Key lymphoma-focused themes at the annual meeting of the American Society of Hematology held in December 2025 (ASH2025) in Orlando, Florida, centered on pioneering concepts for vulnerable patient populations, including T‑cell-directed therapies, reduced chemotherapy, and the rising use of targeted therapeutics. The 5‑year follow-up of the pivotal POLARIX trial comparing R‑CHOP vs. polatuzumab(Pola)-R-CHP as first-line treatment (1L) in a higher-risk (International Prognostic Index ≥ 2) diffuse large B‑cell lymphoma (DLBCL) population confirmed superior progression-free survival (PFS) without statistically significant differences in overall survival (OS) in favor of Pola-R-CHP. Analyses of defined molecular subtypes highlighted a significant PFS benefit with the anti-CD79 antibody–drug conjugate (ADC) in the MCD subgroup. Bispecific antibodies (BsAb)—with glofitamab in combination with chemotherapy already approved in second-line treatment (2L) and glofitamab and epcoritamab monotherapy in 3L—are now being tested in 1L combinations, among them odronextamab plus CHOP (Olympia-3), epcoritamab plus Pola-R-CHP (EPCORE NHL-5), or glofitamab in combination with R‑CHOP or Pola-R-CHP (COALITION). Older/unfit patients with DLBCL might be particularly suitable for BsAb-containing combinations, such as the chemo-light combination of glofitamab plus Pola and rituximab (R-Pola-Glo), or epcoritamab plus rituximab (R)-mini-CHOP (dose-reduced cyclophosphamide, vincristine, doxorubicin and prednisone; EPCORE NHL-2). The 3‑year follow-up data from the STARGLO trial (gemcitabine/oxaliplatin ± glofitamab) in transplant-ineligible relapsed/refractory DLBCL patients (≥ 2L) underscored the durability of responses, in cases where complete response (CR) was achieved. In follicular lymphoma (FL), adding epcoritamab to rituximab plus lenalidomide (R2), the current standard of care (SOC) in 2L, produced impressive results, albeit limited by some additional toxicity, thus underlining the need for careful patient selection, close monitoring, and the use of anti-infective prophylaxis. Several chemo-free 1L strategies for patients with mantle cell lymphoma (MCL) were presented and showed encouraging results in terms of safety and efficacy including for high-risk cases (e.g., with a p53 mutated or blastoid variance). Specifically, they combined the second-generation BTK inhibitor (BTKi) acalabrutinib with the Bcl2 inhibitor venetoclax and rituximab (TrAVeRse), the BTKi zanubrutinib in combination with venetoclax and obinutuzumab (BOVen), or glofitamab plus lenalidomide and obinutuzumab (GLOVe). In essence, ASH2025 provided important data for further optimization of regimens including BsAb, targeted therapeutics, and reduced chemotherapy, especially in high-risk and older or unfit patients with lymphoma.
The treatment of multiple myeloma (MM) has been (r)evolutionized by the approval of 20 new agents and more than 30 new regimens over the past two decades, with population-based data indicating that the 5‑year relative survival rate now approaches 64
The management of hepatobiliary malignancies has undergone a profound transformation, shifting from an empiric, uniform systemic approach to an increasingly stratified paradigm of precision oncology. Advances in molecular characterization, particularly through next-generation sequencing (NGS), have identified actionable alterations in a clinically relevant proportion of patients with cholangiocarcinoma (CCC) and are increasingly informing biomarker-driven treatment strategies in hepatocellular carcinoma (HCC). This review summarizes current clinical standards in molecular diagnostics, with a focus on FGFR2 testing, the implications of CTNNB1 mutations for the immune microenvironment, and the emerging role of liquid biopsy in monitoring clonal evolution and therapeutic resistance.
