Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy worldwide, associated with poor prognosis. Most patients are diagnosed at an advanced stage, where conventional chemotherapy offers limited therapeutic efficacy and is often accompanied by substantial toxicity. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting PD-(L)1 and CTLA-4, have emerged as cornerstone therapies in both first-line and subsequent treatment settings for advanced ESCC. Nevertheless, significant clinical challenges persist, including the complexity of mechanisms underlying immune resistance, suboptimal predictive performance of existing biomarkers, difficulties in the management of immune-related adverse events (irAEs), and underrepresentation of elderly patients in clinical trials. This review summarizes recent advances in immunotherapy for advanced ESCC, evaluating the clinical evidence supporting ICIs as monotherapy or in combination with agents such as anti-angiogenic drugs and tyrosine kinase inhibitors. It further discusses the therapeutic potential of novel approaches, including bispecific antibodies, CAR-T cell therapy, and next-generation ICIs, while addressing current treatment paradigms for elderly patients. The importance of comprehensive, longitudinal management of irAEs is emphasized. Additionally, this article provides an in-depth analysis of mechanisms contributing to immune resistance-such as loss of tumor neoantigens and dysregulation of key signaling pathways-and critically appraises the limitations of established biomarkers, including PD-L1 expression and tumor mutational burden (TMB), alongside emerging developments in biomarker discovery. In conclusion, while immunotherapy has significantly improved outcomes and expanded therapeutic prospects for patients with advanced ESCC, further research is required to elucidate resistance mechanisms, refine treatment strategies, and identify robust predictive biomarkers. These efforts are essential to advance precision medicine in ESCC and ultimately enhance long-term survival outcomes.

Immune checkpoint-targeted immunotherapy has achieved unprecedented success, yet its limitations remain evident. Human leukocyte antigen-G (HLA-G), a novel immune checkpoint, exhibits restricted physiologic expression but is broadly expressed in various tumors, conferring systemic immune suppressive functions via different types of immune inhibitory receptors, and is associated with a poor prognosis for patients with cancer, making it an attractive tumor-site-agnostic candidate target for cancer immunotherapy. Since 2020, clinical trials employing different strategies of HLA-G-targeted immunotherapy for various advanced solid cancers have been conducted. Herein, the molecular characteristics of HLA-G, HLA-G-receptor binding interactions, and HLA-G-targeted preclinical investigations and clinical trials for solid cancer immunotherapy are highlighted, and the challenges associated with translating these findings into clinical settings are also discussed.

Pancreatic ductal adenocarcinoma (PDAC) is regarded as one of the most lethal malignancies, characterized by a poor prognosis and significant resistance to conventional treatments. Although Chimeric Antigen Receptor (CAR)-T cell therapy has been considered to be a revolutionary treatment for B-cell malignancies, its efficacy against solid tumors, including PDAC, has been limited. Nevertheless, after numerous tests pre-clinically and clinically, the acceptance of the first New Drug Application (NDA) for a CAR-T therapy in a solid tumor has sparked considerable hope and interest, which could further accelerate the field. Unlocking the full potential of CAR-T in PDAC requires overcoming significant hurdles, primarily the lack of ideal tumor-specific antigens and the profoundly immunosuppressive tumor microenvironment (TME). Given the shared expression of tumor-associated antigens (TAAs) across diverse solid tumors, this review analyzes promising solid tumor targets to identify candidates with high translational viability for PDAC. We summarize the latest clinical progress of CAR-T cell therapy, highlight emerging therapeutic targets, and explore innovative engineering strategies for developing potent, multi-targeted CAR constructs that are advancing toward future clinical application.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma (CTCL). Due to its rarity and marked biological heterogeneity, SS diagnosis is frequently delayed, as it requires the integration of multiple complex diagnostic tests interpreted by highly specialized biomedical figures. In this context, we investigated the expression of CXCL13-increasingly implicated in several inflammatory and neoplastic skin disorders-as a potential screening biomarker to discriminate SS from mycosis fungoides (MF), the most common CTCL subtype, and from clinically overlapping inflammatory skin diseases, i.e. atopic dermatitis (AD), psoriasis (PS) and eczema (EC). Real-time PCR analysis of CXCL13 mRNA expression in 51 samples showed a significant upregulation in peripheral blood mononuclear cells (PBMCs) from SS patients compared with MF, AD and healthy donors (HD). Protein-level analysis in a larger cohort (n = 142), including allergic and atopic EC patients, revealed significantly higher plasma CXCL13 concentrations in SS than in all other conditions and HD, as assessed by ELISA. Receiver operating characteristic (ROC) analysis confirmed the excellent performance of plasma CXCL13 as a differential marker (AUC = 93%). In contrast, CXCL13 immunohistochemical expression in skin biopsies was broadly detected across all conditions, limiting its diagnostic value. In conclusion, quantification of CXCL13 expression in PBMCs and, more robustly, measurement of its plasma levels by widely available techniques such as RT-qPCR and ELISA may represent practical screening tools to identify patients with suspected SS. These assays could facilitate earlier referral to specialized centres for confirmatory testing and prompt initiation of appropriate therapy.

