related quality of life (QoL) quality-adjusted life-years (QALYs) between the predictive-biomarker- and standard-of-care-based strategy. Implementing a predictive biomarker in pembrolizumab-carboplatin-paclitaxel treatment led to a mean survival reduction of 24 days (- 0.067 LYs) (18 days corrected for QoL (- 0.049 QALYs)), with cost savings of €22,606 compared with standard of care. Pembrolizumab monotherapy and pembrolizumab-pemetrexed-platinum treatments showed survival reductions of 4.5 and 3.9 months, respectively (3.6 and 2.8 months corrected for QoL), with cost savings of €24,345 and €28,456. Sensitivity analyses confirmed consistent cost savings and survival reductions. Survival losses were mainly observed due to the lower survival rates associated with the alternative first-line treatment options available for non-responders in the predictive-biomarker-based strategy within each pembrolizumab-containing treatment regimen. Pembrolizumab-carboplatin-paclitaxel treatment also showed survival gains under certain conditions related to QoL and survival estimates. Our study highlights the importance of careful de-implementation of ICI-treatments in advanced NSCLC, balancing costs reductions and side effects without comprising survival. In the pembrolizumab-carboplatin-paclitaxel treatment regimen, the survival loss could be considered negligible. Future research should define acceptable tradeoffs and thresholds for de-implementation, considering factors such as survival of alternative treatments and responder classification to guide predictive biomarker implementation and optimize health resource allocation.

Impact of Membranous Nectin-4 on Outcomes of Platinum-Based Chemotherapy in Metastatic Urothelial Carcinoma

Background: Platinum-based chemotherapy (Plt-ChT) remains a cornerstone treatment for metastatic urothelial carcinoma (mUC). The nectin-4-targeting antibody–drug conjugate enfortumab vedotin (EV), in combination with immune checkpoint inhibitors, has expanded first-line treatment options. However, biomarkers to guide treatment selection are lacking. Membranous nectin-4 (mNectin-4) expression, a potential marker of EV efficacy, has not been fully explored in the context of Plt-ChT. Methods: We retrospectively analyzed 96 patients with mUC treated with first-line gemcitabine plus cisplatin or carboplatin (GC/GCarbo) and classified mNectin-4 expression using immunohistochemical staining as either high (histochemical score (H-score): 100–300, mNectin-4High) or low (H-score: 0–99, mNectin-4Low). Results: Among these patients, 54.1% exhibited mNectin-4High tumors, which were associated with bladder-origin tumors, a pure urothelial carcinoma histology, de novo presentation, and lymph node-only metastasis. The mNectin-4High subgroup showed a non-significant trend toward better outcomes, including response rate (46.1% vs. 36.3%; p = 0.32), median progression-free survival (7.0 months vs. 4.0 months; adjusted p = 0.06), and median overall survival (20.0 months vs. 8.8 months; adjusted p = 0.06), compared with the mNectin-4Low subgroup. The subgroup analysis revealed that the favorable outcomes for mNectin-4High tumors were predominantly observed in the GC cohort, which was not evident in the GCarbo cohort. Conclusions: Our study suggests a non-significant trend toward improved outcomes with first-line Plt-ChT in patients with mNectin-4High tumors, particularly with the GC regimen. Larger prospective studies are warranted to validate mNectin-4 as a potential predictive biomarker for mUC treatment.

P0811 Comparative efficacy of vedolizumab and infliximab in patients with moderate-to-severe ulcerative colitis: a multicenter real world cohort study

