BACKGROUND: Pulmonary neuroendocrine neoplasms (NENs) comprise a biological spectrum ranging from well-differentiated carcinoid tumors to poorly differentiated neuroendocrine carcinomas. In 2026, the International Association for the Study of Lung Cancer (IASLC) proposed an updated classification introducing pulmonary carcinoid/NET G3 as a distinct category of well-differentiated tumors with increased proliferative activity, incorporating Ki-67 into the diagnostic framework and aligning pulmonary NENs with other organ systems. However, the clinicopathological characteristics and prognostic significance of this newly proposed entity remain incompletely defined. METHODS: We conducted a retrospective single-center study of pulmonary neuroendocrine neoplasms diagnosed between 2007 and 2024. Clinical, histopathological, immunohistochemical, and survival data were collected. Tumors with well-differentiated morphology and increased proliferative activity were identified using predefined study criteria (mitotic count > 10/2 mm and/or Ki-67 > 20 %). Following publication of the 2026 IASLC proposal, these tumors are referred to as carcinoid/NET G3 throughout the revised manuscript. RB1 and p53 immunohistochemistry was performed, and survival was analyzed using Kaplan-Meier estimates and Cox regression. RESULTS: Among 155 pulmonary neuroendocrine neoplasms, eight (5.2 %) fulfilled criteria for carcinoid/NET G3. These tumors exhibited well-differentiated morphology despite elevated proliferative activity, retained RB1 expression, and a wild-type p53 immunophenotype, distinguishing them from LCNEC. Clinically, carcinoid/NET G3 showed an intermediate prognosis between conventional carcinoids and LCNEC. Mitotic count and Ki-67 demonstrated only moderate correlation, and Ki-67 identified additional biologically relevant tumors with relatively low mitotic activity. CONCLUSIONS: Our findings provide independent clinicopathological validation of the recently proposed IASLC carcinoid/NET G3 concept. Integration of morphology, Ki-67, RB1 and p53 may improve diagnostic classification and prognostic stratification of pulmonary neuroendocrine neoplasms while supporting implementation of the emerging pulmonary carcinoid/NET G1-G3 framework.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity worldwide. Although immunotherapy has shown promise in improving outcomes for some patients, the response is variable, largely due to the complex dynamics of the tumor microenvironment (TME). The protein PLOD2, which is often overexpressed in CRC tissues, has been implicated in promoting tumor growth and epithelial-mesenchymal transition (EMT), but its role in immune modulation and response to immunotherapy has not been well understood. In this study, we employed single-cell RNA sequencing to investigate PLOD2 expression and cell interactions. Functional assays in CRC cell lines with PLOD2 knockdown showed a reduction in proliferation, migration, and EMT markers, along with increased apoptosis. Mechanistically, PLOD2 was found to interact directly with c-Myc, stabilizing it by preventing proteasome-mediated degradation, which in turn led to upregulation of PD-L1 expression. Furthermore, silencing PLOD2 enhanced T cell activity, including increased secretion of GZMB and IFN-γ, and boosted T cell-mediated cytotoxicity. In mouse models, combining PLOD2 knockdown with anti-CTLA-4 therapy resulted in significant tumor growth suppression, increased infiltration of CD3/CD8 T cells, and higher proportions of GZMB/IFN-γ CD8 T cells. These findings suggest that PLOD2 contributes to CRC progression by modulating both tumor biology and immune responses through its interaction with c-Myc. Targeting PLOD2 could be a promising strategy to enhance the efficacy of anti-CTLA-4 immunotherapy and serve as a potential biomarker for CRC treatment.

Carboxyamidotriazole (CAI), an inhibitor of mitochondrial complex I, demonstrates anti-inflammatory and anti-tumor properties. While effective against colitis, its potential link to macrophage metabolism in colitis and colitis-associated colorectal cancer (CAC) remained unexplored. This study investigates the role of CAI and its association with macrophage metabolic states in these conditions. In the acute phase, CAI alleviates dextran sulfate sodium (DSS)-induced colitis, which is accompanied by suppressed IL-1β expression in pro-inflammatory macrophages. As a mitochondrial respiratory chain inhibitor, CAI treatment is associated with metabolic alterations characterized by accumulated α-ketoglutarate (α-KG) and decreased succinate and acetyl-CoA. This rewiring correlates with reduced hypoxia-inducible factor 1-alpha (HIF-1α) and decreased H3K27 acetylation (H3K27ac) at the Il1b locus. In the azoxymethane (AOM)/DSS model of CAC, we observed CD86+CD206+ mixed-phenotype macrophages during chronic inflammation. In CD206+ macrophages, CAI treatment is linked to the inhibition of oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation (FAO), concomitant with reactive oxygen species (ROS) reduction and impaired Stat6 phosphorylation. Concurrently, accumulated fatty acids are associated with increased PPARγ signaling. This coordinated modulation of Stat6 and PPARγ pathways correlates with sustained anti-inflammatory effects, as well as with reduced expression of pro-fibrotic and pro-angiogenic mediators. Our findings position CAI's effects in colitis and CAC alongside dynamic changes in macrophage metabolism. This work provides new insights into targeting metabolic pathways in inflammatory carcinogenesis.

