Clinical utility of pleural effusion supernatant cell-free DNA genotyping in previously treated patients with advanced non-small-cell lung cancer and disease progression: a multicenter retrospective study.

Metformin-sulfonylurea combination is a widely prescribed as second-line therapy for type 2 diabetes mellitus (T2DM), yet patient responses vary due to individual genetic variation. These variations, particularly in AMP-activated protein kinase (AMPK) and its upstream regulator liver kinase B1 (LKB1), may contribute to differences in treatment response. This study investigated the association of PRKAA2(rs2746338) and LKB1(rs741765) polymorphisms with metformin-sulfonylurea response in T2DM patients. We enrolled 193 T2DM patients on metformin-sulfonylurea therapy after obtaining written consent. Glycemic and lipid parameters were assessed at baseline and after 3 months. Genotyping was performed by PCR-RFLP and ARMS-PCR for PRKAA2(rs2746338) and LKB1(rs741765), respectively. Statistical analysis was conducted using SPSS v27. Genotype and allele distributions were not significantly different between responders and non-responders. Carriers of PRKAA2(rs2746338) AA and AG and LKB1(rs741765) CT genotypes showed greater FBG reduction (p = 0.028, p < 0.001, and p < 0.001 respectively). Additionally, PRKAA2(rs2746338) AG and LKB1(rs741765) CT genotypes showed significant improvements in PPG, HbA1c, triglycerides, and LDL (all p < 0.05). We conclude that PRKAA2(rs2746338) and LKB1(rs741765) variants were linked to favorable glycemic and lipid changes, suggesting reduced cardiovascular risk in T2DM. These variants may serve as pharmacogenetic markers for personalized therapy, warranting validation in larger studies.

Children with unresectable cervicomedullary tumors (CMTs) demonstrate poor progression-free survival when treated with conventional chemotherapy and radiotherapy. The BRAFV600E mutation, commonly identified in low-grade gliomas, represents a therapeutic target for mutation-specific kinase inhibitors. This study aims to emphasize the potential role of BRAF inhibitors as upfront targeted therapy in selected tumors where surgical resection is not feasible. A retrospective analysis was conducted on four pediatric patients with unresectable cervicomedullary low-grade gliomas harboring the BRAFV600E mutation. All patients were treated with the BRAF inhibitor dabrafenib, either as first-line or second-line therapy. Dabrafenib was administered as first-line therapy in two patients and as second-line therapy in two others. All patients experienced rapid tumor regression with significant and durable clinical and radiologic responses. Three patients tolerated long-term therapy (up to 9years) without significant toxicity. One patient discontinued treatment after 1year due to a serious adverse event, which resolved upon withdrawal of therapy. Dabrafenib demonstrated clinical and radiographic efficacy and was generally well tolerated in pediatric patients with unresectable BRAFV600E-mutant CMTs. These findings suggest that upfront BRAF inhibition may serve as a viable therapeutic alternative to conventional chemotherapy, radiotherapy, or attempted resection in selected cases. Further prospective studies are warranted to define the optimal timing, duration, and long-term safety of targeted therapy in this population.

Most patients with advanced BRAF or NRAS-driven melanoma receive front-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients have effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that, in partnership with cyclophilin-A (CYPA), inhibit RAS[GTP] signaling. Both compounds demonstrate potent anti-proliferative activity against NRAS-mutated melanoma cell lines and robust anti-tumor activity against preclinical melanoma models. However, in preclinical models, resistance to RMC-7977 monotherapy arose through mutations in Ppia (encoding CYPA) or Map2k1 (encoding MEK1). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.

