This review highlights the major unmet needs in diagnosis and treatment of digestive neuroendocrine carcinomas (NEC) and describes the current and evolving evidence on these aspects.

Improved pathological criteria are needed to accurately diagnose NEC and distinguish this entity from high-grade well-differentiated neuroendocrine tumours as well as from adenocarcinoma. Studies on the molecular mechanisms underlying the extreme aggressiveness of the disease are ongoing. Data are lacking on optimal selection of patients with locoregional disease for primary tumour surgery and use of adjuvant or neoadjuvant treatment. For patients with metastatic disease, there has been no improvement in systemic treatment over the last two decades and immunotherapy has limited benefit. Novel antigen-directed strategies targeting DLL3 are evolving. Digestive NEC are among the most aggressive cancers and prognosis remains poor. There have been only minor improvements over the last two decades. To improve diagnosis and therapy, the unmet needs discussed in this review must be addressed.

Castration-resistant prostate cancer (CRPC) represents a lethal stage of prostate cancer that emerges following sustained androgen deprivation therapy (ADT) and remains a major clinical challenge in the era of androgen receptor (AR)-targeted therapies. Although AR reactivation and lineage plasticity are recognized as central mechanisms of resistance, these tumor-intrinsic processes alone cannot fully explain the profound heterogeneity and therapeutic failure observed during CRPC evolution. Here, integrating recent advances in single-cell and spatial profiling, we propose a unified framework in which CRPC is viewed as an adaptive tumor ecosystem shaped by evolutionary selection, cellular plasticity, and microenvironmental co-evolution under therapeutic pressure. ADT not only selects pre-existing resistant populations but also induces cellular reprogramming, expanding tumor state diversity and adaptive capacity. Concurrently, the tumor microenvironment is extensively remodeled to support and stabilize therapy-adapted states. Immune compartments evolve toward myeloid-dominant immunosuppressive configurations characterized by T cell dysfunction and exclusion, whereas cancer-associated fibroblasts (CAFs) promote tumor persistence through stromal remodeling, metabolic coupling, and alternative steroidogenic pathways. Neural remodeling represents an additional regulatory layer that enhances cellular plasticity, stress adaptation, and neuroendocrine differentiation. Together, these alterations establish a multicompartmental and self-reinforcing tumor-microenvironment network that sustains adaptation during AR suppression. This ecosystem framework further extends beyond the primary tumor to distal niches, including bone metastases and the gut microbiome, where tumor-osteoblast-osteoclast interactions and microbial regulation of androgen metabolism and immunity contribute to therapeutic adaptation. By integrating tumor evolution with immune, stromal, neural, and distal ecosystem remodeling, this perspective provides a system-level framework for understanding CRPC progression and highlights therapeutic strategies aimed at reprogramming or destabilizing adaptive tumor ecosystems rather than targeting individual resistance pathways alone.

AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as an innovative and highly effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). This effect is based on redirecting modified T-cells towards plasma cells expressing target antigens, specifically B cell maturation antigen (BCMA). Despite high initial response rates, disease relapse remains a major clinical challenge. Therapeutic options after progression following prior BCMA-directed CAR T-cell therapy are limited, and prognosis is often poor. We report on a 58-year-old male with high-risk IgA kappa multiple myeloma who was heavily pretreated and received idecabtagene vicleucel as sixth-line therapy, achieving a deep response lasting for approximately one year. Following disease progression, the patient received bridging therapy with mezigdomide,carfilzomib, and dexamethasone, followed by a second BCMA-directed CAR T-cell infusion using ciltacabtagene autoleucel. Previous whole genome sequencing had confirmed preserved BCMA expression.Early post-infusion assessment showed a rapid and profound response, with marked declines in serum IgA and free kappa light chains, accompanied by robust CAR T-cell expansion. Treatment-related toxicities were manageable, including grade II cytokine release syndrome and prolonged cytopenias, without evidence of neurotoxicity.This case provides additional knowledge that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly after a durable response to initial CAR T-cell therapy. Bridging therapy and the use of an alternative CAR T-cell construct may further improve outcomes. Prospective studies are needed to define optimal patient selection and treatment sequencing in this setting.

Lung cancer is the most frequently diagnosed malignancy worldwide in recent decades, representing the leading cause of cancer-related mortality globally. Lung cancer is mainly divided into two types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC being the most common, representing about 85% of cases. NSCLC is increasingly recognized to harbor various druggable genetic alterations; among them, activating BRAF mutations are found in approximately 3-4% of NSCLC patients. The objective of this review is to provide a comprehensive overview of the key biological and pathophysiological characteristics of BRAF molecular alterations, their impact on clinical practice, and emerging insights from translational research.