Interleukin-15 (IL-15) has emerged as a central cytokine for next-generation cancer immunotherapy because of its unique ability to sustain the survival, proliferation, and cytotoxic function of memory CD8⁺ T cells and natural killer (NK) cells without promoting the expansion of regulatory T cells (Treg). These properties make IL-15 particularly attractive for achieving durable antitumor immunity, especially in solid tumors where immune persistence remains a major limitation. Although IL-15 shares the same signal-transducing receptor subunits (IL-2Rβ and the common γ chain) with interleukin-2 (IL-2), the two cytokines drive fundamentally different CD8⁺ T-cell fates, a distinction that underlies their markedly divergent therapeutic profiles in cancer immunotherapy. In recent years, multiple IL-15-based therapeutic strategies including recombinant IL-15, and IL-15 immunocytokines have entered clinical evaluation, demonstrating potent immune activation with manageable toxicity profiles. Recent clinical progress includes the FDA approval of Nogapendekin alfa inbakicept (N-803), the first IL-15-based immunotherapy approved for cancer treatment, alongside the advancement of other IL-15 superagonists into Phase II trials and growing evidence that IL-15 can enhance the efficacy of immune checkpoint blockade and engineered adoptive cell therapies such as CAR-T cells, CAR-NK cells, γδ T cells, and invariant NKT cells. Despite these advances, important challenges remain, including cytokine-associated toxicities, optimal delivery strategies, and the immunosuppressive tumor microenvironment. This review summarizes recent progress in IL-15-based cancer immunotherapy, integrates emerging insights into IL-2Rβγ-driven CD8⁺ T-cell fate decisions, and discusses key opportunities and challenges for translating IL-15-mediated immune enhancement into durable clinical benefit.

We report a 36-year-old male with pheochromocytoma presenting solely as progressive bilateral lower limb necrosis for 24 years, lacking classic symptoms (hypertension, headache, palpitations). Misdiagnosed as allergic vasculitis, he developed atrophic scars and toe necrosis despite immunosuppression. Elevated catecholamines and a 4.8 cm adrenal mass confirmed the diagnosis. Postoperatively, ulcers healed, but toe amputation was needed. This case highlights diagnostic pitfalls of atypical pheochromocytoma, emphasizing dynamic biomarker monitoring for early detection.

Gynecomastia is a relatively common condition arising from disproportionate concentrations of estrogen and androgen. Most cases of bilateral gynecomastia in men are idiopathic or drug-induced but can rarely arise secondary to malignancy. We present the case of a 57-year-old male who presented with new-onset gynecomastia and recurrent episodes of hematuria. Laboratory testing revealed elevated estradiol, free testosterone, and β-human chorionic gonadotropin (β-hCG) with suppressed luteinizing hormone (LH) and follicle stimulating hormone (FSH), concerning for ectopic β-hCG secretion. Mammography, breast and testicular ultrasonography, and chest computed tomography demonstrated no evidence of breast, testicular, or lung malignancy. Concurrent evaluation of hematuria with cystoscopy identified a 6-cm tumor on the posterior bladder wall. The patient underwent transurethral resection of the bladder tumor and was diagnosed with papillary high-grade T1 urothelial carcinoma. The β-hCG immunohistochemical staining of the tumor was positive, and the patient's β-hCG level was undetectable 1 month postoperatively. A review of the literature revealed there are only a few reports detailing urothelial carcinomas capable of secreting β-hCG. To the best of our knowledge, this is the first case of a β-hCG-secreting papillary T1 urothelial carcinoma initially presenting as gynecomastia.