Mandibular advancement devices (MADs) represent an established second-line therapy for obstructive sleep apnea (OSA), but therapeutic responses vary considerably. The primary aim of this retrospective pilot cohort study was to evaluate craniofacial characteristics, particularly the ANB angle, as potential diagnostic predictors of treatment response. Anamnestic, clinical, and poly(somno)graphic data were collected from OSA patients before MAD insertion (t0) and after final titration with poly(somno)graphic confirmation (t1). Cephalometric measurements, including hyoid bone position, were analyzed. Patients were stratified based on the ANB angle (ANB ≤ 4°: group1; ANB > 4°: group2). Statistical analysis included independent t‑tests, Pearson correlations, receiver operating characteristic (ROC) curve analysis, and multiple regression models to identify predictors of treatment response. Atotal of 38patients (mean age 57.6 ± 11.7 years; 52% male) were included. Group2 showed significantly greater reductions in Apnea-Hypopnea Index (AHI) at t1 (-84.6% vs. -39.8%, p < 0.001). ROC analysis identified an optimal ANB cut-off of 4.7° (AUC = 0.791), with 75% sensitivity and 81.2% specificity. In addition to ANB, higher Wits values and asmaller Björk polygon sum (hypodivergent pattern) independently predicted greater AHI reduction. Reductions in AHI were significantly correlated with improvements in Epworth Sleepiness Scale (ESS) scores. Cephalometric parameters predict afavorable response to MAD therapy for OSA. Integrating cephalometric analysis into the diagnostic workflow may improve patient selection and prognosis.

Breast cancer remains a malignancy with high global mortality rates. Approximately 15-20% of these cases are Human Epidermal Growth Factor Receptor 2 (HER2) positive subtype, characterized by aggressiveness, high risk of metastasis, and poor prognosis if left untreated. This literature review aims to discuss the pathophysiology, diagnostic methods, and recent advancements in the management of HER2-positive breast cancer. The study utilized a literature review method, sourcing data from PubMed, Google Scholar, and ScienceDirect databases. A total of 23 literatures published within the last 5-10 years were selected based on inclusion criteria. Overexpression of HER2 protein triggers the activation of MAPK and PI3K/AKT/mTOR signaling pathways, stimulating uncontrolled cell proliferation. Diagnosis is established via Immunohistochemistry (IHC) and confirmed by In Situ Hybridization (ISH) following ASCO/CAP 2018 guidelines. Current management shows a significant shift; neoadjuvant and first-line advanced stage therapies prioritize dual blockade (Trastuzumab and Pertuzumab). Furthermore, the new generation Antibody-Drug Conjugate (ADC), Trastuzumab Deruxtecan (T-DXd), has demonstrated superior efficacy compared to T-DM1 as a second-line therapy. Comprehensive understanding of HER2 molecular biology and advances in targeted therapy have transformed the clinical landscape, increasing survival rates and significantly improving the prognosis of HER2-positive breast cancer patients.

Bortezomib for the treatment of anti-N-methyl-d-aspartate receptor encephalitis in a patient with psoriatic arthritis receiving adalimumab: A case report and literature review.

BackgroundGastric cancer is one of the most common malignant tumors worldwide, ranking fifth in incidence and fourth in mortality. While immune checkpoint inhibitor (ICI) combined chemotherapy has become the standard first-line treatment for advanced gastric cancer (AGC), most patients eventually experience disease progression. Currently, there is no unified consensus on second-line treatment strategies following failure of ICI combined chemotherapy. Immunotherapy rechallenge has shown potential efficacy in non-small cell lung cancer and melanoma, but its efficacy in AGC remains unclear. This retrospective study analyzed the effectiveness and safety of immunotherapy rechallenge versus chemotherapy in second-line treatment for AGC patients.MethodsWe retrospectively analyzed 83 AGC patients who progressed after first-line treatment with ICI combined chemotherapy at Qingdao University Affiliated Yantai Yuhuangding Hospital between December 2021 and March 2025. Among them, 49 patients received immunotherapy rechallenge and 34 patients received chemotherapy as second-line therapy. Efficacy was assessed according to the RECIST v1.1 criteria, including Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), Overall Survival (OS), and treatment-related adverse events (TRAEs) of grade 3 or higher.ResultsImmunotherapy rechallenge demonstrated superior outcomes compared with chemotherapy, with higher ORR (30.6% vs. 6.0%) and DCR (83.7% vs. 38.3%). Median PFS and median OS were 4.57 vs. 2.20 months and 12.4 vs. 5.33 months, respectively. Cox regression analysis showed that second-line treatment modality, PD-L1 expression, and pathological type were independent prognostic factors for OS, whereas PFS was only influenced by treatment modality. In subgroup analysis, patients with CPS ≥1 derived significant benefit from immunotherapy rechallenge in both mPFS (4.83 vs. 2.20 months) and mOS (12.6 vs. 7.13 months, P<0.01), whereas no significant difference were observed in CPS<1 patients. Grade ≥3 TRAEs occurred in 26.5% of patients in the immunotherapy rechallenge group versus 35.3% in the chemotherapy group (p=0.049).ConclusionFor AGC patients who progressed after first-line ICI combined chemotherapy, immunotherapy rechallenge confers significant survival benefits compared to chemotherapy. Immunotherapy rechallenge is more effective in patients with high PD-L1 expression, suggesting its potential clinical application value as second-line treatment regimen.