Abstract Background Vedolizumab (VDZ) and infliximab (IFX) are both recognized as first-line treatment options for moderate to severe ulcerative colitis (UC). However, there is a paucity of comparative studies examining their real-world efficacy. Methods Patients with moderate to severe UC were consecutively enrolled from 11 centers. Efficacy were evaluated after 14 and 52 weeks. Logistic regression was conducted to identify independent risk factors for clinical remission. Results A total of 235 patients were enrolled, of which 154 received VDZ treatment and 81 received IFX treatment. 154 (65.5%) were male, with a median age of 40 (32, 49) years, a median disease duration of 7.0 (2.8, 11.9) years. The median baseline Mayo score was 9 (7, 11), and the median baseline partial Mayo score was 6 (4, 8). 16 patients (6.8%) had perianal lesions, and 41 patients (17.4%) had extraintestinal manifestations. At week 14, patients treated with IFX had higher clinical response rate (84.6% vs 66.2%, p = 0.003) but lower endoscopic remission rate (14.5% vs 34.3%, p = 0.003) compared to those treated with VDZ. There were no statistical difference in clinical remission rate between the two groups (39.7% vs 44.8%, p = 0.462). At week 52, there were no statistically difference in the modified Mayo score, partial Mayo score, clinical response rate, clinical remission rate, and endoscopic remission rate between IFX treatment group and VDZ treatment group (p>0.05). Multivariate regression analysis demonstrated that baseline disease extent was a predictor of clinical remission at week 14 of VDZ treatment (OR = 3.55, 95% CI 1.39–9.06, p = 0.008). Conclusion IFX group received higher clinical response rate but not endoscopic remission rate at week 14. The efficacy of IFX was comparable to VDZ at week 52. Disease extent was a predictor of clinical remission at 14 weeks with VDZ.

Cross-sectional study of treatment approaches of luminal HER2negative metastatic breast cancer in real practice in Moscow

Introduction: The systemic therapy of patients with metastatic luminal HER2‑negative breast cancer (mBC) in‑ cludes various options, which can be fundamentally divided into endocrine therapy and chemotherapy. According to the Clinical Guidelines, both international and Russian, the “gold standard” of the 1st line therapy for patients with metastatic luminal HER2‑negative breast cancer (mBC) is a combination of cyclindependent kinase inhib‑ itors 4 / 6 (iCDK4 / 6) with endocrine therapy (ET). However, until recently we did not have complete data on the characteristics of the Russian population of patients with luminal HER2‑breast cancer, their treatment options, and the results of this therapy.Aim: To analyze the patients’ profile and current treatment approaches for patients with luminal HER2 mBC in routine clinical practice in Moscow.Materials and methods: The study was performed as an observational, crosssectional and retrospective study. The data of 2,500 patients from medical institutions in Moscow who received systemic therapy for luminal HER2 mBC in AugustOctober 2021 were analyzed.Results: The largest number of patients received iCDK4 / 6 + ET in the first and second lines: 69.0 % and 52.0 %, respectively. In the first line, 54.6 % of patients received ribociclib, 43.1 % palbociclib and 2.3 % abemaciclib. In the second line, 50.6 % of patients received ribociclib, 47.8 % palbociclib and 1.6 % abemaciclib. As the pretreatment of patients increased, preference was given to other treatment methods, therefore the proportion of combined ET decreased to 34.0 % in the third line and 25.0 % in the fourth and subsequent lines.Conclusion: The data obtained indicate that the appointment of iCDK4 / 6 + ET is made in accordance with the Clinical Guidelines for the treatment of breast cancer of the Ministry of Health of the Russian Federation from 2021 and the preferred firstline treatment option for patients with luminal HER2 mBC in Moscow is combined endocrine therapy.

Percutaneous Balloon Pericardiotomy: A Safe and Effective Approach for Managing Recurrent Massive Pericardial Effusion.

Percutaneous balloon pericardiotomy (PBP) has emerged as a less invasive alternative to surgical interventions for recurrent severe pericardial effusion (PE), particularly in patients with malignancies. This study evaluates the safety and efficacy of PBP in patients with recurrent severe PE. A total of 42 patients with recurrent severe PE underwent PBP between March 2008 and July 2024. PBP was performed under conscious sedation with fluoroscopic guidance using a 20-mm by 60-mm balloon. Data were collected on patient demographics, echocardiographic findings, procedural details, and follow-up outcomes. The study population had a mean age of 58.4 ± 11.2 years, with 54.8% being female. Most patients (76.2%) had malignant PEs. The procedure was technically successful in all cases, with no immediate complications. The median hospital stay was 4 days. Post-procedural transthoracic echocardiography showed no residual effusion in 40.5% of patients and minimal effusion in 50%. Over a median follow-up of 353 days, 54.8% of patients died due to the progression of underlying malignancies, and four patients experienced recurrent effusions requiring additional intervention. PBP is a safe and effective treatment for recurrent severe PE, particularly in patients with malignancies. The procedure's high success rate and favorable safety profile suggest it might be considered a first-line treatment option in appropriate clinical settings.

Hemostatic powder TC-325 as first-line treatment option for malignant gastrointestinal bleeding: a cost-utility analysis in the United Kingdom.

