Search Results (3,159)

Background and Clinical Significance: Interstitial lung disease (ILD) is an uncommon but potentially serious complication of imatinib. Its histopathological characterization has so far relied on surgical biopsy or transbronchial forceps sampling, and no case characterized by transbronchial lung cryobiopsy (TBLC) has been reported. The single previous description of a non-specific interstitial pneumonia (NSIP) pattern with imatinib came from a surgical specimen and was cellular in type, with complete radiological resolution after withdrawal. Case Presentation: A 69-year-old never-smoker began imatinib 400 mg daily for Philadelphia chromosome-positive chronic myeloid leukemia; chest computed tomography performed immediately beforehand was normal. Approximately three months later, she developed dyspnea, dry cough and a cutaneous rash, progressing to acute respiratory failure with forced vital capacity 49% and diffusing capacity 30% of predicted. Avian exposure had ceased one month before symptom onset, and she had never received amiodarone. Although serum precipitins were unavailable, hypersensitivity pneumonitis was considered less likely given the temporal relationship but could not be definitively excluded. TBLC yielded specimens showing fibrotic thickening of the alveolar septa by hyaline collagen deposition with a focal lymphomonocytic infiltrate, corresponding to a fibrotic NSIP pattern. After drug withdrawal and administration of corticosteroids, forced vital capacity rose to 82% of predicted. Multidisciplinary discussion concluded that this was drug-induced ILD, graded probable on the Naranjo scale. Imatinib was subsequently replaced by bosutinib for insufficient molecular response, without pulmonary recurrence. Conclusions: Imatinib-associated ILD may present with an organizing-pneumonia-like radiological pattern followed by a fibrosing pattern, with cryobiopsy performed later demonstrating fibrotic NSIP. Because no tissue was obtained during the acute phase, this sequence remains a hypothesis rather than a demonstrated evolution. Cryobiopsy can be performed safely when surgical biopsy is not appropriate. Full article

Vascular endothelial growth factor (VEGF)-targeted therapies have been associated with thromboembolic events, although the magnitude and nature of this risk vary substantially according to the specific agent, mechanism of VEGF-pathway inhibition, malignancy, concomitant therapy, and patient-related factors. This comprehensive narrative review examines the epidemiology, mechanisms, clinical characteristics, and management of VTE in cancer patients receiving VEGF inhibitors. Evidence from clinical trials, observational studies, pharmacovigilance analyses, and preclinical investigations is synthesized to provide a clinically oriented overview of VEGF-targeted therapy-associated thrombosis. Reported VTE incidence ranges from 2.5% to 15.7% across studies, with substantial heterogeneity according to the VEGF-targeted agent, cancer type, treatment setting, and study design. Bevacizumab-treated patients receiving chemotherapy demonstrated increased arterial and venous thromboembolism risk (relative risk 1.32–2.45). Plasminogen activator inhibitor-1 (PAI-1) upregulation, endothelial dysfunction, and tissue factor activation represent key pathogenic mechanisms. Careful patient selection, risk stratification using validated scoring systems, thromboprophylaxis strategies, and individualized anticoagulation approaches are essential for managing this complication. Direct oral anticoagulants, particularly apixaban, demonstrate favorable efficacy and safety profiles compared to traditional anticoagulants in cancer-associated VTE. This review provides clinicians with comprehensive, evidence-based guidance for preventing and managing VTE in the growing population of cancer patients receiving VEGF-directed therapies. Full article

