First-line Treatment Research Articles

Immune Microenvironment and the Effect of Vascular Endothelial Growth Factor Inhibition in Hepatocellular Carcinoma.

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.

Patient-reported quality of life in Asian patients with ER+/HER2- advanced breast cancer treated with palbociclib plus letrozole in the PALOMA-4 trial.

Palbociclib plus an aromatase inhibitor is approved for treatment of patients with ER+/HER2- advanced breast cancer (ABC). In the PALOMA-4 trial, adding palbociclib to letrozole prolonged median progression-free survival in Asian women with ER+/HER2- ABC. Here, we report patient-reported outcomes (PROs) from PALOMA-4. PALOMA-4 was a randomized, double-blind, phase 3 trial of palbociclib plus letrozole vs. placebo plus letrozole treatment in postmenopausal Asian women with ER+/HER2- ABC. PROs were longitudinally assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL 5D three level (EQ-5D-3L) questionnaires. Group comparisons were analyzed using longitudinal, mixed-effects models. Patients were randomly assigned to palbociclib plus letrozole (n=169) or placebo plus letrozole (n=171) treated groups. No significant between-arm differences in change from baseline were observed in FACT-B and its subscales, or the EQ-5D-3L index. A significant, but not clinically meaningful difference was observed in change from baseline in mean EQ-VAS score favoring palbociclib plus letrozole (3.36; 95% confidence interval [CI], 0.88-5.83; P =0.008). When patients from both arms were combined, significant differences in the mean change from baseline for FACT-B total were observed favoring treatment responders vs. non-responders (3.84; 95% CI, 0.33-7.36; P =0.032) and for the Breast Cancer Subscale favoring patients without disease progression vs. those with progression (0.97; 95% CI, 0.05-1.89; P =0.038). Quality of life was maintained when palbociclib was added to letrozole in Asian women with ABC. These findings are consistent with PALOMA-2 results and support the use of palbociclib as first-line treatment in postmenopausal Asian patients with ER+/HER2- ABC. clinicaltrials.gov, NCT02297438.

Efficacy of local-regional radiotherapy in de novo metastatic nasopharyngeal carcinoma patients receiving chemo-immunotherapy: A multicenter, propensity score matching study.

To evaluate the efficacy of local-regional radiotherapy (LRRT) in de novo metastatic nasopharyngeal carcinoma (dm NPC) patients receiving chemo-immunotherapy as first-line treatment and select the beneficiaries from LRRT. M1-NPC patients receiving platinum-based chemo-immunotherapy with or without LRRT from four centers were included in this study. The propensity score matching (PSM) analysis was employed to balance the baseline characteristics between the LRRT and non-LRRT groups. 546dm NPC patients (140 patients in the non-LRRT group and 406 patients in the LRRT group) were incorporated. Patients receiving LRRT demonstrated significantly improved progression-free survival (3-year PFS rate, 53.2% vs 31.2%, p<0.001). After PSM analysis, there were 244 patients in the LRRT group and 122 patients in the non-LRRT group. Multivariable analysis indicated that LRRT was not an independent prognostic factor in the matched cohort (HR, 1.25, 95% CI, 0.92-1.69, p=0.156). Subgroup analysis among the matched cohort showed a significant increase in PFS for patients with oligo metastatic disease (OMD) who received LRRT (3-year PFS rate, 70.6% vs 49.3%, p=0.043). In contrast, no such benefit was observed in patients with poly metastatic disease (PMD, 3-year PFS rate, 35.8% vs 27.8%, p=0.17). Furthermore, LRRT significantly enhanced survival in patients with undetectable EBV DNA2-6 cycles (3-year PFS rate, 57.9% vs. 43.4%, p=0.043), whereas no survival improvement was noted in patients with detectable EBV DNA2-6 cycles (16.2% vs. 20.3%, p=0.21). LRRT could prolong PFS in M1-NPC patients. OMD and undetectable EBV DNA2-6 cycles are potential indicators for selecting beneficiaries from LRRT.

