The combination of olaparib plus radium-223 improved progression-free survival in patients with metastatic castration-resistant prostate cancer with bone metastases (BM) in the multicenter, randomized, phase 2 COMRADE trial (NCT03317391). Here, the patient-reported outcome (PRO) analysis of this trial is reported.

Index lesion-focused ipsilateral systematic biopsy (iSB) has been proposed as a core-reduction alternative to MRI-targeted biopsy combined with systematic biopsy (TB + SB) for prostate cancer, but prospective multicenter validation is limited.

Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC), but the development of resistance severely limits its effectiveness. The molecular determinants underlying cisplatin resistance in HNSCC remain unclear. Multiple databases were used to screen the core genes related to cisplatin resistance in HNSCC patients. Tumor tissue samples from HNSCC patients were collected and the expression of FOXA2 was verified through various pathological tests to establish the correlation between FOXA2 expression and the clinical characteristics of the patients. The in vitro and patient-derived organoids (PDOs) models were used to verify the regulatory effect of FOXA2 on the cisplatin resistance of HNSCC. Transcriptome sequencing combined with multi-omics analysis demonstrated that LAMC2 is a downstream target of FOXA2 in regulating cisplatin resistance. Bioinformatic screening of cisplatin-resistant cohorts revealed that FOXA2 was the only gene significantly associated with poor survival outcomes in TCGA-HNSCC patients. Transcriptomic profiling and pathway enrichment analyses revealed the activation of the PI3K/AKT signaling cascade. We identified LAMC2 as a direct transcriptional target of FOXA2. Chromatin immunoprecipitation and luciferase reporter assays confirmed FOXA2 binding to the LAMC2 promoter, resulting in transcriptional activation. FOXA2-mediated upregulation of LAMC2 increased PI3K and AKT phosphorylation, and LAMC2 overexpression reversed the impaired malignant phenotypes caused by FOXA2 silencing. In xenograft models and PDO systems, FOXA2 overexpression reduced responsiveness to cisplatin, whereas FOXA2 inhibition significantly increased therapeutic sensitivity. Our research has identified a previously unrecognized regulatory axis involving FOXA2, LAMC2, and PI3K/AKT, which plays a crucial role in the progression and resistance to cisplatin in HNSCC. Therefore, targeting the FOXA2-LAMC2 axis may represent a novel therapeutic strategy to overcome cisplatin resistance in HNSCC.

Chronotherapy, the alignment of treatments with biological rhythms, has been explored in oncology, particularly for chemotherapy and targeted therapies, but its impact on immune checkpoint inhibitor (ICI) efficacy remains underexplored. This research aimed to examine the potential chronotherapeutic effects of morning ICI administration on the long-term response to pembrolizumab in metastatic non-small cell lung cancer (NSCLC), emphasising immune function stability via the neutrophil-to-lymphocyte ratio (NLR), and to assess the clinical significance of circadian synchronisation in immunotherapy. This study utilised a retrospective case study methodology, examining the treatment records and serial hematologic data of a patient with metastatic NSCLC. A patient diagnosed with metastatic NSCLC in 2019 showed a lasting full response to pembrolizumab for more than 6 years. A retrospective analysis revealed consistent morning ICI administration (08:00-11:00 h) and a stable NLR (2.16-3.66) during the treatment period. In addition, serial haematologic analysis showed a stable NLR, ranging between 2.16 and 3.66 throughout the treatment course. This immunological stability may reflect enhanced immune function aligned with early-day innate immune activity, particularly neutrophil and antigen-presenting cell priming, which is known to follow circadian patterns. Although specific molecular circadian markers were not examined, this case highlights a significant issue in current medical practice: there is almost no consistency in the timing of immunotherapy treatments. Taken together with emerging retrospective data, these findings underscore the need for prospective studies evaluating the influence of treatment timing on immunotherapy efficacy and durable immune surveillance in solid tumours.