We report a case of seizure-associated transient early venous visualization (EVV) on cerebral angiography in a patient with glioblastoma mimicking arteriovenous shunting pathology.

A 48-year-old woman presented with new-onset generalized tonic-clonic seizures. Brain MRI revealed a poorly demarcated, non-enhancing lesion in the left temporal lobe. Arterial spin labeling (ASL) demonstrated marked hyperperfusion within the lesion and adjacent venous sinuses. Cerebral angiography performed approximately 2 h following seizure cessation showed posterior temporal artery dilation and an EVV pattern, with shunting into the vein of Labbé and the ipsilateral transverse and sigmoid sinuses; this raises suspicion for an arteriovenous shunting lesion. No definitive arteriovenous fistulae or thromboses were identified. The patient was managed with antiepileptic therapy alone, which led to clinical improvement. Follow-up MRI and angiography 2 weeks later revealed complete resolution of ASL hyperperfusion and the EVV pattern. Subsequent histopathological examination of the resected tumor confirmed isocitrate dehydrogenase (IDH)-wild-type small cell glioblastoma. Despite the underlying malignant tumor and persistent seizure susceptibility, the angiographic abnormalities and altered venous drainage were entirely reversible and seizure-induced, rather than structurally pathological.

This case illustrates that ictal or postictal cerebral hyperperfusion can produce transient EVV on cerebral angiography, even with aggressive neoplasms such as glioblastoma. Recognizing this phenomenon is essential to avoid misdiagnosing a true arteriovenous shunting lesion, thereby preventing unnecessary intervention procedures and guiding appropriate management. When interpreting angiographic abnormalities observed shortly after seizures, integration of perfusion-based MRI findings with the temporal evolution of symptoms is crucial.

Neuroendocrine tumors (NETs) or carcinoid tumors are rare neoplasms originating from neuroendocrine cells, most commonly found in the appendix. While NETs are often asymptomatic, they may present with abdominal pain, flushing, and diarrhea and are frequently discovered incidentally during surgery for other conditions. Endometriosis has been associated with an increased risk of certain malignancies; however, its relationship with NETs remains unclear. Given the high frequency of laparoscopic surgeries for endometriosis, incidental NET findings pose unique clinical challenges.

This retrospective case report was conducted at Avicenna Fertility Center, Affiliated to Avicenna Research Institute, Tehran, Iran, from 2016 to 2024. Medical records of six patients (33-55 years old) who underwent laparoscopic surgery for endometriosis, with incidental NETs found in the appendix, were analyzed. Clinical presentation, intraoperative findings, histopathology, and postoperative outcomes were reviewed.

Six women (mean age: 43.7 years) with endometriosis-related symptoms (dysmenorrhea, dyspareunia, and pelvic pain) underwent laparoscopic surgery with appendectomy. The NETs (2-9 mm, all G1, Ki-67 <3%) exhibited invasion into the muscularis propria in three cases and into the subserosal fat in one case; lymph nodes were not evaluated, and no metastases were detected. Immunohistochemistry confirmed neuroendocrine differentiation, with positive chromogranin and synaptophysin staining. Follow-up over 1-5 years showed no evidence of recurrence.

Incidental NET detection during endometriosis surgery highlights the need for routine pathological examination of appendectomy specimens. While no direct link exists between NETs and endometriosis, recognizing these tumors may influence surgical decisions and postoperative management, emphasizing the importance of multidisciplinary care.

In elderly patients, a smooth concentric esophageal stricture with normal mucosa should raise suspicion of extraesophageal causes, prompting cross-sectional imaging such as computed tomography. Dysphagia may rarely be the initial symptom of lung cancer, and esophageal stenting offers rapid, effective palliation, restoring oral intake, and improving quality of life.