Clinical outcomes after first-line anti-TNF treatment of patients with inflammatory bowel disease - a prospective multicenter cohort study.

Existing findings on outcomes of anti-tumor-necrosis-factor (TNF) therapy in patients with inflammatory bowel diseases (IBD) are largely based on retrospective studies. We aimed to investigate real-world outcomes of anti-TNF therapy and predictors thereof in a prospective IBD cohort. In a Danish multicenter cohort of adult bio-naïve patients with IBD treated with anti-TNF, we assessed clinical response and remission to induction therapy using clinical disease activity scoring indices at week 14. In patients who continued treatment beyond the induction period, we also assessed loss of response (LOR), drug withdrawal, and major IBD surgery during maintenance therapy. This study included 774 patients (706 infliximab, 68 adalimumab) followed for a median duration of 125 weeks Clinical response was achieved in 209/331 (67.4%) of ulcerative colitis (UC) and 125/197 (74.0%) of Crohn's disease (CD) patients, while 143/331 (46.1%) UC and 81/197 (47.9%) CD patients achieved clinical remission. In 294 UC and 309 CD patients who received maintenance therapy, 86/294 (29.3%) UC and 78/309 (25.2%) CD patients experienced LOR. Active smoking and less severe disease activity predicted favorable outcomes in UC, while short disease duration, colonic disease, non-stricturing behavior, and concomitant immunomodulator therapy predicted favorable outcomes in CD. Clinical response was achieved in two in three UC and three in four CD patients, meanwhile, one-third of UC and one-fourth of CD patients experienced LOR despite the short disease duration in this study. Several clinical features were associated with outcomes and may be useful predictors of anti-TNF treatment response.

Personal growth during early and advanced pregnancy according to women’s mode of conception

ABSTRACT Background Pregnancy can be a complex and stressful period, especially for women conceiving through fertility treatment, but this can foster the experience of personal growth (PG). Most of the knowledge on women’s PG during pregnancy is based on a single measurement and relates to conceiving achieved through fertility treatments in general. Relying on Schaefer and Moos’s PG model, the current prospective study sought to (1) investigate the differences in PG according to women’s mode of conception (spontaneous; first-line fertility treatment; IVF) and (2) examine the contribution of the mode of conception, perceived stress, self-mastery, and cognitive appraisal (threat, challenge, and self-efficacy) to PG in two phases during pregnancy. Methods Israeli pregnant women (Mean age = 32) recruited through a convenience sample, completed self-report questionnaires twice: the first or second trimester of pregnancy (Phase 1; n = 400) and the third trimester (Phase 2; n = 268). A total of 268 participants completed both assessments. Results Women who conceived through IVF experienced higher PG and lower self-mastery than women who conceived spontaneously. Regression analyses indicated that IVF, being primiparous, lower self-mastery, lower threat appraisal, and higher challenge appraisal were related to greater PG in Phase 1. Only expecting the first child and challenge appraisal predicted women’s PG in Phase 2. Conclusions The study highlights that women who conceive through IVF experience greater PG than other women and the significant role of cognitive appraisal in PG over time during pregnancy. These findings may inform focused-based interventions to enhance women’s mental health during this period.

Racial differences in real-world outcomes of first-line therapies for advanced renal cell carcinoma.

Given the historical underrepresentation of racial minorities in clinical trials, little is known about racial differences in outcomes of first-line therapies for advanced renal cell carcinoma (aRCC). This study described patient characteristics and clinical outcomes of first-line therapies for aRCC, including nivolumab + ipilimumab, pembrolizumab + axitinib, and tyrosine kinase inhibitors, by race in the real-world setting. We conducted a retrospective medical chart review of patients with intermediate/poor-risk clear-cell aRCC. Treating physicians abstracted patient data from electronic medical charts. Among 346 patients with intermediate/poor-risk aRCC, a higher proportion of African-American/Black (n = 78) versus White (n = 268) patients had poorer baseline functional performance (ECOG-PS ≥ 2: 37.2% versus 21.3%). African-American/Black patients trended toward numerically lower overall response rates and shorter overall survival for nivolumab + ipilimumab or pembrolizumab + axitinib than White patients. These findings provide important insights into racial differences in first-line aRCC treatment outcomes within real-world settings. Additional research with larger sample sizes is warranted.