Oral squamous cell carcinoma (OSCC) is a major global health concern, especially in India, where it is one of the primary causes of cancer-related fatalities. OSCC is notorious for its propensity to spread to distal sites such as the lungs, bones, and liver, but malignant pleural effusions resulting from OSCC are extremely uncommon. This case report details an unusual presentation of OSCC in a 61-year-old male presenting with bilateral malignant pleural effusion from a primary buccal mucosa squamous cell carcinoma with no lung involvement. Through cytological analysis and immunocytochemistry, we confirm the diagnosis of metastatic squamous cell carcinoma, highlighting the significance of comprehensive diagnostic approaches.

We reported a rare case of disseminated diffuse large B-cell lymphoma (DLBCL) initially presenting as refractory orbital cellulitis in a 53-year-old male. The patient presented with acute periorbital swelling, pain, and restricted ocular motility, unresponsive to broad-spectrum antibiotics. Magnetic resonance imaging (MRI) revealed extensive sinusitis with a peripherally enhancing medial extraconal orbital mass and adjacent bony erosions. A prompt functional endoscopic sinus surgery and histopathology revealed a poorly differentiated malignant neoplasm. Immunohistochemistry confirmed DLBCL, non-germinal center B-cell subtype. Systemic evaluation with whole-body MRI and fluorodeoxyglucose-positron emission tomography demonstrated widespread dissemination involving the lungs, gastrointestinal tract, adrenal glands, and skeleton. The patient was initiated on required chemoimmunotherapy with central nervous system prophylaxis and remains under oncology follow-up. This case highlights the diagnostic challenge posed by orbital lymphoma mimicking infectious orbital cellulitis and underscores the need for early imaging and tissue diagnosis in culture-negative, non-resolving cases. A high index of suspicion and multidisciplinary collaboration are essential for timely diagnosis and effective management.

Primary testicular neuroendocrine tumors are exceedingly rare, comprising less than 1% of testicular neoplasms. Their nonspecific presentation and overlap with other testicular tumors make diagnosis challenging. We report the case of a 21-year-old male with a painless left testicular mass. Imaging revealed a hypervascular lesion with calcifications, while serum markers (alpha-fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase) were normal. Radical orchiectomy demonstrated a 3-cm well-circumscribed tumor composed of monotonous cells with "salt-and-pepper" chromatin and low mitotic activity. Immunohistochemistry confirmed neuroendocrine differentiation (synaptophysin, chromogranin, INSM1 positive; Ki-67 < 1%). This profile established the diagnosis of a well-differentiated testicular neuroendocrine tumor, classified under the 2022 WHO framework as "prepubertal-type." Although indolent, these tumors require long-term follow-up due to the risk of late metastasis. Radical orchiectomy remains the treatment of choice. This case emphasizes the critical role of histopathology and immunoprofiling in diagnosis and contributes to refining the clinical understanding of this rare entity.

Although β‑glucan exhibits various biological activities, the anticancer mechanisms of a low‑molecular‑weight β‑glucan isolated from Aureobasidium pullulans (LMW‑AP‑FBG) in colorectal cancer remain unclear. Therefore, this study investigated the anticancer potential of LMW‑AP‑FBG in human colon cancer cells. Treatment of SW480 cells with LMW‑AP‑FBG resulted in a significant reduction in cell viability in a concentration‑ and time‑dependent manner, with half‑maximal inhibitory concentrations (IC50) of 557.2, 497.4 and 300.6 µg/ml at 24, 48 and 72 h, respectively. Apoptotic cell death was evidenced by increased caspase‑3/7 enzymatic activity and proteolytic cleavage of caspase‑3, ‑7, ‑8, ‑9 and poly (ADP‑ribose) polymerase. Notably, pharmacological inhibition of caspases using the pan‑caspase inhibitor Z‑VAD‑FMK only partially restored cell viability, suggesting the involvement of caspase‑independent cell death mechanisms. Mitochondrial dysfunction was further indicated by dissipation of mitochondrial membrane potential, cytosolic accumulation of cytochrome c, and downregulation of the anti‑apoptotic protein Bcl‑2, collectively supporting activation of the intrinsic apoptotic pathway. In parallel, the expression of autophagy‑related proteins was markedly increased, implying concomitant induction of autophagic processes. Mechanistically, LMW‑AP‑FBG suppressed the PI3K/AKT/mTOR signaling axis, a central regulator of cell survival and autophagy. Collectively, these findings demonstrate that LMW‑AP‑FBG exerts anticancer effects in SW480 colon cancer cells through coordinated activation of apoptotic and autophagy‑associated pathways, highlighting its potential as a bioactive anticancer agent and warranting further in vivo validation.