Cervical squamous cell carcinoma (CESC) is frequently complicated by cisplatin (CDDP) resistance, which is a primary cause of treatment failure and poor prognosis. Here, we identified a CLCF1-ZIC5-CNTFR feedback loop that contributes to CDDP resistance in CESC. We found that ZIC5 was significantly upregulated in CDDP-resistant CESC and correlated with worse overall survival. Functionally, ZIC5 promoted CDDP resistance, in part by enhancing properties associated with cancer stem cells (CSCs) through the transcriptional activation of CNTFR. CLCF1, the ligand for CNTFR, was found to induce ZIC5 expression via STAT3 signaling, thereby forming a CLCF1-ZIC5-CNTFR positive feedback loop. Targeting CNTFR with a neutralizing antibody disrupted this regulatory circuit, leading to a reversal of CDDP resistance and suppression of CSC-associated phenotypes in vitro. Furthermore, combining an anti-CNTFR antibody with CDDP resulted in enhanced antitumor effects in patient-derived xenograft (PDX) and organoid (PDO) models. In summary, our findings suggest that the CLCF1-ZIC5-CNTFR positive feedback loop promotes CDDP resistance in CESC, potentially by sustaining CSC properties. Targeting this pathway, particularly CNTFR, may represent a potential therapeutic strategy for patients with CDDP-resistant CESC.

Hepatocellular carcinoma (HCC) develops within an immunologically complex tumor microenvironment that is heavily shaped by infiltrating myeloid cells. Immune-based treatment strategies such as atezolizumab plus bevacizumab have shown promising therapeutic benefits, but patients do not experience durable responses. This shortfall motivates current efforts to elucidate signaling programs that sustain pro-tumor myeloid states. Focal adhesion kinase (FAK, encoded by PTK2) integrates adhesion, growth factor, proliferative, and inflammatory signaling, but the contribution of FAK in myeloid cells to HCC has not been tested. In this study, we used human HCC transcriptomic analyses and a myeloid-specific FAK knockout mouse model to investigate the role of myeloid-intrinsic FAK in HCC progression. Analysis of the PRHCCdb single-cell database showed PTK2 expression was detectable in myeloid populations. Higher PTK2 expression in myeloid-rich TCGA-LIHC tumors was associated with a significantly worse overall survival. Further analysis of the NCI-CLARITY single-cell data set localized the strongest FAK-associated transcriptional programs to a monocyte-derived macrophage state marked by VCAN and COLEC12. Specifically, this population demonstrated hypoxia-associated and inflammatory signatures. To test the functional role of FAK in myeloid cells, we generated myeloid-specific FAK knockout (LysMCre;FAK) mice. Deletion of FAK did not alter baseline liver morphology, liver-to-body weight ratio, or proliferation. When challenged with the MET/β-catenin-driven HCC model via hydrodynamic tail vein injection, myeloid-specific FAK deletion did not significantly affect survival, gross tumor burden, or tumor proliferation. However, tumors from the LysMCre;FAK mice showed significantly reduced F4/80 macrophage accumulation compared with FAK controls. These findings indicate that myeloid-specific FAK promotes macrophage accumulation, but its loss alone is insufficient to alter tumor burden, proliferation, or survival in this oncogene-driven HCC model.

INTRODUCTION: A subset of prostate cancer progresses to aggressive state of metastatic castration-resistant prostate cancer (mCRPC), wherein multiple therapeutic options demonstrate limited success rates. In this observational study, we aimed to evaluate the efficacy, toxicity, and survival outcomes of (a) [Ac]Ac-PSMA-617, (b) rechallenge [Lu]Lu-PSMA-617, (c) cabazitaxel, and (d) oral metronomic cyclophosphamide treatments in postdocetaxel mCRPC patients with progressive disease following initial course of [Lu]Lu-PSMA-617 or without previous [Lu]Lu-PSMA-617 PRLT (PSMA-targeted radioligand therapy). METHODS: The study reviewed the medical records of mCRPC patients who had documented disease progression following treatment with androgen receptor pathway inhibitors and docetaxel. These patients had multiple therapeutic options and treated with [Ac]Ac-PSMA-617(alpha based-PRLT) or rechallenge [Lu]Lu-PSMA-617 or chemotherapy with cabazitaxel or metronomic cyclophosphamide. We stratified the latter group (chemotherapy) based on prior exposure to initial course of [Lu]Lu-PSMA-617 as received and not received. We evaluated and analyzed the response outcomes from these therapies under five headings: (a) symptomatic response, (b) biochemical response, (c) functional and anatomical imaging response, (d) survival outcomes, and (e) toxicity profiles. RESULTS: A total 66 mCRPC patients were included and analyzed in this study. These patients were divided into two cohorts. Cohort 1 (n = 49 patients) received initial course of [Lu]Lu-PSMA-617 and cohort 2 (n = 17 patients) not received initial course of [Lu]Lu-PSMA-617. The patients were divided into arm A to F based upon treatment received as follows: Cohort 1- arm A (n = 15 patients) received [Ac]Ac-PSMA-617, arm B (n = 18 patients) received rechallenge [Lu]Lu-PSMA-617, arm C (n = 8 patients) received cabazitaxel, arm D (n = 8 patients) received metronomic cyclophosphamide. Cohort 2- arm E (n = 14 patients) cabazitaxel and arm F (n = 3 patients) metronomic cyclophosphamide. Patients in arm A showed favorable response outcomes in terms of symptomatic response evaluation and quality-of-life performance, biochemical and imaging response evaluation, with a PSA decline of > 50% and disease control rate (DCR) of 60% patients and 80% respectively. Patients treated with rechallenge [Lu]Lu-PSMA-617 and chemotherapy also showed modest response rates. For toxicity profiles, arm A and arm B patients had mild and manageable toxicities, contrary to arm C, D, E, and F, wherein severe clinical and hematological toxicities were observed in a significant fraction of patients. Median progressive free survival (PFS) for the overall cohort (cohort 1 and 2) was 5 months (95% CI: 4-7 months), with no significant difference across treatment arms (p = 0.28). Median overall survival (OS) for entire cohort was 12 months (95% CI: 9-15 months) with significantly longer OS in arm A and E patients compared to other arms (p = 0.0358). CONCLUSION: Postdocetaxel mCRPC patients with progressive disease following initial course of [Lu]Lu-PSMA-617 when treated with [Ac]Ac-PSMA-617PRLT showed favorable and encouraging clinical, biochemical, and imaging response rates along with longer PFS and OS with minimal treatment-related toxicities. Rechallenge [Lu]Lu-PSMA-617 and chemotherapy-based approaches also provided clinical benefit in selected patients, reflecting the range of salvage treatment strategies employed in real-world practice. Future large-sized, prospective randomized trials are needed to establish the efficacy of all these treatments particularly alpha-based PRLT in clinical practice of mCRPC patients.

BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors (PARPi) have revolutionized cancer care across multiple solid tumor types for patients with BRCA-mutations and homologous recombination deficient malignancies. Sentinel trials for PARPi, however, have had limited participation from non-European populations, limiting interpretation of results, dosing strategies, and quality-of-life implications in these patients. Our objective was to review participation by race and ethnicity in sentinel PARPi trials across disease sites. METHODS: A literature search was conducted using PubMed/MEDLINE. Core search terms included "PARP inhibitor" and the disease sites of interest (breast, ovary, prostate, pancreas). A review of each sentinel trial was conducted utilizing data from ClinicalTrials.gov to obtain and/or confirm demographic information. RESULTS: Sentinel PARPi trials across all disease sites included populations that were predominantly White. TRITON2 (prostate) had the highest proportion of Black participants (5.8%), while Black participation in breast and ovarian cancer trials was almost always <3%. Missing data on race and ethnicity was common, and highest in TRITON2 and TRITON3 (∼20%, prostate) and ARIEL3 (13.3%, ovary). Aggregation into an "other" category was highest in EMBRACA (17.2%). Hispanic ethnicity was reported in only 5 of the 14 trials. CONCLUSION: There is overwhelming underrepresentation of racial and ethnic minorities in sentinel PARPi trials. Systemic issues in accepted clinical trial infrastructure, including reporting practices, site selection, protocol biases, and access challenges are all likely etiologies. Addressing the complexity of inclusion in global oncology research is still a crucial need to ensure cancer care equity.

OBJECTIVES: To compare the dosimetry and robustness of two Radixact Synchrony lung stereotactic body radiotherapy (SBRT) tracking strategies: tumour-based lung tracking with respiratory modelling (LwR) and fiducial-based tracking with respiratory modelling (FwR). METHODS: Ten stage I non-small-cell lung cancer patients were retrospectively analysed. SBRT plans (42 Gy in 4 fractions) were generated on maximum-exhalation computed tomography (CT) using planning target volumes (PTVs) created by 3-7 mm isotropic gross tumour volume (GTV) expansion. Each plan was mapped to all four-dimensional CT (4DCT) phases via isocentre shifts from phase-specific GTV (LwR) or individual fiducial displacement (FwR). Deformable dose accumulation yielded LwR, nearest FwR, and farthest FwR simulated plans. GTV/PTV V100%, representative organ-at-risk (OAR) doses, and robustness versus target localisation error, tumour-fiducial distance, and tumour volume were evaluated. RESULTS: With a 3-mm PTV margin, FwR showed larger losses in GTV coverage and PTV robustness than LwR (maximum decreases of 9.0% and 26.0%). FwR was less robust, particularly with unfavourable tumour-fiducial geometry. Larger PTV margins progressively mitigated FwR coverage degradation while maintaining acceptable OAR doses. CONCLUSION: For lung SBRT delivered with Radixact Synchrony, LwR was more robust than FwR in this cohort, for which all tumour-fiducial distances exceeded 20 mm. When FwR is required, particularly under suboptimal tumour-fiducial geometry, a 3-mm margin should be used cautiously, and patient-specific evaluation of 5-7 mm margins within OAR dose constraints may be necessary. ADVANCES IN KNOWLEDGE: A 4DCT-based simulation using imaging-derived tracking-error scenarios reveals dosimetric robustness differences between LwR and FwR tracking.