Urge fecal incontinence: are intramural rectal injections of botulinum toxin a long-term treatment option?

Unsuccessful first-line conservative treatments for managing fecal incontinence (FI) lead to considering predominantly invasive options, posing challenges in terms of cost and patient acceptance of benefit/risk ratio. Recent data from a prospective randomized study have highlighted intramural rectal botulinum toxin (BoNT/A) injection as a promising minimally invasive alternative for urge FI, demonstrating efficacy at 3months but lacking long-term evidence. This study aimed to evaluate the sustained efficacy and injection frequency of intramural rectal BoNT/A injection in the treatment of urge FI. This retrospective monocentric study enrolled all patients who underwent intramural rectal BoNT/A injection for urge FI after failed conservative therapy or sacral neuromodulation (SNM). Injections were administered during sigmoidoscopy, delivering 200 U of BoNT/A at 10 circumferentially distributed sites. Treatment effectiveness was assessed using the Cleveland clinic incontinence score (CCS) and a visual analog scale (VAS) to measure the severity of discomfort related to episodes of fecal urgency, with reinjection performed upon symptom recurrence. In total, 41 patients (34 females) were included, with a median follow-up of 24.9 (range 3.2-70.3) months. Overall, 11 patients had previously failed sacral nerve stimulation. Significant reductions were observed in the CCS (median 11 versus 7, p = 0.001) and VAS symptoms (median 4, range 0-5 versus median 2, range 0-5, p = 0.001). In total, 22 patients (53%) experienced a reduction in the CCS by over 50%. The median interval between intramural rectal BoNT/A injections was 9.8months (range 5.3-47.9 months). This study provides the first evidence of the sustained efficacy of intramural rectal BoNT/A injection for urge FI. Further investigations are warranted to refine patient selection and reinjection criteria, evaluate socioeconomic impacts, and compare rectal BoNT/A injection with other therapeutic modalities.

Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images

Immune checkpoint inhibitors (ICI) have become integral to treatment of non-small cell lung cancer (NSCLC). However, reliable biomarkers predictive of immunotherapy efficacy are limited. Here, we introduce HistoTME, a novel weakly supervised deep learning approach to infer the tumor microenvironment (TME) composition directly from histopathology images of NSCLC patients. We show that HistoTME accurately predicts the expression of 30 distinct cell type-specific molecular signatures directly from whole slide images, achieving an average Pearson correlation of 0.5 with the ground truth on independent tumor cohorts. Furthermore, we find that HistoTME-predicted microenvironment signatures and their underlying interactions improve prognostication of lung cancer patients receiving immunotherapy, achieving an AUROC of 0.75 [95% CI: 0.61-0.88] for predicting treatment responses following first-line ICI treatment, utilizing an external clinical cohort of 652 patients. Collectively, HistoTME presents an effective approach for interrogating the TME and predicting ICI response, complementing PD-L1 expression, and bringing us closer to personalized immuno-oncology.