Skin is among the most frequent sites of cancer diagnosis, and the global incidence of skin cancer continues to rise despite extensive public health initiatives and preventive strategies. Arsenic, a ubiquitous environmental metalloid classified as a Group 1 carcinogen, remains an important concern due to widespread exposure through contaminated drinking water, food sources and occupational contact. Arsenic‑associated skin carcinogenesis involves complex, interdependent molecular processes and has been linked to the disruption of redox signalling, altered DNA damage signalling and repair responses as well as epigenetic reprogramming. In keratinocytes, arsenic perturbs redox and stress‑response pathways and may disrupt genome maintenance and cellular stress signalling in experimental systems. Arsenic may also alter microRNA networks and affect telomere and mitochondrial homeostasis, although the contribution of these processes to malignant transformation remains context‑dependent; in melanoma, the carcinogenic mechanisms of arsenic are less well characterized. Clinically, arsenic is recognized as a carcinogen in non‑melanoma skin cancer (NMSC) and evidence from high‑exposure endemic regions, together with occupational cohorts, suggest a dose‑responsive association. For melanoma, clinical evidence is more heterogeneous and subject to substantial potential confounding, although some studies suggest modest risk elevation in high‑exposure or occupational settings. Collectively, convergent mechanistic, experimental and epidemiological data support arsenic as an independent carcinogen, particularly in NMSC. These findings underscore the need for heightened clinical vigilance, particularly in exposed populations, and call for renewed public health strategies and regulatory frameworks to mitigate the persistent global burden of arsenic‑associated skin cancer.

Pancreatic cancer (PC) is a lethal malignant tumor of the digestive system with a low survival rate. Current therapies provide only modest benefits for patients and new therapeutic options are urgently needed. Schisandrin B (Sch B) has demonstrated novel antitumor activity in several preclinical models; however, its effects on PC remain unclear. In the present study, the anti‑proliferative effects of Sch B in vitro were evaluated in PC cell lines. The underlying molecular mechanisms were explored using RNA sequencing, drug affinity responsive target stability (DARTS), molecular docking and small interfering RNA transfection. The antitumor effects of Sch B in vivo were evaluated using both a subcutaneous xenograft mouse model and an orthotopic genetically engineered mouse model. The in vitro studies showed that Sch B significantly inhibited the proliferation of PC cells and induced cell death in a dose‑dependent manner. Mechanistically, transcriptome Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that differentially expressed genes were significantly enriched in the 'ferroptosis' signaling pathway. Sch B triggered ferroptosis by promoting iron overload, lipid peroxidation and glutathione (GSH) depletion, as well as regulating the expression of ferroptosis‑related proteins [including GSH peroxidase 4, solute carrier family 3 member 2, acyl‑CoA synthetase long‑chain family member 4 (ACSL4), γ‑glutamyl‑cysteine ligase catalytic subunit and GSH synthetase]. Furthermore, pre‑treatment with the ferroptosis inhibitor ferrostatin‑1 partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. DARTS assays and molecular docking analyses confirmed the direct interaction between Sch B and ACSL4. Notably, silencing ACSL4 expression also partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. The in vivo studies demonstrated that Sch B suppressed tumor growth in subcutaneous xenograft models with good biosafety, and inhibited metastasis in orthotopic genetically engineered mice. In conclusion, Sch B may exert anti‑proliferative effects at least partially by inducing ACSL4‑dependent ferroptosis in PC.