Immune thrombocytopenia (ITP) often presents for the first time in pregnancy, or, in patients with a history of ITP, pregnancy can trigger a relapse. ITP in pregnancy is often mild, leading to minimal or no symptoms; however, treatment may be needed if thrombocytopenia becomes severe, if bleeding occurs, or in anticipation of delivery and neuraxial analgesia. To facilitate the diagnosis of ITP in pregnancy, we present a systematic approach that allows clinicians to first consider urgent pregnancy-related thrombocytopenic conditions such as hypertensive disorders of pregnancy or thrombotic thrombocytopenic purpura; exclude other causes of thrombocytopenia; and determine the need for treatment. We review options for first-line therapies for ITP in pregnancy, including corticosteroids (prednisone or methylprednisolone) and intravenous immune globulin, which has a favorable safety profile in pregnancy, and second-line therapy options that have been used in pregnancy including thrombopoietin receptor agonists, rituximab, and certain immunosuppressant medications such as azathioprine. We summarize the recommendations for platelet targets for delivery, recognizing that the evidence is limited, including a platelet count of 50 × 109/L or higher for caesarean delivery and 70 × 109/L or higher for neuraxial anesthesia. Treatment decisions for ITP in pregnancy should be informed by patients' values and preferences along with a multidisciplinary team that includes hematologists, obstetricians, and anesthesiologists.

Currently, chemotherapy remains the primary treatment modality for advanced intrahepatic cholangiocarcinoma (iCCA). However, the efficacy of existing regimens in patients requiring later-line therapy is limited, with low objective response rates and considerable adverse effects. Therefore, the development of effective and safe novel therapeutic strategies is of critical importance. We report a case of unresectable metastatic iCCA in which first-line therapy with a PD-1 inhibitor combined with a tyrosine kinase inhibitor (TKI) failed. The patient subsequently received second-line treatment with lenvatinib in combination with trifluridine/tipiracil (TAS-102), which resulted in significant tumor shrinkage and a partial response (PR) upon evaluation, without the occurrence of grade 3 or higher adverse events. The progression-free survival (PFS) was 13.33 months. This case suggests that lenvatinib combined with TAS-102 may demonstrate favorable antitumor activity and may represent a promising therapeutic option for advanced iCCA in the later-line setting.

Emulating the target trial framework in pharmacoepidemiology is challenging when there is no active comparator. We evaluate six approaches to finding surrogate index dates for untreated patients with the goal of identifying one or more solutions that indicate they would give potentially unbiased results. This numerical experiment used 73,070 patients from the MarketScan administrative databases (2013-2019) with type II diabetes, first-line therapy with metformin, and second-line therapy with either sodium-glucose cotransporter 2 inhibitors (SGLT2i's) or sulfonylureas. Patients taking sulfonylureas were converted into an experimental "untreated" arm. Part 1 sought to find surrogate index dates for the untreated arm. Part 2 compared the experimental estimates of the effect of SGLT2i's on cardiovascular disease (CVD) compared to sulfonylureas, using the surrogate index dates, to the reference estimate. The reference hazard ratio (HR) was 0.69. The HRs after the respective approaches for selecting surrogate index dates are as follows: rejection sampling 0.61, 0.63; median 1.10, 1.15; prediction model 0.96; matching algorithm 1.07. Only the rejection sampling approaches for selecting a surrogate index date provided results which indicate low amounts of potential bias. Extreme care should be taken when making study design decisions for observational research questions that lack an active comparator group.