Role of Cognitive Behavioral Therapy in Treating Depression among Adults in South Korea

Purpose: The aim of the study was to analyze the role of cognitive behavioral therapy in treating depression among adults in South Korea. Methodology: This study adopted a desk methodology. A desk study research design is commonly known as secondary data collection. This is basically collecting data from existing resources preferably because of its low cost advantage as compared to a field research. Our current study looked into already published studies and reports as the data was easily accessed through online journals and libraries. Findings: Cognitive Behavioral Therapy (CBT) has proven to be an effective approach for treating depression among adults in South Korea, showing significant improvements in symptom reduction and mental well-being. It helps individuals identify and change negative thought patterns, enhancing emotional regulation and coping skills. Clinical findings reveal that CBT leads to substantial decreases in depressive symptoms compared to traditional care. Its structured and goal-oriented nature aligns well with South Korea’s emphasis on practical, evidence-based mental health interventions. Unique Contribution to Theory, Practice and Policy: Cognitive theory of depression, behavioral activation theory &amp; biopsychosocial model may be used to anchor future studies on the role of cognitive behavioral therapy in treating depression among adults in South Korea. Clinicians should continue to integrate CBT as a first-line treatment for depression, emphasizing its role in both reducing symptoms and improving long-term emotional resilience. Policymakers should consider expanding access to CBT, particularly in public health systems, due to its cost-effectiveness and proven success in treating depression.

Enhancing anti-vascular endothelial growth factor with photodynamic therapy for polypoidal choroidal vasculopathy: A meta-analysis.

Anti-vascular endothelial growth factor (VEGF) agents administered as either monotherapy or combination with verteporfin photodynamic therapy (PDT) are the 2 dominant treatment for polypoidal choroidal vasculopathy (PCV); However, controversies remain due to small sample sizes and inconsistency in prognosis from randomized controlled trials (RCTs). In accordance with the PRISMA statement, we investigated the efficacy of PDT plus anti-VEGF combination with anti-VEGF monotherapy. This study was accepted by the International Prospective Register of Systematic Reviews (CRD42023471362). Studies published up to July, 2024, were retrieved from PubMed, Embase, and Cochrane databases. A total of 7 RCTs with 926 eyes were reviewed. In 6 trials, combination therapy showed significantly higher rate of complete polyp regression (risk ratio [RR]: 1.56, 95% CI: 1.15-2.13, p = 0.005). In 5 trials, combination therapy also significantly reduced the number of anti-VEGF injections (SMD: -0.65, 95% CI: -0.95 to -0.35, p < 0.0001). For best corrected visual acuity improvement, central retinal thickness reduction, and rate of ocular adverse events, the performance of the 2 modalities were comparable. We conclude that PDT plus anti-VEGF combination therapy constitutes a safe and effective modality and should be considered the first-line treatment for PCV.

Refining management strategies for Lennox-Gastaut syndrome: Updated algorithms and practical approaches.

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy (DEE) characterized by multiple types of drug-resistant seizures (which must include tonic seizures) with classical onset before 8 years (although some cases with later onset have also been described), abnormal electroencephalographic features, and cognitive and behavioral impairments. Management and treatment of LGS are challenging, due to associated comorbidities and the treatment resistance of seizures. A panel of five epileptologists reconvened to provide updated guidance and treatment algorithms for LGS, incorporating recent advancements in antiseizure medications (ASMs) and understanding of DEEs. The resulting consensus document is based on current evidence from clinical trials and clinical practice and the panel's expert opinion, focusing on new ASMs with novel mechanisms of action, such as highly purified cannabidiol and fenfluramine. For a patient presenting with newly diagnosed LGS or suspected LGS, the recommended first-line treatment continues to be valproate. If this is ineffective as monotherapy, adjunctive therapy with, firstly, lamotrigine and secondly, rufinamide, is recommended. If seizure control remains suboptimal, subsequent adjunctive ASM treatment options include (alphabetically) cannabidiol, clobazam, felbamate, fenfluramine, and topiramate, although evidence for these is more limited. Whenever possible, no more than two ASMs should be used together. Nonpharmacological treatment approaches should be used in conjunction with ASM therapy and include ketogenic diet therapies, vagus nerve stimulation, and corpus callosotomy. Patients with LGS that has evolved from another type of epilepsy who are not already being treated with valproate should be transitioned to valproate and then managed using the same algorithm as for newly diagnosed LGS. Older patients with established LGS should be reviewed at least annually by a suitably experienced neurologist. The revised guidance aims to improve seizure control and quality of life for patients with LGS through personalized, evidence-based treatment strategies while addressing the challenges of accurate diagnosis and management in a rapidly evolving therapeutic landscape. PLAIN LANGUAGE SUMMARY: Lennox-Gastaut syndrome (LGS) is a severe type of epilepsy that usually starts in childhood but continues into adulthood. It is characterized by a variety of different types of seizures (abnormal electrical activity in the brain), which are difficult to treat and often cause people with the condition to fall and injure themselves. Most people with LGS have learning difficulties and need a lot of support, often in residential care. The authors are experts in treating people with LGS and this article provides up-to-date guidance and advice on how best to care for those with the condition.