The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents. Full article

Epigenetic regulation through histone acetylation plays a critical role in gene expression and cancer progression. Because of its pivotal role in chromatin remodeling, Histone deacetylase 3 (HDAC3) has become a promising therapeutic target. In this study, an artificial intelligence (AI)-driven strategy was utilized to prioritize potential HDAC3 inhibitors among FDA-approved compounds to accelerate drug repurposing for cancer therapy. Existing HDAC3 inhibitors were identified in the BindingDB and were used to develop a machine learning (ML) model trained on the most potent inhibitors to identify molecular descriptor patterns associated with HDAC3 inhibition. The ML workflow then screened 1615 FDA-approved compounds, yielding 120 candidates with predicted HDAC3 inhibitory activity. Among these, known HDAC inhibitors, including romidepsin, vorinostat, and panobinostat, were selected, suggesting that the workflow can recover known HDAC inhibitors during virtual screening. Interestingly, tyrosine kinase inhibitors such as imatinib and osimertinib were also identified, indicating potential structural overlap between kinase- and HDAC3-binding pharmacophores. The analysis of the predicted docking scores also supported the prioritization results since the top 10 compounds had more negative predicted docking scores than the bottom 10 (p = 0.0074). This shows that the suggested workflow is useful for prioritizing FDA-approved compounds as potential HDAC3 inhibitors for further study. Full article

Conjunctival lymphoma classically appears as a painless salmon-pink subepithelial infiltrate, but its indolent forms can closely imitate inflammatory ocular surface disease and delay diagnosis, particularly when an uncommon subtype such as small lymphocytic lymphoma presents bilaterally and in isolation. A woman in her early fifties presented with one month of left ocular discomfort and sectoral redness, and slit-lamp examination revealed two multilobulated hyperaemic bulbar conjunctival nodules, clinically indistinguishable from nodular episcleritis. Topical corticosteroids and a topical non-steroidal anti-inflammatory drug relieved the ocular discomfort and hyperaemia, but the nodules regressed only partially and at no point resolved. This dissociation between symptomatic relief and persistence of the lesions was, in retrospect, the earliest argument against a purely inflammatory process. The initial work-up pointed toward inflammatory and granulomatous causes: elevated serum angiotensin-converting enzyme and lysozyme raised the possibility of sarcoidosis, although thoracic computed tomography, bronchoscopy and a first conjunctival biopsy performed without a lymphoma-directed panel were unrevealing, showing only reactive lymphoid hyperplasia. Approximately one year later, recurrent and now bilateral disease prompted a repeat biopsy with directed immunohistochemistry, which demonstrated a CD20-positive small B-cell infiltrate co-expressing CD5 and CD23 with negative cyclin D1 and CD10, consistent with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Systemic staging with ¹⁸F-FDG PET/CT and bone marrow biopsy revealed no definite extra-conjunctival disease. After multidisciplinary review of observation, local radiotherapy and surgical excision, systemic therapy was preferred given the bilateral, recurrent and symptomatic course, and oral ibrutinib 420 mg once daily achieved complete clinical regression at three months and a sustained ocular response at two years, with indefinite haematological and ophthalmological surveillance planned. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory condition that is marked by the growth of lesions outside the uterus, along with angiogenesis, fibrosis, immune dysregulation, and pain sensitization. There is now growing evidence that receptor tyrosine kinase (RTK) signaling networks are central to these processes, integrating proliferative, angiogenic, inflammatory, endocrine, and microenvironmental signals. This review summarizes the roles of six major RTK axes in endometriosis and evaluates their receptor-specific mechanisms, therapeutic relevance, and modulation by representative phytochemicals. An English-language literature search of PubMed was conducted with no publication date restrictions using combinations and variations of the following keywords: phytochemicals, endometriosis, EGFR, VEGFR, IGF1R, PDGFR, FGFR, MET, curcumin, resveratrol, epigallocatechin gallate (EGCG), quercetin, naringenin, berberine, apigenin, luteolin, genistein, and baicalein. Additional search terms related to receptor signaling mechanisms, downstream pathways, cellular phenotypes, and therapeutic relevance were also incorporated to ensure comprehensive coverage of the literature. The RTK signaling pathways control stromal activation, lesion survival, angiogenic support, extracellular matrix remodeling, neuroimmune sensitization, and malignant progression. Of the six RTK axes examined, EGFR, VEGFR, and IGF1R have the strongest mechanistic and pharmacological support, whereas PDGFR, FGFR, and MET remain biologically plausible targets. Even though phytochemicals do not consistently act as receptor-selective RTK inhibitors, evidence shows they reduce RTK-centred signaling networks by targeting common downstream hubs. As a result of their effects at the network level, the phytochemicals may help to suppress lesion proliferation, angiogenesis, invasion, fibrosis, inflammation, oxidative stress, and pain sensitization. Endometriosis should be viewed as an RTK-centered network disease rather than a single-pathway disorder. In this context, phytochemicals act as modulators that attenuate signaling hubs, offering a mechanistically aligned strategy for a disease driven by redundancy and microenvironmental crosstalk. Full article