Randomized controlled trials have shown that hemostatic powder (TC-325) results in greater immediate hemostasis and lower 30-day rebleeding rates than standard endoscopic therapy (SET) for management of malignant upper gastrointestinal bleeding (MUGIB). We explored whether TC-325 would be a cost-effective first-line option for patients with MUGIB compared with SET in the United Kingdom. A decision tree was developed for patients with MUGIB, assessing initial therapy with TC-325 or SET over a 30-day period. Patients with failed initial hemostasis or a rebleed within 30 days underwent further endoscopic treatment, escalation to either transcatheter arterial embolization or surgery, or radiotherapy. Overall 30-day mortality was applied. Costs, in GBP, were based on the United Kingdom National Health Services costs for 2023/2024. Results were reported as incremental differences in cost, quality-adjusted life years (QALY), and net monetary benefit. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The cost of treating MUGIB patients with TC-325 was £245.88 lower than treatment with SET, with an incremental increase of 0.001 QALYs. TC-325 remained a cost-saving approach in sensitivity and scenario analyses. Probabilistic sensitivity analysis revealed that TC-325 was more effective and cost saving in 80.1% of simulations (range 67.5%-98.63%). Initial treatment of MUGIB with TC-325 compared with SET was more effective (higher primary hemostasis and lower 30-day rebleeding) and cost saving owing to the requirement for fewer interventions, readmissions, and length of stay. Additional studies are needed to address model uncertainties in the follow-up management of these complex patients.

The Role of Image-Guided Superficial Radiation Therapy in the Treatment of Nonmelanoma Skin Cancer

Background: Basal cell carcinoma (BCC) and squamous cell carcinoma, collectively referred to as nonmelanoma skin cancer (NMSC) are the most common type of skin cancer and can lead to significant morbidity and mortality. There are several treatment options available for NMSC including superficial radiation therapy (SRT), which has improved in recent years with the addition of image guidance (IGSRT). In some cases, patients are not offered IGSRT as a treatment option and additional guidance on its benefits may be beneficial. Objective: For a panel of expert dermatologists to review published studies on IGSRT for the treatment NMSC and create consensus recommendations on its use. Methods: A comprehensive literature search of PubMed, EMBASE, Scopus, and Google Scholar was completed for English-language original research articles on the use of IGSRT to treat NMSC. A panel of six dermatologists with significant expertise in treating NMSC convened to review the articles and create consensus statements based on the available data. A modified Delphi process was used to approve each statement for adoption and a strength of recommendation was assigned using Strength of Recommendation Taxonomy (SORT) criteria. Results: After screening the articles that met the initial search criteria, 12 articles were distributed to the panelists for review prior to the roundtable discussion. The panel unanimously voted to adopt eight statements with an additional two statements receiving five out six votes for adoption. Eight of the statements received a strength of recommendation of “A” while two of the statements were given a strength of recommendation of “B” based on SORT criteria. Conclusion: IGSRT is a safe and effective treatment for NMSC that often results in highly favorable cosmetic outcomes. It can be considered a first-line treatment option for appropriately selected cases of NMSC.

Trastuzumab-Pertuzumab Plus Eribulin or Taxane as First-Line Chemotherapy for Human Epidermal Growth Factor 2-Positive Locally Advanced/Metastatic Breast Cancer: The Randomized Noninferiority Phase III EMERALD Trial.

Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC. In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.gov identifier: NCT03264547/UMIN000027938), patients were randomly assigned (1:1) to receive eribulin 1.4 mg/m2 once daily on days 1 and 8 (eribulin group) or a taxane (docetaxel 75 mg/m2 once on day 1 or paclitaxel 80 mg/m2 once daily on days 1, 8, and 15; taxane group) intravenously in a 21-day cycle, each with HP on day 1. The primary end point was progression-free survival (PFS; intention-to-treat population). Secondary end points included objective response rate, overall survival (OS), patient-reported quality of life (QoL), and safety. Noninferiority was tested using the stratified Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events, with a noninferiority HR margin of 1.33. Between August 2017 and June 2021, 446 patients (median age, 56.0 years) were enrolled. The median PFS was 14.0 and 12.9 months in the eribulin group (n = 224) and taxane group (n = 222 [docetaxel/paclitaxel, n = 186/36]), respectively (HR, 0.95 [95% CI, 0.76 to 1.19]), which confirmed the noninferiority of the study regimen. The median OS was 65.3 months in the taxane group but has not been reached in the eribulin group. Median time to QoL deterioration was numerically longer with eribulin than with taxane. Adverse event (AE) rates were similar, despite the longer duration of eribulin use. Infusion reaction, skin-related AEs, diarrhea, and edema were more common with taxane, whereas neutropenia was more common with eribulin. The results suggested that eribulin + HP is an option for first-line treatment of locally advanced/metastatic HER2+ BC.

