This preliminary study aimed to evaluate the safety and efficacy of 225Ac-DOTA-IBA in the treatment of bone metastases. Fourteen patients with bone metastases were enrolled and received at least one cycle of 225Ac-DOTA-IBA at a fixed dose of 3.7 MBq per cycle. Treatment-related adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Efficacy assessments included Eastern Cooperative Oncology Group (ECOG) performance status, Karnofsky Performance Status (KPS), and pain Numeric Rating Scale (NRS) scores at baseline and 2-4 weeks post-treatment, as well as 68Ga-DOTA-IBA PET/CT scans within 1 week before treatment and 4-8 weeks post-treatment. Imaging responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). 225Ac-DOTA-IBA was well tolerated, with no grade 3/4 AEs. On the basis of NRS scores, the pain relief rate was 92.9% (13/14) after the first cycle and was maintained at this level after subsequent cycles. ECOG performance status remained stable in the majority of patients, with improvement (from grade 2 to 1) observed in 2 cases (14.3%). KPS improved in 71.4% (10/14) of all patients after treatment. 68Ga-DOTA-IBA PET/CT analysis showed PR in 50.0% (7/14), SD in 35.7% (5/14), and PD in 14.2% (2/14). Among 7 patients who had previously received 177Lu-DOTA-IBA, 57.1% (4/7) improved in KPS, and 85.7% (6/7) in NRS. Regarding imaging response in these 7 patients, 42.9% (3/7) achieved PR, 42.9% (3/7) had SD, and 14.3% (1/7) showed PD. Subgroup analysis revealed that patients with bone-only metastases (n=9) had a significantly higher rate of KPS improvement (77.8% vs. 60.0%, P=0.012) and achieved a greater median reduction in pain scores (3.0 vs. 2.0 points, P=0.008). This study indicated that 225Ac-DOTA-IBA was a promising and well-tolerated therapeutic for bone metastases, demonstrating acceptable toxicity and notable efficacy, including 177Lu-DOTA-IBA-refractory cases. Subgroup analyses indicated that patients with bone-only metastases derived particular clinical benefit.

Prurigo nodularis (PN) is a chronic, intensely pruritic skin disorder characterized by hyperkeratotic nodules and a debilitating itch-scratch cycle. Conventional therapies have limited efficacy and safety issues, while biologics have recently emerged as a promising alternative. A systematic search of PubMed, Embase, and CENTRAL databases was conducted on November 20, 2023, to identify studies assessing treatments for PN. Primary outcomes were changes in pruritus and quality of life. Safety was evaluated by adverse event incidence. Random-effects meta-analyses were conducted when sufficient data were available. Of 4914 records screened, 128 studies met the inclusion criteria, of which 25 were included in the meta-analysis. In studies of dupilumab, treatment was associated with marked reductions in pruritus (mean difference [MD], -5.76; 95% confidence interval [CI],-6.86 to -4.67) and significant improvement in quality of life (MD, -11.84; 95% CI, -22.76 to -0.92), with adverse events reported in 13% of patients (95% CI, 0.02-0.52). Phototherapy achieved complete responses in 23% (95% CI, 9%-48%), partial responses in 60% (95% CI, 39%-78%), and no response in 7% (95% CI, 1%-40%). Thalidomide was associated with complete, partial, and no response rates of 15% (95% CI, 1%-71%), 49% (95% CI, 23%-75%), and 12% (95% CI, 6%-23%), respectively. Dupilumab offers consistent, clinically meaningful improvements in PN with a favorable safety profile, supporting its use as the preferred first-line treatment. Phototherapy and thalidomide remain alternatives for selected patients but achieve complete clearance in few cases and carry greater safety concerns.

Evaluation of Chemotherapy Efficacy in Primary Gastric Diffuse Large B-cell Lymphoma on a Point-based Scoring System: A Multicenter Study.

High-dose dexamethasone (HDD) is widely used as first-line therapy for immune thrombocytopenia (ITP) and is administered at a fixed dose regardless of body weight. The impact of body mass index (BMI) on treatment response to HDD remains unclear. This retrospective, two-center study included 60 adult patients with newly diagnosed ITP who received HDD as first-line therapy. Demographic characteristics, BMI, baseline laboratory values, and treatment responses at1, 6, and 12months were analyzed. BMI was evaluated using cut-off values of 25, 27, and 30. The median number of HDD cycles administered was 1 (range: 1-4), and the median BMI at diagnosis was 27.0kg/m2 (range: 18.0-44.0). No significant differences were observed between BMI categories with regard to treatment responses at months 1 and 6 (p > 0.05 for both). However, at month 12, a complete response (CR) was more likely in patients with BMI < 30, and a partial response (PR) in those with BMI ≥ 30 (p = 0.023). Across all time points, no other demographic or clinical variable emerged as an independent predictor of treatment response (p > 0.05). The results of this study indicate that in newly diagnosed ITP patients receiving HDD as first-line treatment, BMI does not influence early or durable treatment responses, although it may have a modest adverse effect on late response. Larger prospective studies are needed to clarify underlying mechanisms and assess whether obesity-related factors should inform individualized treatment.