Chronic respiratory diseases - including asthma, chronic obstructive pulmonary disease (COPD), interstitial lung diseases, lung cancer, and post-COVID conditions - are associated with substantial morbidity and reduced quality of life. In addition to pharmacological therapy, chest physiotherapy and pulmonary rehabilitation play a crucial role in improving functional capacity and patient outcomes. This review aims to summarize contemporary approaches in pulmonary rehabilitation, with particular emphasis on the integration of digital technologies and telerehabilitation strategies. A narrative review of the literature was conducted focusing on the structure of pulmonary rehabilitation programs, training modalities, maintenance strategies, and the clinical applicability of telemedicine-based solutions. Pulmonary rehabilitation, particularly when combined with structured exercise programs, maintenance interventions, and telemonitoring systems, can significantly improve exercise tolerance, symptom control, and health-related quality of life. Modern digital technologies enable real-time monitoring of patient status, facilitate individualized rehabilitation strategies, and support early detection of disease exacerbations. Telemedicine platforms, smart inhalers, and wearable sensors represent promising tools for the management of chronic respiratory diseases. Data generated by these technologies may contribute to improved clinical decision-making and optimization of rehabilitation outcomes. The integration of pulmonary rehabilitation with digital health technologies may play a key role in the future management of chronic respiratory diseases and in maintaining long-term functional stability in affected patients. Orv Hetil. 2026; 167(30): 1199-1206.

Ulcerative colitis (UC) is associated with an increased risk of infectious complications, particularly during anti-tumor necrosis factor (anti-TNF) therapy. Pyogenic hepatic abscess is a rare but potentially life-threatening extraintestinal complication of UC. Optimal biologic management following deep infection during anti-TNF therapy remains unclear. Mirikizumab, a selective interleukin-23 p19 inhibitor, may have a more favorable infectious safety profile than anti-TNF agents. We report the case of a 19-year-old woman with pancolitis-type UC who developed persistent fever, worsening diarrhea, hematochezia, and subsequent right upper quadrant abdominal pain during maintenance therapy with adalimumab. Contrast-enhanced computed tomography revealed active colitis complicated by hepatic abscess. Adalimumab was discontinued, and intravenous ceftriaxone plus metronidazole therapy was initiated. After confirmation of infection control and abscess regression, induction therapy with mirikizumab was initiated for active UC. Clinical symptoms rapidly improved, and the patient achieved sustained clinical and endoscopic remission without recurrence of the hepatic abscess during long-term follow-up. This case suggests that mirikizumab can be successfully administered after adequate infection control in a patient with UC complicated by hepatic abscess during anti-TNF therapy. However, larger studies are needed to determine the optimal biologic option as a second-line treatment for patients requiring treatment reintroduction after deep infection.

Sinusoidal obstruction syndrome is a well-known hepatic vascular injury associated with oxaliplatin-based chemotherapy and can lead to non-cirrhotic portal hypertension. Although splenomegaly and thrombocytopenia are common clinical manifestations, clinically significant gastrointestinal varices may persist or newly develop after oxaliplatin cessation. The optimal therapeutic strategy for multiple gastrointestinal varices caused by oxaliplatin-induced sinusoidal obstruction syndrome remains unclear. Here, we report a case of a 71-year-old man who developed non-cirrhotic portal hypertension after oxaliplatin-based adjuvant chemotherapy for rectal cancer. Contrast-enhanced computed tomography and ultrasonography revealed splenomegaly, portal collateral vessels, gallbladder wall thickening, and decreased portal venous flow velocity without findings suggestive of liver cirrhosis or hepatic venous outflow obstruction. Esophagogastroduodenoscopy revealed esophageal, duodenal, and gastric varices. Considering that portal hypertension persisted > 3 years after oxaliplatin cessation, spontaneous regression was considered unlikely. A staged endoscopic treatment strategy was adopted to avoid abrupt changes in portal hemodynamics. Endoscopic injection sclerotherapy was first performed for esophageal varices, followed by n-butyl-2-cyanoacrylate injection for duodenal and gastric varices. High-risk bleeding varices were completely eradicated without adverse events. No variceal bleeding occurred during 6 months of follow-up. This case suggests the safety and effectiveness of risk-based prioritization and staged endoscopic treatment strategy for multiple gastrointestinal varices associated with oxaliplatin-induced sinusoidal obstruction syndrome.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is an extremely rare gastric cancer subtype with high rates of vascular and lymphatic invasion, lymph node and liver metastasis, leading to poor prognosis and early recurrence. We report a 73-year-old woman with stage IV GAED and portal vein tumor thrombus (PVTT) treated with multimodal therapy. She received S-1 plus oxaliplatin (SOX), SOX plus nivolumab, S-1 plus nivolumab, and radiotherapy for PVTT without major adverse events. Imaging showed marked tumor and lymph node shrinkage and complete PVTT disappearance. Laparoscopic distal gastrectomy with D2 dissection achieved R0 resection; pathology confirmed GAED, ypT2N1M0, Stage IIA, with Grade 1b response. This case suggests SOX plus nivolumab is effective for advanced GAED and that radiotherapy for PVTT enables curative surgery. Preoperative chemoradiotherapy and conversion surgery may provide a promising strategy for otherwise unresectable GAED.