Radiotherapy represents a cornerstone treatment modality in oncology and primarily mediates tumor cell death through the generation of reactive oxygen species (ROS). Nevertheless, elevated glutathione (GSH) levels within tumor cells can scavenge these ROS, thereby compromising the efficacy of radiotherapy and promoting the emergence of radioresistance. The contemporary understanding of redox regulation in cancer underscores the strategic relevance of targeting GSH metabolism in the context of radiotherapy. This review comprehensively describes the mechanisms through which GSH metabolism contributes to radioresistance and surveys novel therapeutic approaches aimed at inhibiting GSH synthesis or promoting its depletion to achieve radiosensitization. Both pharmacological compounds and nanotechnology‑enabled delivery systems have been investigated, with an emphasis on their ability to intensify oxidative stress in tumors characterized by high GSHcontent, thus potentially improving radiotherapeutic outcomes.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide, characterized by persistently high and increasing rates of incidence, recurrence and mortality, thereby posing a considerable global public health challenge. Within the complex molecular network driving the malignant progression of HNSCC, Dickkopf‑1 (DKK1), a classical secreted antagonist of the Wnt signaling pathway, has garnered considerable attention due to its pleiotropic roles in tumor initiation, progression and therapeutic resistance. The expression of DKK1 is regulated by a sophisticated network involving both canonical and non‑canonical Wnt pathways, and it exhibits high spatiotemporal specificity and context dependency. The present narrative review discusses the regulatory mechanisms underlying DKK1 expression, its prognostic significance in HNSCC, pro‑tumorigenic molecular mechanisms, immunomodulatory functions and its clinical translational potential as a biomarker and therapeutic target. The present review aims to provide novel insights into the pathogenesis of HNSCC and establish a theoretical foundation for advancing DKK1‑based precision diagnostics and therapeutic strategies.

Cancer‑associated fibroblasts (CAFs) in the tumor microenvironment (TME) are involved in tumor pathogenesis. Fibroblast activation protein (FAP)+ CAFs are the predominant CAF subtype across multiple cancer types, including breast, lung and pancreatic cancer. FAP+ CAFs are crucial contributors to tumor progression. However, incomplete understanding of the biology of FAP+ CAFs limits their potential for clinical application. The present review aimed to summarize the characteristic features, functions and underlying mechanisms of FAP+ CAFs in tumor growth, including their involvement in extracellular matrix organization, tumor expansion and immunomodulation within the TME, in which FAP plays an important role, and FAP+ CAF‑based strategies for tumor diagnosis and therapeutic intervention. The present study aimed to provide a conceptual framework for the multifaceted roles of FAP+ CAFs in cancer progression to guide development of optimized FAP+ CAF‑targeted diagnostics and therapies.

YY‑20394 (linperlisib), a highly specific PI3Kδ inhibitor, has demonstrated promising efficacy in a variety of hematological malignancies in clinical trials. ABT199 (venetoclax) as a monotherapy shows limited effects in acute myeloid leukemia (AML), underscoring the need for novel combinatorial therapeutic strategies. The drug sensitivity and potential synergistic effects of YY‑20394 and ABT199 were evaluated in three AML cell lines, MV‑4‑11, U937 and THP‑1, using a Cell Counting Kit‑8 assay. Apoptosis and cell cycle distribution were assessed using dual acridine orange/ethidium bromide staining and flow cytometry. Reverse transcription‑quantitative PCR and western blot analyses were employed to quantify the levels of Bcl‑2 apoptotic family members, c‑Myc, Akt and ERK. YY‑20394 inhibited the viability of MV‑4‑11, U937 and THP‑1 cells in a concentration‑dependent manner. In U937 cells, the highest IC50 value was observed, and YY‑20394 effectively suppressed their proliferation, induced apoptosis and caused cell cycle arrest. Furthermore, the combination of YY‑20394 and ABT199 demonstrated a synergistic effect in MV‑4‑11 cells, significantly enhancing apoptosis compared with either agent alone. Compared with the negative control group, the levels of c‑Myc and Akt phosphorylation were significantly reduced in the YY‑20394 group, and their inhibitory effects were retained in the combination group. ERK phosphorylation was significantly increased in the combination group. However, alterations in the Bcl‑2 pathways did not show a pattern consistent with the observed apoptotic phenotype. In summary, YY‑20394 is effective for inhibiting proliferation of AML cells, and its combination with ABT199 has synergistic pro‑apoptotic effects in MV‑4‑11 cells, which provides new insights and potential avenues for the treatment of AML and its subtypes. Further studies are warranted to explore the therapeutic efficacy and underlying molecular mechanisms of this combination in additional AML subtypes.