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a rare inflammatory disease that manifests as a paraneoplastic manifestation of malignant tumors. Although its association with non-small cell lung cancer (NSCLC) is rare, vascular endothelial growth factor (VEGF)-A has been suggested to be involved in the pathogenesis. Cases with pleural and pericardial effusions are even rarer, and differentiation from metastasis of malignant tumors is important. A 51-year-old Asian man presented with fever, bilateral edema, tenosynovitis, pleural effusion, and pericardial effusion. Cytology of both effusions was negative for malignant cells, but mediastinal lymph node biopsy revealed adenocarcinoma. He was diagnosed with RS3PE syndrome associated with NSCLC. Oral prednisolone and chemoradiotherapy improved the edema and effusions. Serum VEGF‑A measured after clinical improvement was lower than that observed at recurrence. After curative resection of synchronous double primary lung cancers (adenocarcinoma and squamous cell carcinoma) and adjuvant chemotherapy, central nervous system metastases developed 10 months later. This recurrence was accompanied by elevated serum and cerebrospinal fluid VEGF‑A levels and recurrence of RS3PE symptoms. Immunohistochemical analysis showed strong VEGF‑A expression in pretreatment tumor tissue, which decreased after treatment. This case suggests that VEGF‑A may have contributed to paraneoplastic RS3PE syndrome in NSCLC. The association among the available VEGF‑A measurements, RS3PE activity, and cancer progression suggests that VEGF‑A may serve as a potential disease activity biomarker in selected patients. This case also highlights the importance of recognizing RS3PE syndrome as a paraneoplastic process and carefully evaluating pleuropericardial effusions and thrombotic complications in complex oncological patients.
To briefly review the current status of prostate-specific membrane antigen (PSMA) theranostics. A literature search was conducted from 2020 to 2026 for systematic reviews addressing both diagnostic and therapeutic PSMA use in vivo in prostate cancer, excluding original works, case reports, and abstracts. Out of an initial 1315 results, ten systematic reviews were included. Various diagnostic PSMA radiotracers that can be labeled with gallium-68 and/or fluorine-18 exist, showing comparable results. For therapeutic applications, the widely used lutetium-177 PSMA ligands and the emerging actinium-225-labeled PSMA ligands have demonstrated prolonged progression-free survival in recent ongoing prospective trials, while no effect for overall survival could be demonstrated. Prostate-specific membrane antigen has therapeutic value beyond prostate cancer, while the role of other ligands in prostate cancer remains experimental. The development of PSMA radiotracers has revolutionized the diagnostic approach in nuclear medicine, while their therapeutic application offers a completely novel treatment option in patients with prostate cancer.
Bone sarcomas are rare, biologically heterogeneous malignancies in which progress in systemic therapy has historically been slow. In Ewing sarcoma, dose-dense VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) has become the global induction standard, with EURO-EWING 2012 and AEWS0031 demonstrating survival benefits through interval compression. Contemporary international platforms, including INTER-EWING and iEuroEwing, now provide harmonized, biomarker-integrated frameworks to evaluate novel agents, radiotherapy optimization, and maintenance strategies. In relapsed disease, the rEECur trial has redefined standards by identifying high-dose ifosfamide as the most active salvage regimen, while deprioritizing less effective combinations; additional rational combinations such as ifosfamide plus lenvatinib and trabectedin plus irinotecan are under active investigation. In osteosarcoma, MAP (high-dose methotrexate, doxorubicin, cisplatin) chemotherapy remains the first-line standard, and postoperative intensification with MAPIE (MAP, ifosfamide, etoposide) has not improved outcomes. Targeted multikinase inhibitors (TKIs), including cabozantinib and regorafenib, provide meaningful but time-limited activity in refractory disease. A large ongoing National Cancer Institute (NCI) phase II/III trial is currently evaluating the addition of cabozantinib to frontline MAP in newly diagnosed patients. Antibody–drug conjugates (ADCs) targeting LRRC15 and B7-H3 represent further promising strategies. Chondrosarcoma remains largely chemoresistant, but targeted approaches are beginning to alter the therapeutic landscape. Isocitrate dehydrogenase (IDH) 1 inhibition with ivosidenib has shown durable disease control, and death receptor (DR) 5 agonism with INBRX-109 has delivered the first positive randomized systemic therapy signal in conventional chondrosarcoma. Continued international collaboration and biomarker-driven trial design are essential to translate these advances into clinical practice.