BACKGROUND: Perineural invasion (PNI) is an established adverse prognostic factor in gastric cancer, but whether its prognostic effect varies with nodal burden and first metastatic site remains unclear. METHODS: We retrospectively analyzed 12,898 patients with stage I-III gastric cancer who underwent curative-intent R0 gastrectomy at Fudan University Shanghai Cancer Center between 2000 and 2022. Multivariable Cox models with a pre-specified PNI-by-positive-node interaction estimated associations with overall survival (OS) and progression-free survival (PFS). First distant metastatic site was evaluated using Fine-Gray and Firth logistic site-contrast models. The PNI-nodal-burden association was assessed in an independent pathology cohort and the ACRG cohort. RESULTS: Each additional positive lymph node attenuated the PNI-associated hazard ratio for OS (interaction HR, 0.976) and PFS (interaction HR, 0.977; both interaction P < 0.001). PNI was independently associated with poorer OS (HR, 1.38; 95% CI 1.20-1.59) and PFS (HR, 1.32; 95% CI 1.15-1.51) in N0-N1 disease, but the associations were attenuated in N2-N3 disease (OS: HR, 1.12; 95% CI 1.00-1.24; PFS: HR, 1.09; 95% CI 0.99-1.21). Among N0-N1 patients with pT3-pT4 disease and liver-only or peritoneal-only first metastasis, PNI was associated with peritoneal rather than hepatic dissemination (OR, 3.87; 95% CI 1.54-10.63). CONCLUSIONS: The prognostic association of PNI was modified by nodal burden and was most evident in N0-N1 gastric cancer. These site-specific findings support prospective evaluation of PNI-informed, peritoneum-directed surveillance.

PURPOSE: To describe the humanistic and economic burden among informal caregivers of individuals with transfusion-dependent β-thalassemia (TDT) across the US and Europe. METHODS: A mixed-methods study was conducted with qualitative interviews in the US and UK and an online survey in the US, UK, France, Italy, and the Netherlands. The survey included CarerQoL-7D, ZBI-12, and WPAI: CG and captured time spent providing informal care and out-of-pocket (OOP) expenses. Interviews were analyzed using the Framework Method, and survey data with descriptive analyses. Monetary values were standardized to US dollars (2025 USD). RESULTS: Interviews with 10 caregivers revealed five key themes: (1) Need for a strong support network; (2) Burden of disease management and constant care; (3) Barriers and facilitators to optimal care; (4) Impact on caregivers' daily life, work, and aspirations; and (5) Emotional distress and impacts on well-being. Seventy caregivers completed the survey. The CarerQoL-7D indicated adverse impacts on quality of life (QoL), with > 60% reporting mental health, daily activity, and physical health problems. On average, US and European caregivers spent 34.7 and 40.5 h per week performing caregiving activities, respectively. WPAI: CG results indicated overall work impairment of 33 and 43% among US and European caregivers, respectively. Average annual OOP expenses were $6000 in the US and $3348 in Europe. CONCLUSION: Caregivers of people with TDT experience negative impacts on QoL and work productivity. There is a need for healthcare policies to address caregiver's distinct challenges. Improving access to emerging therapies may ease caregiver and patient burden.

PURPOSE: To explore whether adjuvant immunotherapy can improve postoperative prognosis for non-small cell lung cancer (NSCLC) patients harboring oncogenic driver alterations beyond EGFR and ALK, a population with unclear benefit. METHODS: Main inclusion criteria included resected NSCLC, stage IB-IIIB, and oncogenic driver alterations of KRAS mutation, ROS1 fusion, RET fusion, HER2 mutation, NTRK fusion, BRAF V600E mutation, and MET exon 14 skipping mutation. The positive PD-L1 cut-off was 1%. Adjuvant immunotherapy would be administered for one year or up to 16 cycles. Disease-free survival (DFS) after surgery was the endpoint. RESULTS: 190 patients with specific gene alterations were included, 25.8% of patients received adjuvant immunotherapy. The benefit from adjuvant immunotherapy in DFS was not observed in the overall population (hazard ratio [HR] 0.85, 95% confidence interval [CI 0.51-1.44, p = 0.551), while a numerical DFS benefit trend in the PD-L1-positive population was observed (HR 0.56, 95% CI 0.31-1.03, p = 0.059). After inverse probability of treatment weighting (IPTW) for the population with PD-L1 positivity who also received adjuvant chemotherapy, no statistical DFS benefit difference from adjuvant immunotherapy was observed between the KRAS (HR 0.29, 95% CI 0.10-0.88, p = 0.028) and non-KRAS mutation (HR 0.77, 95% CI 0.32-1.82, p = 0.549) subgroups (interaction p = 0.179), though with a marked numerical difference. Among the PD-L1-positive population, NSCLC harboring KRAS, MET exon 14 skipping, and BRAF V600E mutations showed a trend toward benefit from adjuvant immunotherapy, whereas NSCLC with HER2 mutation, RET fusion, and ROS1 fusion exhibited a weaker trend toward benefit. CONCLUSIONS: Patients with NSCLC harboring driver oncogenes other than EGFR/ALK and positive PD-L1 showed a trend toward benefiting from adjuvant immunotherapy. Although no significant interaction was observed, KRAS-mutant NSCLC demonstrated numerically superior DFS benefit compared with non-KRAS-mutant NSCLC.