We performed a search of the PubMed database on April 22, 2026. A review of retrieved literature related to BRAF mutations and their clinical implications in NSCLC was completed. The Catalogue of Somatic Mutation in Cancer (COSMIC) database and the NCCN-NSCLC Guidelines were evaluated.

Functional classification of BRAF genetic alterations, molecular assays for detection of BRAF gene mutation, advancements of targeted therapies and immunotherapy for BRAF‑mutant NSCLC, and treatment resistance mechanisms were described. Several ongoing studies currently evaluating novel agents with broader biological activity and various drug combinations were reported. Emerging strategies-including next-generation MAPK inhibitors, ADCs, and engineered cellular therapies-were discussed, offering promising avenues to enhance efficacy, overcome resistance, and expand therapeutic options for these patients.

Despite limited clinical data, particularly in first line and neoadjuvant settings, remain major challenges, addressing critical questions will be useful to optimize the management of BRAF-mutant NSCLC.

To develop and externally validate a model combining contrast-enhanced ultrasound (CEUS), clinical, and laboratory features to identify adverse pathology in clinically localized clear cell renal cell carcinoma (ccRCC).

This retrospective study included 370 surgically treated patients with cT1-T2 ccRCC. Center 1 patients were randomly split into training (n = 210) and internal test (n = 91) sets; Center 2 provided external validation (n = 69). Adverse pathology comprised WHO/ISUP grade 3-4, tumor necrosis, invasion, or nodal metastasis. Two blinded readers assessed images. All 41 preoperative candidates entered logistic least absolute shrinkage and selection operator regression with stratified ten-fold cross-validation and the one-standard-error rule. Internal validation used 200 bootstrap resamples of the complete modeling procedure.

Adverse pathology was present in 138 patients. Seven predictors were retained, including four CEUS features. Areas under the receiver operating characteristic curve (AUCs) were 0.810 (95% CI, 0.752-0.868), 0.875 (0.805-0.944), and 0.799 (0.688-0.910) in the training, internal test, and external cohorts, respectively; optimism-corrected training AUC was 0.747. External predictions were compressed (calibration slope, 2.380). At the training-derived threshold of 0.3051, adverse pathology was present in 61.5% (24/39) of external patients with positive results and 6.7% (2/30) with negative results, compared with 37.7% overall.

The model showed moderate external discrimination and may support preoperative assessment by identifying patients at lower risk. Prospective multicenter studies are needed to validate individual risk estimates and assess clinical impact.

Testicular tumors are relatively rare, yet represent one of the most common solid neoplasms in young adult males. They are a heterogeneous group of neoplasms with distinct biological behaviors and can be diagnostically challenging due to their relative unfamiliarity. The vast majority are of germ cell origin [testicular germ cell tumors (TGCTs)], predominantly arising from the precursor lesion, germ cell neoplasia in situ (GCNIS), and are broadly classified as seminomas or nonseminomas. TGCTs are highly curable, with efforts focused on reducing treatment intensity. The second most common group of testicular neoplasms is sex cord-stromal tumors (SCSTs). These usually follow a benign clinical course, but 5% to 10% are malignant and metastasize. In contrast to TGCTs, SCSTs are largely unresponsive to chemotherapy and radiotherapy; therefore, surgical resection, such as early retroperitoneal lymph-node dissection, may be the only effective treatment. Accurate tumor classification, staging, and risk stratification of TGCTs and SCSTs have a profound effect on patient care and rely on a thorough histopathologic examination, from macroscopic evaluation to microscopic assessment. In this review, we summarize the clinicopathological features most relevant and robust for the prognostication of patients with testicular tumors, with a focus on practical guidance on reporting and the avoidance of diagnostic pitfalls. Recent molecular insights that refine classification and predict clinical outcomes are also discussed.

We compared the superficial circumflex iliac artery perforator (SCIP) flap with the radial forearm flap (RFF) to identify limitations restricting its widespread use.

We retrospectively evaluated unilateral tongue reconstruction using propensity score matching for age, sex, T stage, body mass index, and Charlson comorbidity index from a nonfunctional perspective.

Matching 118 patients yielded 27 pairs. Flap survival was comparable. SCIP improved donor-site aesthetics (92.6% vs. 40.7%), preserved strength (100.0% vs. 66.7%), and shortened hospitalization (10.9 vs. 11.9 days). Overall recipient-site and flap-related complications were significantly higher (33.3% vs. 3.7%), driven by Grades I-II events (25.9% vs. 0%). No individual complication category differed significantly. SCIP had a shorter pedicle, more tracheotomies, and greater superior thyroid artery use. Before matching, salvage failed in 5/5 SCIP versus 2/5 RFF cases, an exploratory finding.

SCIP improves donor-site outcomes, but more low-grade complications and vessel considerations may limit widespread adoption.