The ASH Annual Meeting 2025 highlighted major advances in allogeneic hematopoietic stem cell transplantation (HSCT), cellular immunotherapy, and graft-versus-host disease (GvHD). A key focus was graft engineering. In the Phase I ORCA-Q trial, selectively engineered allogeneic grafts achieved reliable engraftment without primary graft failure and showed low rates of severe acute and chronic GvHD, infections, and non-relapse mortality. Notably, favorable outcomes were observed even without conventional pharmacological GvHD prophylaxis, supporting graft engineering as a promising strategy to improve immune reconstitution while reducing transplant-related toxicity. Another innovative approach, termed “DLI 2.0,” combines memory T cells with leukemia-specific T-cell receptors (TCRs) to enhance graft-versus-leukemia effects while minimizing GvHD risk. In a Phase I study, TCR-modified memory T cells demonstrated excellent safety, with no GvHD, cytokine release syndrome, or neurotoxicity. Clinical responses were observed in several patients, including a durable remission in high-risk AML. In multiple myeloma, the first clinical data on in vivo CAR-T generation were presented. Using a targeted lentiviral vector, anti-BCMA CAR T cells were generated directly in patients without ex vivo manufacturing or lymphodepletion. All treated patients achieved MRD negativity, with only mild cytokine release syndrome and no neurotoxicity reported. The ROCCA analysis addressed sequencing of CAR-T therapy and HSCT in adult B-ALL. Patients receiving brexucabtagene autoleucel after post-transplant relapse showed superior relapse-free survival, while transplant-naïve patients benefited from consolidative HSCT after CAR-T therapy. In GvHD prevention, the ABA2 trial demonstrated that adding abatacept to standard prophylaxis significantly reduced severe acute GvHD and improved survival outcomes in mismatched unrelated donor transplantation. Finally, elevated thymic stromal lymphopoietin (TSLP) levels emerged as a potential biomarker for severe intestinal GvHD, supporting future evaluation of TSLP-targeted therapies such as tezepelumab. Refined strategies of immunomodulation and immunosuppression are increasingly used to optimize efficacy while improving safety.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the major success stories of modern medicine. Cure rates now approach 90–95
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved substantially over the past decade with the integration of androgen receptor signaling inhibitors (ARSI), taxane chemotherapy, radioligand therapy, and molecularly targeted agents. Among the most relevant recent developments is the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with ARSI in the first-line mCRPC setting. This strategy is supported by a strong biological rationale, as androgen receptor signaling interacts with DNA damage repair pathways, and AR blockade may induce a “BRCAness” phenotype that enhances tumor sensitivity to PARP inhibition [1, 2]. Randomized phase III trials, including PROpel, MAGNITUDE, and TALAPRO‑2, have consistently demonstrated significant improvements in radiographic progression-free survival (rPFS) with PARPi–ARSI combinations [3–5]. However, overall survival (OS) outcomes remain heterogeneous and appear to depend largely on homologous recombination repair (HRR) mutation status. Patients with BRCA 1/2 alterations derive the most pronounced benefit, whereas evidence supporting use in unselected populations remains inconsistent, with no uniform demonstration of OS improvement [6, 7]. In addition, combination therapy is associated with increased hematologic toxicity, raising concerns regarding overtreatment in biologically less responsive subgroups. Taken together, current data support a biomarker-driven approach, positioning PARPi plus ARSI as a standard option for HRR-mutated mCRPC, while a generalized treatment strategy for all patients remains uncertain.
Chimeric antigen receptor T‑cell (CAR T) therapy has been a breakthrough in the treatment of multiple hematologic malignancies, yet its expanding use has revealed a spectrum of cardiotoxic effects. Cardiotoxicity is primarily mediated via cytokine release syndrome, with clinical manifestations including arrhythmias, hypotension, and heart failure. Severe cardiovascular events, such as myocardial infarction and cardiogenic shock occur less commonly, but are associated with significant morbidity and mortality. The risk of cardiotoxicity is heightened in patients with high-grade cytokine release syndrome and those with pre-existing cardiovascular disease or those with a history of exposure to anthracyclines. The pathophysiology is multifactorial, involving both direct T cell-mediated injury and indirect cytokine-driven myocardial dysfunction. This narrative review evaluates