Cancer continues to be a leading cause of global mortality, highlighting the ongoing need for novel anticancer compounds that offer high efficacy with improved side effect profiles. In the present study, a series of 3H-1,2-dithiole-3-thione derivatives (DTT-S1-18) were synthesized as promising anticancer agents, and the structures of products were confirmed by spectral techniques. HS-releasing experiments showed that most of the compounds released higher amounts of HS slowly over time compared to standard ADT-OH. All compounds were tested for antiproliferative activity on HT-29, PC-3, MCF-7, and HUVEC cell lines. Compounds DTT-S6 (3-nitrophenyl derivative) and DTT-S8 (methionine derivative) have the lowest IC values of 41.6 and 38.9 µM on the MCF-7 cell line, respectively. Based on the wound healing and colony formation assays performed in MCF-7 cells, the wound areas were not significantly changed after treatment with compounds DTT-S6 and DTT-S8, whereas compound DTT-S8 at double IC dose inhibited colony formation by 81.82%. In addition, molecular docking, MD simulations, MM/GBSA binding free energy calculations, and binary QSAR analyses were performed to explore the potential target interactions and predicted activity profiles of the synthesized compounds toward inflammation-related proteins, including COX-1, COX-2, 5-LOX, and iNOS, thereby supporting the development of mechanistic hypotheses for future validation. Furthermore, structure-activity relationship (SAR) analyses were conducted to correlate the structural characteristics of the synthesized compounds with their HS releasing potential and biological profiles. Overall, this work integrates experimental anticancer evaluation with computational pathway and structure-based cancer/inflammation analyses to characterize novel DTT-based HS donors. The findings identify particularly compound DTT-S8, as a promising in vitro anticancer candidate, while the computational results suggest a putative involvement of inflammation-related targets, particularly the COX-2/5-LOX axis, which requires direct biochemical and cellular validation.

BACKGROUND: Hepatocellular carcinoma is one of the most common cancers worldwide and the third leading cause of cancer-related mortality. The therapeutic landscape of hepatocellular carcinoma, especially systemic therapies, is constantly changing and characterized by a multimodal approach. OBJECTIVE: The aim of this study was to investigate whether and how treatment sequencing according to tumor stage and liver function has changed over time and if the introduction of new therapeutic options has led to improved survival rates. METHODS: Therapy concepts were retrospectively recorded and evaluated in a cohort of 1288 patients with hepatocellular carcinoma with a first diagnosis between January 2013 and December 2022 who were divided into two cohorts with a cut-off for dividing in 2020 owing to the approval of atezolizumab and bevacizumab for the treatment of hepatocellular carcinoma by the European Medicines Agency (Cohort A initial diagnosis 2013-19, Cohort B initial diagnosis 2020-22). All patients were treated at Hannover Medical School, Germany. RESULTS: Baseline characteristics differed significantly between cohorts, with Cohort B presenting at earlier tumor stages and with better preserved liver function. Across all treatment modalities, liver function emerged as the primary determinant of prognosis, independent of tumor stage and performance status. Over time, a treatment shift from transarterial chemoembolization towards systemic therapies was observed. Median overall survival from initial diagnosis did not differ between cohorts. In unadjusted analyses, patients treated with immune checkpoint inhibitor-based regimens demonstrated longer median overall survival compared with those receiving tyrosine kinase inhibitors. However, after multivariable adjustment for baseline imbalances, no independent survival difference between treatment groups remained. CONCLUSIONS: This study provides a detailed longitudinal assessment of evolving treatment patterns and outcomes, highlighting a clear shift in therapeutic strategies over time with the increasing adoption of systemic therapies. Despite evolving treatment strategies and increased use of systemic therapies, liver function remained the dominant prognostic factor across treatment settings. Observed survival differences between treatment modalities were strongly influenced by baseline patient characteristics and treatment selection.

BACKGROUND AND OBJECTIVE: Personalizing anti-tumor necrosis factor (TNF) therapy in pediatric Crohn's disease (CD) remains challenging due to variable drug clearance and response. Identifying pharmacokinetic (PK) and pharmacodynamic (PD) predictors of deep remission could enable precision dosing strategies. The primary aim was to define PK metrics and PD biomarkers associated with deep remission. METHODS: Patients initiating infliximab or adalimumab were prospectively enrolled from four pediatric centers with longitudinal blood and stool biospecimens collected for one year. Deep remission was defined as a combination of weighted pediatric CD activity index (wPCDAI) < 12.5 and Simple Endoscopic Score-CD < 3. Trough concentrations (cTrough) were measured throughout the study. Drug exposure (area under the curve, AUC) and clearance were estimated using drug-specific population PK models and Bayesian estimation using nonlinear mixed-effects modeling (NONMEM). RESULTS: Deep remission was achieved in 34/70 (48.6%) with no difference in outcomes between biologics. Infliximab cTrough thresholds associated with deep remission were 33 µg/mL (Week 2), 15 µg/mL (Week 6), and 4.7 µg/mL (Month 3) with Week 6 cTrough targets ranging 15-26 µg/mL depending on the outcome of interest. Higher AUC during induction for both infliximab and adalimumab was associated with deep remission, whereas rapid infliximab clearance at various timepoints was inversely associated with deep remission. Baseline predictors of rapid infliximab clearance included older age, low albumin, and elevations in body mass index, C-reactive protein, soluble CD64, and wPCDAI. CONCLUSIONS: We identified PK/PD cut-points associated with deep remission and rapid infliximab clearance, providing actionable metrics to individualize induction dosing and optimize maintenance therapy for children starting anti-TNF therapy.