Treatment outcomes of primary salivary gland squamous cell carcinoma: A multi-institutional retrospective study in Japan.

Primary salivary gland squamous cell carcinoma (SCC) is extremely rare, accounting for 0.3-10.4 % of all salivary gland malignancies. Due to this rarity, the clinical characteristics of primary salivary gland SCC remain unelucidated. In the present study, we conducted a multi-institutional retrospective analysis-including a large number of cases compared with that of previous studies-to reveal the prognosis, treatment outcomes, and prognostic factors of primary salivary gland SCC. The clinical course of patients with primary salivary gland SCC between January 2012 and December 2022 was retrospectively investigated. Thirteen university hospitals and cancer centers in Japan participated in this study. The diagnosis of primary salivary gland SCC was based on the following criteria: 1) pathological diagnosis of SCC and exclusion of other histological types and 2) exclusion of metastatic SCCs from other organs. Progression-free and overall survival rates were compared using Kaplan-Meier curves and log-rank tests. Treatment outcomes were assessed using univariate and multivariate analyses with Cox proportional hazards models. In total, 723 patients with salivary gland cancer were admitted to the participating institutions. Among them, 63 patients (8.7 %) were diagnosed with primary salivary gland SCC. The clinical courses of the 58 patients that received definitive treatment and had complete data were analyzed. Primary treatments included surgery in 35 patients (60.3 %), chemoradiotherapy in 16 (27.6 %), radiotherapy in 5 (8.6 %), and chemotherapy in 2 (3.4 %). Complete response and objective response rates to chemoradiotherapy were 62.5 % and 93.8 %, respectively. Five-year progression-free and overall survival rates were 30.1 % and 60.1 %, respectively. Five-year progression-free survival rates for each treatment were 37.7 % (surgery), 33.0 % (chemoradiotherapy), 0 % (radiotherapy), and 0 % (chemotherapy). Overall survival rates were 71.5 % (surgery), 39.5 % (chemoradiotherapy), 53.3 % (radiotherapy), and 0 % (chemotherapy). Multivariate analysis revealed that age ≥70 years, N classification ≥1, and surgery were independent predictors of progression-free (hazard ratios: 3.75, 2.46, and 0.33, respectively) and overall survival (hazard ratios: 3.11, 6.24, and 0.32, respectively). Adjuvant radiotherapy significantly improved progression-free and overall survival in patients with stage Ⅳ cancer or positive surgical margins. Log-rank tests revealed no significant difference between patients with or without elective neck dissection in progression-free and overall survival; however, a relatively high percentage of occult lymph node metastasis (50.0 %) was observed. Surgical resection is a favorable first-line treatment option in salivary gland SCC, and definitive chemoradiotherapy would show acceptable complete and objective response rates.

Oncolytic Viruses and Immunotherapy for the Treatment of Uveal Melanoma and Retinoblastoma: The Current Landscape and Novel Advances.

Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities for UM and RB have been proposed, with chemotherapy for RB cases and plaque radiation therapy for localized UM as first-line treatment options. Extraocular extension, recurrence, and metastasis constitute the major challenges of conventional treatments. To overcome these obstacles, immunotherapy, which encompasses different treatment options such as oncolytic viruses, antibody-mediated immune modulations, and targeted immunotherapy, has shown great potential as a novel therapeutic tool for cancer therapy. These anti-cancer treatment options provide numerous advantages such as selective cancer cell death and the promotion of an anti-tumor immune response, and they prove useful in preventing vision impairment due to macular and/or optic disc involvement. Numerous factors such as the vector choice, route of administration, dosing, and patient characteristics must be considered when engineering an oncolytic virus or other forms of immunotherapy vectors. This manuscript provides an in-depth review of the molecular design of oncolytic viruses (e.g., virus capsid proteins and encapsulation technologies, vectors for delivery, cell targeting) and immunotherapy. The most recent advances in preclinical- and clinical-phase studies are further summarized. The recent developments in virus-like drug conjugates (i.e., AU011), oncolytic viruses for metastatic UM, and targeted immunotherapies have shown great results in clinical trials for the future clinical application of these novel technologies in the treatment algorithm of certain intraocular tumors.