Cell culture is a common methodology used in tumor research. However, the manner in which initial tissue conditions, such as storage in the operating theatre, can affect proliferation has not been well‑established. Additionally, there is little information about the behavior of primary cell cultures in meningiomas. Therefore, the present study analyzed the physiology of primary meningioma cultures under different tissue conditions. For the present study, 10 meningioma tissue samples were collected after surgery at Saarland University (Homburg, Germany) between June 2022 and December 2022. Primary cell cultures were separately established on the day of surgery and 1 day later, before the tissues were stored overnight in nutrient solutions. Cultures were split into two flasks, one was used for fluorescence in situ hybridization (FISH), whereas the other was frozen in liquid nitrogen. After 6 months, frozen cultures were thawed and recultivated. The proliferation rates were found to be ≥80% for cell cultures as a minimum. No significant difference was found between cultures established on the surgery day or postoperative day 1 in terms of proliferation rate and growth pattern. FISH revealed loss of the short arm of chromosome 1 (1p) in one meningioma, loss of the long arm of chromosome 22 (22q) in three samples, combined 1p and 22q loss in three samples, and diploid chromosome sets in three samples. In total, 16 out of 17 initially shock‑frozen specimens were successfully recultivated after 6 months of cryopreservation. To conclude, meningioma cultures appeared to proliferate similarly regardless of whether the tissue was processed on the day of surgery or the following day, if viable cells were present. Frozen cultures could be revived after 6 months if cells remained viable. FISH provided evidence that primary meningioma cultures accurately reflected initial chromosomal aberrations of the tumor, even after freezing.

The concept of ferroptosis debuted as a newly defined programmed cell death in 2012. Among programmed cell death mechanisms, ferroptosis stands out as being fundamentally dependent on iron. At the heart of this mechanism lies the progressive accumulation of lipid peroxides - a chain reaction propelled by available iron, terminating when intracellular levels become fatally toxic. Inhibition of cystine transporters within cells (notably induced by compounds like Erastin) initiates a chain reaction: when intracellular levels of glutathione (GSH) become depleted, downstream suppression of glutathione peroxidase 4 (GPX4) activity impedes lipid peroxide clearance, whose accumulation drives the cell toward death upon exceeding a critical concentration.

Background Ovarian cancer is globally third most common cancer in women. The incidence of a symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1000 which increases to 3:1000 at the age of 50. Objective To compare the diagnostic accuracy of International Ovarian Tumor Analysis (IOTA) simple rules and risk of malignancy index (RMI) IV scoring to differentiate between benign and malignant adnexal masses pre-operatively. Method An observational analytical study carried out to compare two cancer prediction tools among the ovarian tumor patients undergoing surgery in the Department of Obstetrics and Gynecology at Nobel Medical College, Biratnagar in the year 2024 and 2025. The diagnostic accuracy of risk of malignancy index IV and international ovarian tumor analysis SR was compared using SPSS version 16. Histopathology was the gold standard for the final diagnosis. Ethical approval was taken from institution review committee. Result Out of total 52 cases, 20 cases were classified as malignant tumors by international ovarian tumor analysis simple rules that was confirmed by histopathology in only 17 cases. 32 cases predicted by international ovarian tumor analysis SR was confirmed to be benign in 31 cases reporting Sensitivity of international ovarian tumor analysis SR to be 94.4%, specificity of 94.2%, Positive predictive value of 89.5%, negative predictive value of 96.9% and Diagnostic accuracy of 94.23%. On calculation of risk of malignancy index IV and comparing it with the histopathology report, sensitivity of 88%, specificity of 91.2%, positive predictive value of 84.2%, negative predictive value of 94% and diagnostic accuracy of 90.38%. The risk of malignancy index IV showed the highest Area Under Curve (AUC) of 0.936 followed by CA 125 of 0.783 area under curve and size of tumor demonstrated area under curve of 0.662 in the present study. International ovarian tumor analysis had better diagnostic performance than risk of malignancy index IV (chi squared test 36.45 vs 32.53). Conclusion Diagnostic performance of international ovarian tumor analysis SR is relatively better for prediction of adnexal mass in comparison to risk of malignancy index IV.