the current states of knowledge regarding CAR T‑cell therapy, its cardiovascular toxicity, clinical manifestations, pathophysiology, and outcomes. Eligible studies for this narrative review were included if they reported original data on cardiovascular events associated with CAR T therapy in patients with hematologic or solid malignancies. Eligible study designs included: randomized controlled trials, cohort studies, case–control studies, case series, systematic reviews, and meta-analyses. Editorials and commentaries were excluded unless they provided pooled data relevant to cardiotoxicity. Studies published in languages other than English were excluded. A comprehensive literature search was conducted across the following electronic databases: PubMed/MEDLINE, Embase, Web of Science Core Collection, the Cochrane Library, and Google Scholar. The search included studies published from January 1, 1990, through March 31, 2026. In addition, the reference lists of all included studies and relevant review articles were searched to identify additional eligible publications. No filters for age, sex, or geographic region were applied. The search was limited to human studies. ClinicalTrials.gov was also searched for completed or ongoing trials reporting cardiovascular safety data. Search terms involved keywords related to “chimeric antigen receptor T cell,” “CAR T,” “cardiotoxicity,” “cytokine release syndrome,” “arrhythmia,” and “cardiac dysfunction.” Extracted variables included study design, CAR T product, sample size, incidence and type of cardiovascular event, association with cytokine release syndrome, and biomarker data. The selection process was documented using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram adapted for narrative reviews. Titles and abstracts retrieved from the database searches were screened for relevance by one reviewer. Full-text articles of potentially eligible studies were then assessed against the predefined inclusion and exclusion criteria. Cardiotoxicity was strongly associated with higher grades of cytokine release syndrome. The most common cardiovascular events included: hypotension, arrhythmias, and heart failure. Elevated cardiac biomarkers, including troponin and pro-BNP were frequently observed and correlated with adverse outcomes. Subgroup analyses demonstrated increased risk of cardiotoxicity in patients with pre-existing cardiovascular conditions. Early recognition of cardiotoxicity, with utilization of a multidisciplinary management approach, remains critical to improving long-term outcomes in patients undergoing CAR T therapy. While most events are nonfatal, severe complications can occur and are associated with increased mortality. Long-term cardiovascular sequelae remain poorly defined, underscoring the need for ongoing surveillance and further prospective studies.
Metastatic luminal breast cancer remains an incurable disease; however, survival outcomes have improved substantially in recent years due to the development of novel endocrine-based and targeted therapeutic strategies aimed at overcoming endocrine resistance. Nevertheless, therapeutic decision-making after disease progression on CDK4/6 inhibition represents a major clinical challenge. Treatment selection after progression is guided by multiple factors, including prior treatment duration, tumor biology, metastatic pattern, molecular alterations, and patient preferences. The clinical definitions of primary and secondary endocrine resistance remain useful in daily practice and are increasingly complemented by biomarker-driven concepts, such as the detection of acquired ESR1 mutations. Alongside ESR1 mutations, alterations in the PI3K/AKT/mTOR pathway, germline BRCA 1/2 or PALB2 mutations, changes in estrogen receptor expression, emergence of RB1 mutations, and intra-tumoral heterogeneity contribute to endocrine and CDK4/6 inhibitor resistance and inform subsequent treatment strategies. Recent clinical trials have expanded therapeutic options across different molecular subgroups, including oral selective estrogen receptor degraders, PI3K/AKT inhibitors, PARP inhibitors, and antibody–drug conjugates. Combination strategies and biomarker-guided treatment adaptations are emerging as promising approaches to improve disease control, particularly in patients with endocrine-resistant disease. However, in a substantial proportion of patients, no actionable molecular alteration can be identified, highlighting the continued need for individualized treatment strategies. This review summarizes current evidence and provides a clinically oriented overview of treatment sequencing in metastatic luminal breast cancer, highlighting the importance of integrating clinical characteristics, molecular profiling, and patient preferences in an increasingly complex therapeutic landscape.