The effectiveness of repetitive transcranial magnetic stimulation (rTMS) in patients with catatonia associated with another mental disorder: A systematic review.

Catatonia is a rare but life-threatening condition characterized by a constellation of psychomotor disturbances. The most widely used treatments of catatonia include benzodiazepines and electroconvulsive therapy. Despite the widespread use of benzodiazepines and the high response rate of catatonia to ECT, there are instances where catatonia does not respond to first-line treatments. This study aimed to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in managing catatonia. A systematic literature search was conducted on the following databases: Medline, PubMed, Cochrane Library, Embase, PsycINFO and ClinicalTrials.gov for registered but not yet published studies. Out of 244 initially identified articles, there remained eight case reports and 1 case series eligible after screening. Of the twelve total cases, nine showed clinical improvement. However, there was significant heterogeneity in the complexity of the clinical situation, the severity of clinical features of catatonia, underlying causes, and rTMS treatment protocols between studies. The results of this study are inconclusive. However, rTMS might be trialed for the management of catatonia when first-line treatment options fail, are unavailable, or need to be used with caution. Our review incorporating the most up to date evidence highlights the need for more extensive, standardized, randomized clinical trials to investigate the efficacy of rTMS for treating catatonia.

Real-World Effectiveness and Safety of Isavuconazole Versus Amphotericin B for Patients with Invasive Mucormycosis.

Invasive mucormycosis (IM) poses a substantial morbidity and mortality burden among immunocompromised patients. We aim to compare the real-world effectiveness and safety of isavuconazole with those of amphotericin B in patients with IM. In this observational cohort study, we enrolled patients who were diagnosed with IM and treated with either isavuconazole or amphotericin B. A total of 106 patients met the study criteria. Of these, 47 received isavuconazole, and 59 received amphotericin B as the primary treatment. The two cohorts had similar baseline characteristics, including a history of malignancy, use of immunosuppressants, infection sites, and pathogens. The amphotericin B group demonstrated a significantly greater incidence of renal disorders (p < 0.001) and hypokalemia (p < 0.001) than the isavuconazole group. The proportion of patients who received salvage therapy was greater in the amphotericin B group than in the isavuconazole group (42% vs. 6%, p < 0.001). Eighteen patients in the amphotericin B group discontinued treatment because of adverse events, whereas no patients in the isavuconazole group discontinued treatment because of adverse events. A significant difference in the primary therapeutic response between the isavuconazole and amphotericin B groups was noted (p = 0.013), with a higher treatment failure rate in the amphotericin B group (68% vs. 36%, p = 0.001). However, there were no significant differences in all-cause mortality or mucormycosis-attributable mortality rates between the two groups. Isavuconazole outperformed amphotericin B as a first-line treatment option for IM in terms of its clinical effectiveness and safety.

Prognostic impact of primary versus secondary resistance to sorafenib in patients with HCC.

Sorafenib is a first-line treatment option for patients with hepatocellular carcinoma (HCC). However, the impact of sorafenib resistance type on patient survival prediction and choice of second-line treatment regimen is unknown. This study aims to explore the factors predicting resistance in patients with HCC receiving sorafenib, the impact of resistance on survival, and the optimal second-line treatment regimen. This was a retrospective cohort study. We recruited all patients with advanced HCC who received first-line sorafenib from January 2019 to January 2023 in two medical centers in China. They were divided into primary and secondary resistance groups according to tumor progression within 3 months. Resistance was the primary outcome of this study. The secondary outcomes were progression-free survival (PFS) and overall survival (OS). A total of 424 patients met the inclusion criteria, including 165 patients (38.9%) in the primary group and 259 patients (61.1%) in the secondary group. The independent risk factors for primary resistance were alpha-fetoprotein (AFP) > 400 ng/mL and alanine aminotransferase (ALT) > 40 U/L. Patients in the primary group had significantly shorter median OS than those in the secondary group (9.0 months vs 23.0 months, p < 0.001). Compared with tyrosine kinase inhibitor (TKI) monotherapy, the use of TKI plus PD-1 inhibitor combination therapy as second-line treatment conferred a longer median PFS (6.0 vs 10.0 months, p < 0.001) and OS (13.0 vs 22.0 months, p < 0.001). Sorafenib has a high incidence of primary resistance and short survival in patients who develop primary resistance. AFP and ALT are influential factors in primary resistance, and it is valuable to use these two metrics to guide the use of sorafenib. As second-line therapy, a TKI plus PD-1 inhibitor regimen should be preferentially recommended.