Background Pancreatobiliary malignancies (PBM) are often diagnosed at an advanced stage, leading to poor outcomes. Studies on the clinical profile and diagnostic efficacy in research limited settings like Nepal are scarce. Objective To describe the clinico-demographic profile characteristic and evaluate the diagnostic yield of endoscopic techniques in-patient with suspected pancreatobiliary malignancy undergoing Endoscopic Retrograde Cholangiopancreatography. Method A retrospective, cross-sectional study was conducted at the endoscopy unit of a tertiary care center of Nepal from January 2017 to January 2023. We included 597 Patients over 18 years of age with suspected pancreatobiliary malignancy who underwent endoscopic retrograde cholangiopancreatography. Data on demographics, clinical presentation and diagnostic results (brush cytology and intraductal biopsy) were analyzed using descriptive statistics. Result Among 597 patients, the majority of patients (70.1%, n=419) were aged 50 years or older, with the highest proportion found in the 60-69 year age group. Significant cases were from the hilly region (52.9%) and Brahmin/Chhetri ethnic group (35.51%). In this study 52.4% were male and the most common presenting symptoms were obstructive jaundice (42.4%), abdominal pain (37.7%), and pruritus (22.8%). Endoscopic retrograde cholangiopancreatography was technically successful for biliary drainage in 93.6% (559/597), primarily using plastic stent (77.4%). Endoscopic retrograde cholangiopancreatography guided tissue diagnosis was done in 57.1% of patients (n=341) to establish histological diagnosis. The most frequent Endoscopic retrograde cholangiopancreatography finding was a distal common bile duct stricture (52.8%). Conclusion The diagnostic yield of Endoscopic retrograde cholangiopancreatography -guided tissue sampling remains suboptimal with biopsy proving superior to cytology. In a resource-constrained setting like Nepal, while considering the cost-effective and most sensitive diagnostic tool for pancreatobiliary malignancy, the preferred sequence for diagnostic tools is sonography, followed by CT scan for initial triage, and then Endoscopic retrograde cholangiopancreatography with brush and/or biopsy with drainage.

Background Breast-conserving surgery with radiation therapy is the standard approach for early breast cancer. It provides much better cosmetic effects as well as the same level of overall survival as compared to a mastectomy. Despite strong global evidence supporting breast-conserving surgery, it is less preferred in Nepal, and its outcome in the Nepali context is poorly documented. Objective To assess the oncological outcomes of breast-conserving surgery at a tertiary cancer centre in Nepal. Method This hospital-based retrospective cohort study was done in Bhaktapur Cancer Hospital, Nepal, from 2012 to 2018. All the breast cancer patients who underwent breast-conserving surgery were included in the study and were followed up for at least 5 years postoperatively till 2024 with clinical examination and radiological investigations. The statistical analysis was done using SPSS version 22. The measurement data with a normal distribution were expressed as the mean ± standard deviation. Result The study included 100 patients, with a median age of 43 years (range 25-73 years), and a mean tumor size of 26.34 ± 8.6 mm. The mean hospital stay was 3.9 ± 1.08 days, and 94% patients had no complications. Histologically, invasive carcinoma of no special type was the most common. Five-year disease-free survival and five-year overall survival rate were 96% and 97% respectively. Conclusion Our study concluded that Breast Conserving Surgery has a shorter hospital stay, fewer complications, and good oncological outcomes, so it is a simple and feasible technique for patients with early breast cancer.

Pancreatic adenocarcinoma is a highly aggressive cancer with very limited treatment options. This study aimed to optimize the efficacy of a previously developed tumor immunotherapy for the treatment of this disease and its recurrences.