Epidemiology, Clinical, Radiological and Biological Characteristics, and Outcomes of Mucormycosis: A Retrospective Study at a French University Hospital.

Mucormycosis is a rare but emerging and life-threatening infection caused by environmental mold, with a mortality rate of 30-70% despite progress in management. A better understanding could improve its management. We conducted a single-center retrospective study of all cases of mucormycosis observed over a decade at the University Hospital of Caen. Between 2014 and 2024, 18 cases of mucormycosis were identified, predominantly in males (n = 11, 65%). Most patients had hematological malignancies (n = 16, 89%). Seven cases were proven, and eleven were classified as probable. The main locations of infection were pulmonary (n = 12, 67%). Since 2021, we have observed an increase in the number of cases, rising from three between 2014 and 2021 to fifteen between 2021 and 2024. Among the 12 patients with pulmonary mucormycosis, all presented with fever except 1, and 67% required oxygen therapy. Chest computed tomography scans revealed an inverse halo sign in one-third of the patients. The first-line treatment consisted of amphotericin B in seventeen patients, posaconazole in one patient, and isavuconazole in one patient. Surgery was performed on seven patients. In cases of cutaneous mucormycosis, all patients underwent surgery, and none died within three months after the diagnosis. Overall, the three-month mortality rate was 39%. Surgical management was associated with a reduction in mortality (0% vs. 64%, p = 0.013). This study highlights the role of PCR for early diagnosis and the key role of surgery in improving clinical outcomes while underscoring the need for better-adapted therapeutic protocols for these rare infections.

Disruption of Epithelial Barrier Integrity via Altered GILZ/c-Rel/RACK1 Signaling in Inflammatory Bowel Disease.

Given the role of Receptor for Activated C Kinase 1 (RACK1) in both immune cell activation and in the maintenance of the intestinal epithelial barrier integrity, we investigated whether it was involved in inflammatory bowel disease (IBD). RACK1 expression was analyzed in intestinal mucosal samples of healthy and IBD patients, in mice with chemically induced colitis, and in diseased in vitro 2D and 3D coculture models by luciferase assay, reverse transcription-quantitative PCR, Western blotting, immunofluorescence, and immunohistochemistry. Based on our finding that glucocorticoid-induced leucine zipper (GILZ or tsc22d3) positively correlates with RACK1 expression in IBD patients, GILZ knockout mice and cell silencing experiments were performed. RACK1 was significantly decreased in IBD, especially in ulcerative colitis. This was associated with an NF-κB/c-Rel-related mechanism, correlating with decreased GILZ protein expression. GILZ depletion confirmed a decrease in RACK1 expression, which favored SRC activation and led to a significant reduction in E-cadherin, resulting in impaired epithelial barrier integrity. Finally, our data highlighted that this novel mechanism could be considered to develop new therapies since dexamethasone, the first line of treatment in IBD, restored RACK1 expression through the glucocorticoid receptor in a c-Rel/GILZ-independent manner. We provide the first evidence that an alteration of RACK1/SRC/E-cadherin regulatory mechanism, correlating with decreased GILZ protein expression, is involved in epithelial barrier disruption. The clinical relevance is based on the fact that this mechanism involving GILZ/c-Rel-related RACK1 expression could be considered to improve IBD therapies, particularly in patients with low or no response to glucocorticoid treatment.