Toripalimab combined with bevacizumab plus chemotherapy as first-line treatment for refractory recurrent or metastatic cervical cancer: a single-arm, open-label, phase II study (JS001-ISS-CO214).

To evaluate the efficacy and safety of adding toripalimab to bevacizumab and platinum-based chemotherapy as first-line treatment for refractory recurrent or metastatic (R/M) cervical cancer (CC). Patients were administered toripalimab (240 mg) + bevacizumab (7.5 mg/kg) combined with platinum-based chemotherapy once every three weeks for six cycles, followed by the maintenance therapy involving toripalimab + bevacizumab once every 3 weeks for 12 months or when disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were safety profiles, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Twenty-four patients were enrolled in this study and in the final analysis. The median follow-up duration was 18.6 (range, 3.3-28.5) months. The ORR was 83.3% (95% confidence interval [CI]=62.6-95.3) and the DCR was 95.8% (95% CI=78.9-99.9); 9 (37.5%) patients achieved complete response, 11 (45.8%) achieved partial response, and 3 (12.5%) had stable disease. The median PFS was 22.6 (95% CI=10.4-34.7) months and the median OS was not reached. The most common grade 3 treatment-related adverse events (AEs) were neutropenia (41.7%) and leukopenia (16.7%). The most common immune-related AEs (irAEs) were thyroid dysfunction (37.5%) and increased adrenocorticotropic hormone (37.5%) and serum cortisol levels (33.3%). No grade ≥3 irAEs were observed. Toripalimab combined with bevacizumab and platinum-based chemotherapy show promising clinical efficacy and favorable safety profile, providing an alternative first-line treatment option for patients with R/M CC. ClinicalTrials.gov Identifier: NCT04973904.

Systemic Therapy in Metastatic Pancreatic Cancer: A Review

The prognosis for pancreatic cancer is still poor, because it is typically identified at an advanced, frequently metastatic stage. Recently, a sequential treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC) has been developed. When the performance status is good, combination chemotherapy regimens such FOLFIRINOX and gemcitabine plus nab-paclitaxel are options for first-line treatment. Gemcitabine monotherapy is a viable choice for patients with lower performance status. Recently, olaparib, a PARP inhibitor, was showed to enhance the amount of time patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a BRCA1/-2 germ line mutation can live without their disease worsening. If the initial treatment is unsuccessful, patients should be provided with an alternative treatment option if their ECOG score allows for continued treatment. The combination of 5-FU/FA with nanoliposomal irinotecan has demonstrated better overall survival compared to 5-FU/FA alone. Immune checkpoint drugs like PD1/PD-L1 mAbs are particularly efficacious in malignancies with high microsatellite instability (MSI-h). Limited data in mPDACs suggests that only a part of the already tiny subgroup of MSI-H mPDACs (frequency approximately 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of other subgroups, may further increase therapeutic efficacy.

Stroke in Athletes with Atrial Fibrillation: A Narrative Review.

Atrial fibrillation (AF) is the most common sustained arrhythmia, linked with a significantly heightened risk of stroke. While moderate exercise reduces AF risk, high-level endurance athletes paradoxically exhibit a higher incidence. However, their stroke risk remains uncertain due to their younger age, higher cardiovascular fitness, and lower rate of comorbidities. Several key studies highlight that AF may increase the risk of stroke in endurance athletes, particularly those over 65. However, the overall risk within this population remains relatively low. Notably, older male athletes show a higher AF incidence but experience lower stroke risk than their non-athletic counterparts. Regular physical activity prior to a first stroke appears to reduce mortality, though recurrent stroke risk in athletes with AF mirrors that of non-athletes, despite an elevated AF incidence. Management of AF in athletes is complex, with limited evidence guiding anti-thrombotic strategies. In this setting, specific recommendations are sparse, particularly in sports where bleeding risk is heightened. Individualized management, emphasizing shared decision-making, is critical to balance stroke prevention with athletic performance. Rhythm control strategies, such as catheter ablation, may be a reasonable first-line treatment option for athletes, particularly in those desiring to avoid long-term medication. This review synthesizes the current literature on the incidence, predictors, and management of stroke in athletes with AF.