Background: Evidence regarding long-term outcomes among offspring following maternal or paternal exposure to BCR::ABL1 tyrosine kinase inhibitors (TKIs) is limited. We described pregnancy outcomes and offspring health through adolescence and early adulthood in a single-centre cohort of patients with chronic myeloid leukemia (CML). Methods: This retrospective, descriptive cohort study included patients with chronic-phase CML who experienced a pregnancy, or whose partner experienced a pregnancy, in association with TKI exposure and for whom longitudinal offspring follow-up was available. Long-term offspring outcomes were ascertained from detailed obstetric and pediatric medical records supplemented by parental reports. Fourteen patients (nine women and five men) contributed 21 pregnancy events and 23 live-born offspring, including two twin pregnancies in the paternal-exposure group. Results: In the maternal-exposure group, median gestational age at delivery was 38.0 weeks (range, 35–40), and four of 15 deliveries were preterm. In the paternal-exposure group, median gestational age was 39.0 weeks (range, 38–41), with no preterm deliveries. Median offspring follow-up was 252 months (range, 212–295), extending through adolescence and into early adulthood. One offspring had a primum atrial septal defect that was surgically corrected. No additional clinically documented major abnormalities in growth or developmental progress were identified during available follow-up. Given the small cohort, these observations were interpreted descriptively and were not considered evidence of equivalence with population-level rates. Conclusions: This small retrospective cohort provides unusually long observational follow-up of offspring after selected maternal or paternal TKI exposures. The findings are clinically informative but cannot establish reproductive safety or exclude rare adverse outcomes. Larger multicentre registries using standardized long-term developmental, neurocognitive, and endocrine assessments are needed. Full article

This review aims to provide a comprehensive overview of the currently available therapies for primary vitreoretinal lymphoma (PVRL) and to evaluate emerging therapeutic strategies that may improve patient outcomes. A comprehensive literature search was conducted in databases including PubMed/MEDLINE, Embase, and Scopus for studies published up to 2026. Search terms included “primary vitreoretinal lymphoma”, “intravitreal methotrexate”, “rituximab”, “radiotherapy”, “targeted therapy”, and “immunotherapy”. Eligible publications included randomized controlled trials, prospective and retrospective studies, observational studies, systematic reviews, relevant clinical guidelines, case series, and case reports. Studies were independently screened and assessed by two reviewers. Current therapeutic strategies include intravitreal chemotherapy, systemic high-dose methotrexate-based regimens, and radiotherapy, either as monotherapy or in combination. While intravitreal approaches provide effective local disease control, they fail to address occult or subsequent central nervous system (CNS) dissemination, necessitating the use of systemic treatments in selected patients. In recent years, significant progress in the understanding of PVRL pathophysiology, including the role of MYD88 mutations and interleukin-10 signaling, has paved the way for the development of targeted and immunomodulatory therapies. Agents such as Bruton’s tyrosine kinase inhibitors, immunomodulatory drugs, and immune checkpoint inhibitors have demonstrated promising results in early clinical studies, particularly in relapsed or refractory disease. Despite advances in diagnostic techniques, the management of PVRL remains challenging due to its heterogeneous presentation, high relapse rates, and frequent progression to CNS involvement. Full article

Advances in lung cancer treatment have progressively improved survival across all disease stages. Some patients now achieve long-term survival, while others may remain on treatment for several years, particularly with immune checkpoint inhibitors and selected tyrosine kinase inhibitors. These advances have increased recognition of the survivorship needs of patients with lung cancer, including persistent symptoms, treatment-related toxicities, and social, psychological, and caregiver-related concerns. The integration of palliative care has also become increasingly relevant, reflecting a shift in the traditional care paradigm by extending supportive approaches beyond the end-of-life setting to patients living long-term with active disease. However, evidence and care models addressing lung cancer survivorship remain fragmented and focus predominantly on patients treated with curative intent. This narrative review provides a comprehensive overview of survivorship in lung cancer, from screening and early-stage to locally advanced and metastatic disease, while also examining more cross-cutting physical, psychological and social domains. Greater recognition and systematic assessment of these needs is essential to develop structured, coordinated, and personalized survivorship pathways for the growing and clinically heterogeneous population of individuals living with and beyond lung cancer. Full article