Cervical cancer is the fourth most prevalent oncological condition affecting the global female population in 2022, considering both disease occurrence and fatality rates. Although surgical intervention is the curative approach for early stage cervical cancer, recurrent progression is associated with unfavorable clinical outcomes. The current therapeutic protocols outlined in the National Comprehensive Cancer Network Guidelines 4.2025 edition propose that for second-line or subsequent therapies of cervical carcinoma, prioritized protocols incorporate pembrolizumab administration specifically for patients demonstrating high tumor mutational burden characteristics, positive for programmed cell death ligand 1 expression, or exhibiting microsatellite instability-high/mismatch repair deficiency molecular profiles. Other proposed therapeutic approaches include bevacizumab, paclitaxel, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). To date, no standardized systemic combination protocol has been established for the management of recurrent/metastatic cervical carcinoma after first-line treatment. The clinical application of camrelizumab combined with nab-paclitaxel as a second-line intervention for recurrent human papillomavirus (HPV)-associated cervical cancer remains rare in existing medical literature. This case report documents complete remission achieved through second-line camrelizumab combined with nab-paclitaxel therapy in a 65-year-old Chinese female with recurrent HPV-associated cervical cancer with positive programmed cell death ligand 1 (PD-L1) in whom initial treatment failed. Clinical outcomes included the disease-free survival of 22 months, accompanied by the first progression-free survival (PFS1) of 10 months and the PFS2 of 58 months. The overall survival was recorded at 92 months. The patient continues to undergo active clinical surveillance. Our case report illustrates that second-line immunochemotherapy utilizing camrelizumab in combination with nab-paclitaxel exhibits notable efficacy and manageable safety profile.

This study aimed to describe first-line venetoclax in the Medicare population and its impacts on treatment patterns, utilization, and costs. This retrospective cohort study used Medicare Fee-For-Service data from 1 September 2016, to 31 December 2022. Patients were continuously-enrolled, had incident acute myeloid leukemia (AML) and no confounding diagnoses, and were treated with first-line venetoclax-based regimens. Initiation of second line of therapy was modeled using cumulative incidence functions. Among 2,765 included patients, median age was 76 years. Median venetoclax dosage was 140.4 mg/day - lower than the 400-600 mg/day recommended by clinical guidelines. Patients were less likely to initiate second-line therapy if they were older or had more comorbidities.Patients had a per-month median of 5.3 outpatient visits, 0.3 emergency department visits, and 0.2hospitalizations; length of stay was 10 days. Mean monthly healthcare costs were $18,092 (SD=$14,289) per patient, with $12,042 (SD=$12,147) and $6,050 (SD=$7,841) attributable to medical services and drug costs, respectively. A growing number of patients enrolled in Medicare Fee-For-Service with AML use first-line venetoclax. Older patients and those with comorbidities are less likely to initiate second-line therapy. Costs were lower and length of stay was shorter than described in previous research.

Treatment sequences of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a nationwide population-based study in France.

452eP Phase II study of adebrelimab combined with apatinib and nab-paclitaxel as second-line therapy in patients with advanced gastric cancer previously treated with immunotherapy

This prospective, observational study evaluated the real-world safety of osimertinib in a broad Chinese population with non-small cell lung cancer (NSCLC). Chinese NSCLC patients who received osimertinib were enrolled and followed up for 12 months. The primary endpoint was the incidence of adverse drug reactions (ADRs). From 20 April 2020 to 1 August 2022, 1,700 patients were enrolled from 30 centers, with 706 (41.5%) patients ≥65 years old. Osimertinib was administered as first-line, second-line, third/later-line and adjuvant therapy in 44.9%, 34.2%, 14.3% and 4.5% of the patients, respectively. ADRs, adverse events (AEs), Grade ≥3 AEs, and serious AEs were reported in 627 (36.9%), 959 (56.4%), 165 (9.7%), and 102 (6.0%) patients, respectively. AEs of special interests occurred in 59 (3.5%) patients, with 41 (2.4%) and 19 (1.1%) reporting QTc prolongation and interstitial lung disease/pneumonitis-like events, respectively. The safety profiles in patients ≥65 years old and those usually not included in randomized clinical trials were similar to that in the total population. This largest real-world safety study of osimertinib in China demonstrated that osimertinib was well-tolerated in a broad NSCLC population, including patients usually not included in randomized clinical trials, without new safety signals identified. NCT03485326 (www.clinicaltrials.gov).