Comparison of the Effectiveness of Different Antidepressants in Preventing Psychiatric Rehospitalization.

Patients with major depressive disorder (MDD) often face poor health outcomes. Additionally, patients with multiple hospitalizations tend to have worse predicted disease prognosis. Antidepressant medications remain a first-line treatment option for MDD, but data evaluating the effects of different antidepressants on psychiatric readmission rates is lacking. The objective of this study was to assess readmission rates based on antidepressant selection upon discharge from an inpatient psychiatric hospitalization. This was a single-center, retrospective chart review evaluating psychiatric readmission rates of adults with MDD discharged on antidepressant therapy. The primary outcome was to compare 30-day psychiatric rehospitalization rates based on antidepressant treatment and secondary outcomes included six-month and one-year psychiatric rehospitalization based on antidepressant treatment.Odds ratios (OR), 95% confidence intervals (CI), and p-values were calculatedto determine the odds of readmission in patients who were discharged on each antidepressant compared to patients who were discharged on an antidepressant other than that particular antidepressant. Patients who were discharged on sertraline were four times less likely to be readmitted within 30 days compared to the combined readmission rate of other antidepressants or multiple antidepressants (OR: 0.228, 95%CI: 0.053-0.978, p<0.05). Meanwhile, patients discharged on any combination of multiple antidepressants were more likely to be readmitted than patients discharged on only one antidepressant (OR: 4.517, 95%CI: 1.581-12.908, p<0.05). The antidepressant medications included in the study were bupropion, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, trazodone, and venlafaxine. Careful consideration should be taken when choosing antidepressant therapy for inpatient psychiatric patients as this may impact relapse of symptoms and readmission rates. Further research is needed to evaluate other factors that may influence psychiatric readmissions for MDD.

Ecteinascidin synthetic analogues: a new class of selective inhibitors of transcription, exerting immunogenic cell death in refractory malignant pleural mesothelioma

BackgroundMalignant pleural mesothelioma (MPM) is a highly chemo-refractory and immune-evasive tumor that presents a median overall survival of 12–14 months when treated with chemotherapy and immunotherapy. New anti-tumor therapies as well as the concomitant reactivation of immune destruction are urgently needed to treat patients with this tumor. The aim of this work is to investigate the potential effect of ecteinascidin derivatives as lurbinectedin as new first-line treatment option in MPM, alone and in combination with immunotherapy.MethodsThe antitumor activity of ecteinascidin synthetic analogues: lurbinectedin, ecubectedin and PM54 was evaluated in an array of patient-derived MPM cells in terms of cell proliferation, cell cycle, apoptosis, DNA damage and repair. Immunoblot was used to assess the cGAS/STING pathway. ELISA and flow cytometry-based assays were used to evaluate immunogenic cell death parameters and the effect on the immunophenotype in autologous peripheral blood monocyte-MPM cells co-cultures. Patient-derived xenografts (PDX) in humanized mice were used to evaluate the efficacy of ecteinascidins in vivo.ResultsLurbinectedin, ecubectedin, and PM54 were effective in reducing cell proliferation and migration, as well as inducing S-phase cell cycle arrest and DNA damage in malignant pleural mesothelioma cells. These effects were more pronounced compared to the standard first-line treatment (platinum-based plus pemetrexed). Mechanistically, the drugs downregulated DNA repair genes, activated the cGAS/STING pathway, and promoted the release of pro-inflammatory cytokines. They also induced immunogenic cell death of mesothelioma cells, enhancing the activation of anti-tumor CD8+T-cells and natural killer cells while reducing tumor-tolerant T-regulatory cells and myeloid-derived suppressor cells in ex vivo co-cultures. These promising results were also observed in humanized patient-derived xenograft models, where the drugs were effective in reducing tumor growth and increasing the ratio anti-tumor/pro-tumor infiltrating immune populations, either alone or combined with the anti-PD-1L atezolizumab.ConclusionsCollectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.