OBJECTIVE: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) provides a survival advantage in metastatic castration-resistant prostate cancer (mCRPC). However, the physiologically high PSMA-ligand uptake in salivary glands makes these organs susceptible to radiation damage. The aim of this study is to examine the changes occurring in salivary glands after PSMA-RLT and to evaluate their relationship with treatment-related parameters, including cumulative administered activity and number of RLT cycles. METHOD: The study included 68 mCRPC patients who received 177Lu PSMA-617 treatment. Volume, surface area, density, and PSMA uptake levels were calculated for the parotid and submandibular glands in pre- and post-treatment imaging. Treatment-related changes and their associations with baseline imaging parameters, treatment timing, cumulative administered activity, and number of RLT cycles were statistically analyzed. FINDINGS: After RLT, parotid glands showed significant decreases in SUVmean, volume, surface area, and PSMA total activity (all p < 0.001), whereas parotid density remained stable. Submandibular glands also demonstrated significant reductions in SUVmean, volume, surface area, PSMA total activity, and CT-derived density (all p < 0.001). In the exploratory correlation analyses, the number of RLT cycles and cumulative administered activity showed weak nominal positive associations with parotid density change; however, these associations did not remain statistically significant after Benjamini-Hochberg false discovery rate correction. BMI was not significantly associated with glandular SUVmean, HU measurements, or post-treatment glandular changes after correction for multiple testing. CONCLUSION: PSMA-targeted RLT was associated with significant imaging-detectable structural alterations and reductions in PET-derived glandular activity in the major salivary glands. CT-derived density significantly decreased in the submandibular glands, whereas parotid density remained stable. No baseline imaging-, BMI-, time-, or administered activity-related parameter remained significantly associated with post-treatment glandular changes after correction for multiple testing.

Targeting the colony-stimulating factor 1 receptor (CSF1R) to remove tumour-associated macrophages is being explored as cancer therapy. This strategy may be relevant for chronic lymphocytic leukaemia (CLL), which strongly depends on support from myeloid cells. However, it is unclear how CSF1R expression affects the CLL microenvironment and leukaemic progression. To examine this question, we created Eμ-TCL1 transgenic mice for CLL with Csf1r haploinsufficiency to investigate changes in myeloid cells, Csf1r expression and leukaemia progression. Csf1r haploinsufficiency reduced Csf1r expression on circulating monocytes, but did not significantly impair its expression in tissue macrophages or change the overall numbers of monocytes or macrophages in blood and lymphoid tissues. Eμ-TCL1 transgenic mice with lower Csf1r levels had less leukaemia during early disease, but this effect faded with disease progression, and their overall survival was similar to controls. Furthermore, in vitro co-culture demonstrates that depletion of CSF1R expression on cell lines did not affect the survival or migration of patient-derived CLL cells. In summary, our results show that while the CSF1R pathway is important for maintaining the myeloid cells that support CLL, simply reducing CSF1R expression has only a limited effect on disease progression. Attempts to target the CSF1R for leukaemic therapy might benefit from a stronger depletion of macrophages or the combination with other agents.

PURPOSE: Psychological stress, here used as an umbrella term encompassing depression, anxiety, psychosocial stress, stressful life events, perceived stress, and job strain, is hypothesized to influence cancer development and prognosis, yet epidemiologic evidence is inconsistent. This umbrella review with secondary quantitative synthesis evaluated associations between stress-related exposures and cancer incidence and mortality. METHODS: PubMed was searched from inception to March 1, 2026, alongside Scopus, the Cochrane Library, citation tracking, and manual screening. Eligible studies included systematic reviews, meta-analyses, or pooled individual participant data analyses assessing depression, anxiety, psychosocial stress, stressful life events, perceived stress, or job strain in relation to cancer incidence or mortality, reporting adjusted HRs, RRs, or ORs. Random-effects models were used for secondary pooling. Overlap was assessed with corrected covered area, and evidence credibility with the Ioannidis framework. RESULTS: Fifteen publications met inclusion criteria; eight were quantitatively synthesized, representing over four million participants. Psychological stress was not significantly associated with overall cancer incidence (pooled RR/HR 1.06; 95% CI 0.99-1.14; I = 72.5%) or breast cancer incidence (RR/OR 1.13; 95% CI 0.95-1.34; I = 77.8%). In contrast, cancer mortality was consistently elevated across 4 analyses (RR/HR 1.23; 95% CI 1.19-1.27; I = 0%). Site-specific mortality risks ranged from HR 1.15 for lung cancer to HR 3.86 for leukemia. Review overlap was moderate (7.4%). Associations between depression/anxiety and cancer mortality reached Class I evidence. CONCLUSION: Psychological stress-related exposures were not significantly linked to cancer incidence in the available meta-analytic evidence, whereas depression, anxiety, and related distress were consistently associated with increased cancer mortality. These findings should be interpreted cautiously because residual confounding and measurement heterogeneity remain important limitations.