The use of targeted therapies has improved outcomes in patients with resected epidermal growth factor receptor-mutated non-small cell lung cancer, but uncommon and persistent dermatologic toxicities remain poorly characterized. We report a 71-year-old woman with resected lung adenocarcinoma harboring an epidermal growth factor receptor exon 21 L858R mutation. Following right upper lobectomy and systematic mediastinal lymph node dissection, pathological staging was pT2aN1M0 (stage IIB). She received four cycles of adjuvant cisplatin plus pemetrexed followed by planned three-year adjuvant Osimertinib. During Osimertinib treatment, she developed a persistent violaceous rash accompanied by progressive cutaneous hyperpigmentation. Osimertinib was temporarily interrupted, and dermatologic evaluation was performed, resulting in partial clinical improvement. Hyperpigmentation, however, persisted during follow-up. Other adverse events included grade 1 diarrhea, transient arthralgia, anorexia, and weight loss. Osimertinib was subsequently resumed and maintained. Nearly two years after surgery, the patient remains free of disease recurrence, with stable pigmentary skin changes. This case highlights an uncommon and prolonged dermatologic manifestation associated with Osimertinib and emphasizes the importance of recognizing atypical cutaneous toxicity to facilitate appropriate management and to facilitate appropriate dermatologic evaluation and individualized management of treatment-related toxicity. Full article

Background: Immune checkpoint inhibitors have improved outcomes in metastatic clear-cell renal cell carcinoma (mRCC), yet clinically applicable tissue biomarkers remain limited. Growth differentiation factor-15 (GDF-15) promotes tumour immune evasion and has emerged as a potential therapeutic target in immuno-oncology. We evaluated the prognostic significance of tumour GDF-15 expression in patients with intermediate-risk clear-cell mRCC treated with second-line nivolumab. Methods: Forty-six patients with intermediate-risk clear-cell mRCC who received nivolumab after one line of tyrosine kinase inhibitor therapy were retrospectively evaluated. Tumour GDF-15 expression was assessed by immunohistochemistry and classified as low (0–1+) or high (2–3+). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the development of cancer-associated cachexia were compared between expression groups. Results: High tumour GDF-15 expression was observed in 23 patients (50%). ORR was significantly higher in the low-expression group than in the high-expression group (57% vs. 26%, p = 0.036). Low tumour GDF-15 expression was associated with significantly longer PFS (24.5 vs. 7.5 months; HR 0.38, 95% CI 0.18–0.80; p = 0.009) and OS (28.6 vs. 12.6 months; HR 0.43, 95% CI 0.19–0.98; p = 0.041). The association with OS remained significant after adjustment for age. The frequency of cancer-associated cachexia did not differ according to tumour GDF-15 expression (43% vs. 35%, p = 0.546). Conclusions: Low tumour GDF-15 expression was associated with better objective response and longer progression-free and overall survival in patients with intermediate-risk metastatic clear-cell renal cell carcinoma treated with second-line nivolumab, with the association with overall survival remaining significant after adjustment for age. Tumour GDF-15 represents a promising tissue biomarker for prognostic risk stratification and warrants validation in larger prospective studies. Full article