Axillary surgery in breast cancer has undergone a profound transformation in recent decades. While axillary lymph node dissection (ALND) was the unquestioned standard until the 1990s [1], associated morbidity including lymphedema rates as high as 25
This clinical case describes the course of a woman with metastatic triple negative breast cancer involving the brain, lungs, and lymph nodes who was enrolled in the phase II clinical trial TUXEDO‑2 investigating datopotamab deruxtecan (Dato-DXd) for the treatment of active (newly diagnosed or progressing after prior local treatment) brain metastases. After six cycles of therapy, she discontinued the study to undergo neurosurgical resection followed by radiotherapy of a single progressing cerebellar metastasis causing compression of the fourth ventricle, while all other intra- and extracranial lesions demonstrated a significant response to Dato-DXd. The patient subsequently continued Dato-DXd treatment off-trial and remained on therapy for a total duration of 2.5 years at the time of last follow-up.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies, with a dismal prognosis and limited therapeutic options. The 9th CECOG Pancreas Cancer Academy brought together leading international experts to review recent advances and establish a consolidated expert opinion on the biology, diagnosis, and treatment of pancreatic cancer. Pancreatic ductal adenocarcinoma is characterized by extensive molecular heterogeneity, with KRAS mutations being the primary driver of most cases. Diagnosis relies on a multimodal imaging approach, while molecular diagnostics are increasingly essential for identifying actionable biomarkers and understanding resistance mechanisms. Multidisciplinary tumor boards are crucial for addressing all aspects of diagnosis and treatment. Treatment strategies are tailored to disease stage and patient performance status. For resectable disease, upfront surgery followed by adjuvant chemotherapy (preferably mFOLFIRINOX) remains the standard, although neoadjuvant therapy is gaining importance for borderline resectable tumors. In metastatic disease, FOLFIRINOX, NALIRIFOX, and gemcitabine–nab-paclitaxel are first-line options. Second-line therapies focus on switching drug classes and tailoring therapies according to patient fitness. Novel therapies, including targeted agents, immunotherapies, and antibody–drug conjugates, are currently being assessed in clinical trials. Despite progress, the complexity of pancreatic cancer demands continued research into biologically driven treatments and early detection strategies to improve patient survival and quality of life.
Positive results of the FLOT4-AIO trial in 2019 have established perioperative chemotherapy with FLOT (5-fluorouracil [5-FU], oxaliplatin, and docetaxel) as the standard approach for resectable adenocarcinoma of the stomach and gastroesophageal junction. Despite the improvement of clinical outcome when compared to the former anthracycline-based triplet chemotherapy, more than half of patients experience disease relapse and/or death with perioperative FLOT during follow-up. While the phase 3 KEYNOTE-585 trial—investigating the addition of pembrolizumab to the chemotherapy backbone cisplatin +5-FU/capecitabine—was a negative trial, the phase 3 MATTERHORN trial demonstrated superiority of FLOT combined with durvalumab (D-FLOT) compared to FLOT alone in terms of improved event-free survival (EFS) and overall survival (OS) and established D‑FLOT as the new standard of care for all-comers. Preliminary results of the ongoing DANTE phase 3 trial corroborate higher pathological complete remission (pCR) rates by combining perioperative FLOT + immune checkpoint blockade; however, EFS and OS results are pending. In light of the encouraging pCR rates achieved by the addition of pembrolizumab and trastuzumab to FLOT in HER2+ disease in the single-arm PHERFLOT phase 2 trial, the use of additional trastuzumab in this subgroup warrants further investigation.
The introduction of prophylactic human papillomavirus (HPV) vaccines has been a major step forward in preventive oncology. Initial randomized trials demonstrated that vaccination effectively prevents persistent HPV infection and precancerous disease. More recently, population-based data have shown striking reductions in invasive cervical cancer. Long-term follow-up studies confirm sustained immunity without evidence of waning protection, indicating that booster doses are not required. Evidence is also accumulating that a single vaccine dose may provide protection comparable to two doses, a finding with major implications for affordability and global access. Reaching the World Health Organization 2030 elimination target will, however, require continued progress.
The increasing prevalence of cancer among older adults underscores the need for individualized therapy approaches. Chronological age alone is insufficient to guide oncological decision-making, as comorbidities, frailty, and functional status vary widely across patients. Risk assessments offer a structured method for evaluating the multidimensional health status of older patients with cancer, encompassing physical, psychological, cognitive, nutritional, and social domains. While a comprehensive geriatric assessment (CGA) remains the gold standard, it is time-intensive. Therefore, screening tools can help identify patients who would benefit most from full evaluation. The Practical Geriatric Assessment (PGA) provides a feasible, validated, and resource-efficient alternative. Tools such as the Cancer Aging Research Group (CARG) score and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) further aid in predicting chemotherapy-related toxicities more accurately than conventional indices. Implementing GA-driven management can reduce treatment-related toxicity, improve adherence, and enhance quality of life, although mortality benefits remain unproven. Integrating risk assessments into routine oncology practice represents a pragmatic, evidence-based approach to personalizing cancer therapy for older adults. Even a brief assessment can meaningfully influence outcomes, enabling oncologists to balance efficacy, tolerability, and quality of life—ultimately ensuring that the best supportive care begins before therapy starts.