The Effectiveness of Afatinib as First-Line Treatment in Vietnamese Patients With EGFR-Mutant Non-Small Cell Lung Cancer and Brain Metastases.

The role of afatinib in the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients has been proven through clinical trials and real-world studies. However, additional data on the effectiveness of afatinib in patients with brain metastases are lacking. EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed across nine cancer centers in Vietnam from April 1, 2018 to June 1, 2022. The primary endpoints included central nervous system progression-free survival (CNS-PFS) and overall survival (OS). The secondary endpoints were the objective response rate (ORR) and CNS-ORR. Among 87 enrolled patients, 21.8%, 17.2%, and 60.9% received whole-brain radiation, gamma knife, and no locoregional therapy, respectively. With a median follow-up of 32.2 months for CNS-PFS and 35.3 months for OS, the median CNS-PFS and OS were 17.9 and 29.9 months, respectively. In multivariate analysis, patients receiving whole-brain radiation had significantly shorter CNS-PFS than those untreated with local therapy (16.1 vs. 22.6 months, p = 0.019), but not translating to an inferior OS. Furthermore, both the CNS-PFS and OS of patients with uncommon mutations were significantly worse than those of patients with Del19 (11.3 vs. 24.2 months, p = 0.013 and 17.7 vs. 34.0 months, p = 0.003, respectively). Univariate and multivariate analyses showed that a lower afatinib starting dose did not significantly affect CNS-PFS or OS. The CNS-ORR and ORR were 77.4% and 71.3%, respectively. In our real-world study, afatinib showed encouraging effectiveness in Vietnamese patients with EGFR-mutant NSCLC and brain metastases at baseline.

Carbon monoxide poisoning: a clinical case report

BackgroundCarbon monoxide (CO) poisoning is a serious yet frequently overlooked condition with diverse and nonspecific clinical presentations. The analysis of Lithuanian statistics reveals fluctuations in patient admissions and consultations through the poisoning center over a four-year period, with notable variations in fatality rates. Despite these trends, CO poisoning remains a significant public health concern due to its potential for severe long-term sequelae or death.CaseThis case report focuses on two distinct presentations of CO poisoning in a young couple, illustrating the varied manifestations and outcomes of this toxic exposure. The first case describes a 23-year-old male presenting with altered consciousness and neurological symptoms, while the second case involves a 21-year-old pregnant female presenting with cardiovascular symptoms, including Takotsubo cardiomyopathy.DiscussionHighlights include the challenges in diagnosing CO poisoning; factors influencing the severity and symptoms of CO poisoning; potential complications; and considerations for hyperbaric oxygen therapy (HBO) in severe cases and pregnancy.ConclusionThese cases illustrate the importance of recognizing CO poisoning, advocating for oxygen therapy as the first-line treatment, and calling for further research to improve understanding, treatment, and prevention of this potentially fatal condition.

Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: a systematic review and meta-analysis.

Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with substantial differences in morphology, genetic profiles, clinical behavior, and prognosis. Optimal treatment for nccRCC remains unclear, largely extrapolated from evidence available for clear cell renal cell carcinoma (ccRCC). This study aimed to compare the efficacy of current mainstream drug treatments for nccRCC to provide clinical treatment guidance for advanced cases. We systematically searched PubMed, Embase, and Cochrane databases for trials published up to January 2, 2024, including controlled and single-arm trials. Primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We selected six randomized controlled trials (RCTs) comparing mammalian target of rapamycin inhibitors (mTORi) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These trials included four first-line and two second-line studies, with a total of 398 advanced nccRCC patients. Pooled results showed that VEGFR-TKIs significantly improved PFS compared to mTORi in first-line treatment (relative risk [RR] = 1.387; 95% confidence interval [CI]: 1.04-1.85; p = 0.026). In a single-arm meta-analysis, we included 22 VEGFR-TKI trials, three mTORi trials, 12 immune checkpoint inhibitor (ICI) therapies, five chemotherapy trials, and 10 combination therapy trials. The pooled ORR ranged from 6% (95% CI: 0-16%) to 36% (95% CI: 27-44%), and the pooled DCR ranged from 54% (95% CI: 50-58%) to 81% (95% CI: 70-91%). Subgroup analysis of ICI showed a higher ORR in the PD-L1 positive group compared to the PD-L1 negative group (RR = 3.044; 95% CI: 1.623-5.709; p = 0.001). This systematic review and meta-analysis demonstrate that VEGFR-TKIs improve PFS in first-line treatment compared to mTORi. The single-arm meta-analysis suggest that combination therapies with different mechanisms result in better ORR and DCR. Furthermore, PD-L1 positive patients showed significantly better therapeutic responses with ICI treatment than PD-L1 negative patients.

Managing menopause in women with diabetes

The impact of the current diabetes pandemic on the menopause experiences and health outcomes of women with diabetes is under-researched and poorly understood. Type 2 diabetes mellitus (T2DM) often emerges during midlife and, in women, frequently presents synchronously with menopause, which independently increases the cardiometabolic risk. Recent interest in menopause has highlighted the lack of clinical evidence upon which to base menopause management recommendations for women with diabetes. Most evidence relating to safety and efficacy of menopause hormone therapy (MHT), the first-line treatment for menopause symptoms, is based mainly on Caucasian, socially advantaged women with low rates of co-morbidity. The dearth of data relating to MHT in women with diabetes means that much evidence for women with diabetes relies on extrapolation. A nuanced and judicious approach to the management of menopause in women with diabetes and associated co-morbidities is, therefore, crucial. This review focuses on the postmenopausal health risks in women with diabetes and the impact of different types of MHT. It highlights areas of uncertainties and unmet need in menopause care for this cohort of women.

Corticosteroids plus metformin versus corticosteroids as front-line treatment for patients with newly diagnosed ITP and pre-existing type 2 diabetes mellitus: A multicentre propensity score-matched study.

Corticosteroids are the standard first-line treatment for primary immune thrombocytopenia (ITP), with a high initial response but unsatisfactory sustained response (SR). Additionally, corticosteroids usually lead to hyperglycaemia especially in patients with pre-existing type 2 diabetes mellitus (T2DM). Besides reducing the blood glucose levels, metformin was found to have immunomodulatory effects. We hereby conducted a multicentre propensity score matching analysis of corticosteroids plus metformin versus corticosteroids for newly diagnosed ITP patients with pre-existing T2DM. After matching at a ratio of 1:1, there were 57 patients in each group. Baseline characteristics, comorbidities and other medications including concurrent hypoglycaemic medications were balanced between the two groups. No statistical difference was observed in the initial response rate at day 14. It was notable that patients in the metformin group had a significantly higher SR rate and longer duration of response compared to the non-metformin group. Metformin inclusion was associated with a higher incidence of stomach upset, which were generally tolerable. Our study provided evidence that the addition of metformin to corticosteroids might be a promising front-line treatment for newly diagnosed ITP patients with pre-existing T2DM.

Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study

BackgroundRecent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.MethodsIn this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.ResultsThis study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1–4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high “ABC transporters” signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.ConclusionsAdding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1–4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.

First-Line Treatment of Massive Pulmonary Embolism: Counterpoint-Tried-and-True Catheter-Directed Thrombolysis Is a More-Established Therapy for Massive Pulmonary Embolism.

First-Line Treatment of Massive Pulmonary Embolism: Counterpoint-Tried-and-True Catheter-Directed Thrombolysis Is a More-Established Therapy for Massive Pulmonary Embolism.