BACKGROUND: Although rebiopsy at progression on osimertinib is recommended for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), its real-world impact on clinical outcomes remains unclear. Rebiopsy on Osi is a multicenter, retrospective study assessing rebiopsy patterns, resistance mechanisms, and their impact on second-line treatment choices and outcomes in routine clinical practice. METHODS: A total of 457 patients with advanced NSCLC harboring a common EGFR mutation (exon 19 deletion or L858R) who progressed on first-line osimertinib were identified from the Italian ATLAS registry. Patients were stratified according to rebiopsy status (tissue and/or plasma-based next generation sequencing) and receipt of biomarker-driven adaptive second-line therapy. RESULTS: Rebiopsy was performed in 206 patients (45.1%), predominantly via tissue sampling (66.2%). A resistance mechanism was identified in 80 cases (38.8%), with higher detection rates by tissue rebiopsy (46.6%) versus liquid (13.5%). MET amplification/overexpression emerged as the most frequent actionable resistance mechanism. Among 239 patients treated with second-line therapy, 39 (16.3%) received adaptive treatment, including 29 out of 39 patients (74.3%) with MET amplification/overexpression treated with a MET-TKI-based regimen. Median progression-free (PFS) and overall (OS) survival were longer with adaptive therapy (7.3 and 14.1 months) than with rebiopsy without treatment adaptation (6.5 and 12.2 months) or no rebiopsy (5.1 and 8.2 months). CONCLUSION: In real-world practice, rebiopsy identifies a resistance mechanism in slightly more than one third of patients, with actionable MET amplification/overexpression accounting for approximately one fifth of cases. Biomarker-driven adaptive therapy may improve clinical outcomes, supporting implementation of rebiopsy in routine practice.

BACKGROUND: The importance of maintaining planned dose intensity (DI) of methotrexate (MTX), adriamycin, and cisplatin (MAP) chemotherapy in high-grade osteosarcoma has been highlighted in clinical trials. However, DI is frequently reduced in routine practice, particularly in adults, and its prognostic relevance in real-world settings remains unclear. METHODS: We retrospectively analysed patients with high-grade osteosarcoma treated with MAP at a single center between 2014 and 2021, stratifying patients into pediatric (PED; ≤19 years), young adult (YA; 20-39 years), and older adult (OA; ≥40 years) groups. Treatment intensity was assessed using intended dose per cycle, cumulative dose over 200 days, and relative DI. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: Among 78 patients who received MAP therapy, 51 were eligible for analysis. The 3-year PFS was 61.1% (95% CI, 45.5-73.5), with no significant difference among age groups. Higher DI was not consistently associated with improved PFS or OS; metastasis at diagnosis was the only independent prognostic factor. Treatment completion rates were similar in PED and YA patients (72% and 69%, respectively) but markedly lower in OAs (22%). Delayed MTX elimination occurred more frequently in OAs. CONCLUSIONS: In this real-world cohort, reductions in chemotherapy delivery-particularly in OAs-were common; however, higher DI was not consistently associated with better survival outcomes. These findings highlight the complexity of interpreting DI metrics and support age-adapted treatment considerations.

BACKGROUND: Peripheral edema is an adverse event associated with docetaxel (DTX). However, previous studies on DTX-induced peripheral edema have been limited to patients with breast cancer. Therefore, evaluation of symptoms in other cancer types is essential. We aimed to identify the factors associated with this symptom in patients with non-small cell lung cancer (NSCLC). METHODS: This retrospective multicenter observational study evaluated 170 patients with NSCLC who received DTX between April 2014 and December 2024. The primary endpoint was factors associated with grade ≥ 2 DTX-induced peripheral edema during up to seven cycles. Additionally, we evaluated the factors for all-grade symptoms. RESULTS: The incidences of grade ≥ 2 and all-grade DTX-induced peripheral edema were 13.5% and 30.0%. The median cumulative DTX dose at symptom onset was 144 (interquartile range, 60-254) mg/m2 for grade ≥ 2 DTX-induced peripheral edema and 120 (60-210) mg/m2 for all-grade symptoms. The Fine-Gray sub-distribution hazard models revealed that the co-administration of ramucirumab (RAM) was significantly associated with the incidence of DTX-induced peripheral edema (grade ≥ 2: sub-distribution hazard ratio [SDHR], 3.51; 95% confidence interval [CI], 1.34-9.24; P = 0.011) (all-grade: SDHR, 2.17; 95% CI, 1.20-3.92; P = 0.011). The Gray's test demonstrated that the cumulative incidence of DTX-induced peripheral edema was significantly higher in the DTX + RAM group than in the DTX monotherapy group (P = 0.003 and < 0.001 for grade ≥ 2 and all-grade symptoms, respectively). CONCLUSIONS: We revealed that co-administration of RAM is a risk factor for DTX-induced peripheral edema in patients with NSCLC.