Background: Objective: To compare the efficacy of intravenous levetiracetam (LEV) versus phenytoin (PHT) as second-line therapy for status epilepticus (SE) in children aged 1 month to 12 years in a tertiary care hospital in Pakistan. Study Design: This was a randomized controlled trial. Place and Duration: This study was conducted at Ruth km pfau Civil Hospital Karachi from May 2024 to May 2025. Materials and Methods: Children with SE (n=180) were split into two groups (n=90 each): Group A (LEV) and Group B (PHT). After benzodiazepine failure, participants who met eligibility criteria were assigned to either LEV (Group A: 30 mg/kg loading dose, 30 mg/kg/day maintenance) or PHT (Group B: 20 mg/kg loading dose, 5 mg/kg/day maintenance). The definition of efficacy was the cessation of seizure after 24 hours. Age, seizure type, and efficacy data were collected, and vital parameters were monitored at several time points. Statistical analyses were carried out in SPSS version 25, using chi-square tests (p&lt;0.05 as the criterion for significance). Results: Mean ages were 6.52 ± 2.68 years (Group A) and 6.59 ± 2.72 years (Group B), with most children aged 1-6 years (55.6% vs. 51.1%). Seizure types in Group A: 33.3% generalized tonic-clonic (GTC), 27.8% focal tonicclonic, 38.9% complex partial; Group B: 26.7% GTC, 18.9% focal tonicclonic, 54.4% complex partial. Overall efficacy was higher in Group A (91.1%, n=82/90) than Group B (71.1%, n=64/90; p=0.005). For focal tonicclonic seizures, efficacy was 86% (49/57) in Group A vs. 78% (42/54) in Group B (p=0.118). For GTC, it was 85% (22/26) in Group A vs. 67% (20/30) in Group B (p=0.295). Conclusion: Levetiracetam demonstrated superior efficacy over phenytoin for convulsive SE in children, though subtype differences were non-significant. Future multicenter studies should assess long-term outcomes. Keywords: Status Epilepticus, Levetiracetam, Phenytoin, Pediatric, Seizure Control.

In many pediatric malignant germ cell tumor (MGCT) protocols, patients who do not achieve a complete response (CR; normal tumor markers, no radiological/histological residual) after three cisplatin-etoposide-bleomycin (PEb) cycles receive two to three "consolidation" cycles of the same regimen. Evidence for this practice is limited, and historical outcomes for non‑CR patients remain poor. We retrospectively reviewed patients diagnosed with intermediate-risk MGCT, enrolled in AGCT0132, between 2003 and 2011. All patients received three cycles of PEb and underwent response assessment at the end of induction. Patients not in CR were prescribed three additional cycles of PEb as consolidation. We compared event-free survival (EFS) and overall survival (OS) for patients who did and did not receive consolidation. Among 210 patients enrolled, two patients were excluded from analyses: one without complete information, and one had rapid progressive disease (PD) and did not complete induction therapy. Out of 208 patients, 193 had a CR after three cycles of induction chemotherapy, and their post-induction 4-year EFS and OS were 93% and 99%. Fifteen patients were not in CR at the end of the first three cycles. Twelve received consolidated chemotherapy as mandated per protocol, and their 4-year EFS and OS were 61% and 65%, respectively. Three patients were deemed to have progressive disease at the end of induction and received second-line therapy. Children with MGCTs who did not achieve CR after the first three cycles of chemotherapy had an inferior outcome compared to those with a CR, despite receiving additional cycles of PEb chemotherapy. We conclude that consolidation is of unclear benefit. We suggest that pediatric MGCT patients who fail to achieve a CR after standard induction chemotherapy may receive a salvage regimen with different agents rather than consolidation with more of the same chemotherapy.

Plasma metabolic profiling identifies elevated hippurate as a potential biomarker of methotrexate non-response in juvenile idiopathic arthritis.

An anti-PD-1 antibody (SCT-I10A) plus anti-EGFR antibody (SCT200) and chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer: A phase Ib study.