Understanding the mechanisms of metastasis is one of the most pressing issues in cancer therapy. Metastasis-associated in colon cancer 1 (MACC1) is an important biomarker and functional driver of tumor progression and metastasis. However, the molecular mechanisms underlying its activity remain incompletely understood. Here, we demonstrate that MACC1 acts as an important adaptor protein that promotes hyperactivation of receptor tyrosine kinase (RTK) signaling pathways in colorectal cancer (CRC) cells. Based on mass spectrometry-based interactomics, we identified key MACC1 interactors, including GRB2, SHP2, SHC1, and STAT5B, that preferentially associate with tyrosine-phosphorylated residues Y365, Y379, and Y789. Site-directed mutagenesis of Y379 and Y789 reduced MACC1-induced migration, proliferation, and ERK phosphorylation. Using digital Western blotting (DigiWest), we observed a broad MACC1-dependent hyperactivation of downstream signaling effectors, including MEK, ERK, β-catenin, SRC, FAK, CREB, and VASP. Targeting MACC1-induced signaling with clinically relevant inhibitors effectively reversed MACC1-driven clonogenicity. Our findings support a role for MACC1 in promoting hyperactivation of RTK-associated signaling and reveal pharmacological vulnerabilities of potential relevance to metastasis-prone cancers characterized by elevated MACC1 expression. Full article

Monitoring prognostic biomarkers is essential for evaluating cancer treatment efficacy in real time. Here, we present a rapid, proof-of-concept microfluidic assay for cancer biomarker quantification and functional therapy evaluation. The assay requires only 5 µL of sample, eliminates tedious sample manipulation, and uses commercial antibodies to track both biomarker concentration and functional activity. We demonstrated the successful detection of VEGF and EML4-ALK proteins in both lung cancer cell culture supernatant and serum-spiked samples, achieving a detection sensitivity 15 times greater than standard ELISA using the same antibody pairs for the respective antigens. Crucially, we showcase the platform’s distinct applicability to functional assays by monitoring dynamic phosphorylation changes in EML4-ALK following treatment with the tyrosine kinase inhibitor alectinib, successfully capturing a significant, rapid decrease in phosphorylation levels. At this preclinical stage, the platform demonstrates analytical and functional feasibility for highly sensitive and rapid biomarker monitoring, providing a foundation for future validation in patient-derived ALK-positive samples for therapeutic-response assessment. Full article

Bispecific antibodies (bsAbs) and bispecific antibody–drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC. Full article

Background and Objectives: The modified Glasgow Prognostic Score (mGPS)—a composite of serum C-reactive protein (CRP) and albumin—simultaneously reflects systemic inflammatory activity and nutritional reserve. Its specific prognostic role in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab in the second-line setting has not previously been examined in a large multicentre cohort. The aims of this study are to determine whether baseline mGPS independently predicts overall survival (OS) and progression-free survival (PFS) in this population and whether its discriminatory capacity compares favourably with the International Metastatic RCC Database Consortium (IMDC) risk score. Methods: This multicentre retrospective cohort study included 174 consecutive patients with histopathologically confirmed mRCC who progressed on first-line VEGF-targeted tyrosine kinase inhibitor (TKI) therapy and subsequently received nivolumab monotherapy at six oncology centres in Türkiye between January 2015 and December 2023. Baseline mGPS was calculated from serum albumin and CRP measured within four weeks before treatment initiation. Kaplan–Meier analysis with log-rank testing and Cox proportional-hazards regression were used for survival analyses; discriminatory capacity was quantified using Uno’s concordance (C) statistic. Results: The median follow-up was 24.2 months. The median OS was 44.5, 15.3, and 10.0 months for the mGPS 0, 1, and 2 groups, respectively (log-rank p < 0.0001); the median PFS was 6.7, 4.2, and 2.6 months (p = 0.022). On multivariable analysis, mGPS 2 independently predicted inferior OS (hazard ratio [HR] 3.61, 95% confidence interval [CI] 1.78–7.31; p < 0.001) and PFS (HR 1.87, 95% CI 1.17–2.97; p = 0.008). Uno’s C-statistic for OS was numerically higher for the combined mGPS + IMDC model (0.70) than for either the mGPS (0.66) or IMDC (0.63) alone; these differences were not formally tested and are presented descriptively. Conclusions: Baseline mGPS is a simple, inexpensive, and independent prognostic biomarker in mRCC patients treated with second-line nivolumab, providing discriminatory information that may be complementary alongside IMDC risk stratification. Prospective validation in randomised trials is warranted. Full article