Inflammatory rhabdomyoblastic tumor (IRMT) is a newly defined subtype of skeletal muscle neoplasm with uncertain malignant potential. Herein, we present a series of 22 IRMT cases to further expand its clinical and pathologic spectrum. This cohort enrolled 20 males and 2 females, with a median age of 42 years (range: 18 to 60 y). The tumors were predominantly located in the deep soft tissues of the lower extremity (n=11, 50%), followed by the trunk (n=4, 18.2%), head and neck region (n=3, 13.6%), upper extremity (n=2, 9%), and abdomen/retroperitoneum (n=2, 9%). Most patients presented with a slowly growing, deeply seated soft tissue mass, with a median diameter of 6 cm (range: 3 to 23 cm). Histologically, 12 cases (54.5%) showed a spindled to pleomorphic morphology, 7 cases (32%) exhibited a monomorphic spindled morphology, and 3 cases (13.6%) displayed a spindled to epithelioid phenotype. All lesions were characterized by dense inflammatory and histiocytic infiltrates. Focal calcification, cholesterol clefts, and histiocytic necrosis were noted in a subset of cases. Three cases demonstrated progression to rhabdomyosarcoma. Immunohistochemically, all tumors exhibited diffuse and strong desmin expression, with variable MyoD1 immunoreactivity and limited myogenin staining. Molecular analysis identified somatic mutations in NF1 (n=4), TP53 (n=2), and KRAS (n=1) genes among the tested cases. With a median follow-up of 17.5 months (range: 3 to 77 mo) in 22 patients, 2 cases with rhabdomyosarcomatous transformation developed lung metastases, whereas the remaining patients remained disease-free following complete surgical resection. Our study further validates IRMT as a distinct myogenic neoplasm with an indolent behavior. Correlation of clinical manifestations and morphologic features with ancillary studies is essential to avoid overdiagnosing IRMT as a high-grade rhabdomyosarcoma.

Clear cell sarcoma (CCS) is a rare soft tissue neoplasm characterized by melanocytic differentiation and recurrent EWSR1 rearrangements. Owing to its overlapping morphology and immunophenotype with malignant melanoma (MM), distinction between these entities can be challenging, particularly in small biopsies or metastatic settings. Preferentially Expressed Antigen in Melanoma (PRAME) has emerged as a valuable marker in melanocytic pathology; however, its utility in CCS remains to be fully elucidated. We conducted a retrospective analysis of 26 CCS cases from 2 sarcoma referral centers, assessing PRAME immunohistochemistry (IHC) alongside a validation cohort of 120 cutaneous melanomas. Clinicopathologic features, EWSR1 rearrangement status, and survival data were reviewed. The patient cohort (65.4% female) had a mean age of 36.1±15.4 years, with most tumors arising in the extremities. The mean tumor diameter was 4.9±2.8 cm. PRAME was negative in 25/26 (96.2%) CCS cases, with only one case showing focal weak staining. Nineteen CCS cases demonstrated EWSR1 gene rearrangement on molecular analysis. In contrast, PRAME was positive in 110/120 melanomas (91.7%), displaying diffuse (80%) or focal (11.7%) staining. Our findings indicate that PRAME is almost uniformly absent in CCS, in sharp contrast to its strong and prevalent expression in melanoma. PRAME immunohistochemistry may therefore serve as a useful and cost-effective adjunct in the differential diagnosis of melanocytic soft tissue tumors. In an appropriate morphologic and clinical context, the absence of PRAME expression supports a diagnosis of CCS over melanoma, particularly when molecular confirmation of EWSR1 rearrangement is unavailable or inconclusive.

Pericardial decompression syndrome (PDS) is an uncommon but potentially fatal complication that can follow technically successful drainage of a hemodynamically significant pericardial effusion. A 61-year-old woman with stage IVB lung adenocarcinoma presented with progressive dyspnea and edema. Computed tomography and transthoracic echocardiography demonstrated a large pericardial effusion with right ventricular diastolic collapse and preserved left ventricular ejection fraction (LVEF) of 65% to 70%. Emergent echo-guided pericardiocentesis removed 360 to 380 mL of serosanguineous fluid, followed by catheter drainage totaling approximately 1.51 L. The next morning, echocardiography showed new severe biventricular systolic dysfunction with basal sparing and only trivial residual effusion. High-sensitivity troponin remained 10 ng/L or less without a meaningful rise. The clinical course was managed supportively with close hemodynamic and echocardiographic surveillance, cautious diuresis, and low-dose guideline-directed therapy as tolerated. LVEF improved from a nadir of 15% to 20% to 50% to 55% at follow-up, with resolution of the wall-motion abnormality and no recurrent effusion. The temporal association with large-volume drainage, absence of recurrent pericardial constraint, low troponin, and reversible dysfunction supported PDS. New heart failure after malignant pericardial effusion drainage should prompt urgent evaluation for PDS.