Advanced cutaneous squamous cell carcinoma (cSCC) is associated with a poor prognosis. Although anti-PD1 immunotherapy has improved cSCC management, its efficacy remains limited in some patients. Second-line options, including anti-EGFR antibodies and chemotherapies, exhibit transient efficacy and often good tolerability. Given the lack of successive treatment lines, new strategies are emerging, such as the combination of anti-PD1 and anti-EGFR agents. We conducted a retrospective, monocentric cohort study including patients treated in our oncodermatology department between 2013 and 2024 for advanced cSCC refractory to anti-PD1 monotherapy and who received a combination of anti-PD1 and anti-EGFR as second- or third-line therapy. The aim was to assess the efficacy and safety of this combination. Fourteen patients were included, predominantly male (12/14), with a median age of 63 years. Most tumors originated from head and neck primary sites (n = 8). Eleven patients had progressed after prior exposure to both anti-PD1 therapy and cetuximab combined with chemotherapy. Thirteen patients received cetuximab (500 mg/m2) combined with pembrolizumab every 3 weeks, and one received cetuximab with nivolumab.The overall response rate was 38.5%, including 15.5% complete and durable response after treatment discontinuation, observed à 9 and 16 months, and 23% partial responses. Responses occurred early, with subsequent deepening observed in two patients. Adverse events were mainly grade 1, and only two cases experienced grade 3 toxicity (acneiform rash). In a heavily pretreated real-life population with advanced cSCC, the anti-PD1/anti-EGFR combination showed clinical activity with acceptable safety, supporting its role as later-line strategy.

To assess the efficacy and safety of osilodrostat in adrenal Cushing syndrome (CS). International study of patients with adrenal CS: patients treated with osilodrostat at any time were enrolled in the safety evaluation and those treated for longer than 4 weeks, in the efficacy evaluation. Patients were classified as responders if they experienced a reduction in urinary free cortisol (UFC) > 50% (complete responders when UFC levels were below the upper limit of normal (ULN) and partial responders if there was a reduction >50% but not normalization). Twenty-eight patients with adrenal CS were enrolled: 16 with adrenocortical carcinoma and 12 with benign disease. Osilodrostat was used in monotherapy in 22 patients and in combination with metyrapone in 6 cases. In those patients treated for longer than 4 weeks (n = 21), 66.7% were classified as responders (28.6% with complete response and 38.1% with partial response) and for those treated for longer than 12 weeks, the rate of response increased to 87.5% The use of osilodrostat as a non-first-line therapy (Odds ratio [OR] 15.0, P = 0.010) was a predictor of response. Osilodrostat led to a significant decrease in systolic blood pressure and body weight (P < 0.05). Nine patients developed one or more adverse events and in 56% (n = 5) led to osilodrostat discontinuation. Osilodrostat controls hypercortisolism in 66.7% of patients with adrenal CS treated for longer than 4 weeks and in 87.5% of cases treated for longer than 12 weeks, with a positive impact on blood pressure and body weight. Patients who received osilodrostat after other previous steroidogenesis inhibitors have a higher probability of response.

Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) quantifies changes in radiotracer uptake to assess therapeutic response in cancer. However, the accuracy of these quantifications depends on imaging parameters, tumor size, and the local tumor-to-background uptake ratio (local-TBR). In this study, 'background' refers to the surroundings of the lesion rather than a standardized reference tissue. A NEMA Image Quality phantom was filled with 18F-FDG at varying sphere-to-background ratios to simulate clinical scenarios corresponding to PERCIST-defined thresholds for partial metabolic response (-30%) and progressive metabolic disease (+30%). Positron emission tomography (PET)/computed tomography imaging revealed that measured uptake changes systematically underestimated the true ±30% differences, particularly in smaller spheres. These findings indicate a potential source of systematic error in PET-based tumor response assessment, which may influence clinical interpretation. Further studies are recommended to investigate the effects of varying imaging parameters, tumor types, and clinical settings to improve the robustness of PERCIST-based evaluations.

Background. In unresectable hepatoblastoma (HB), particularly “pre-treatment extent of tumor” (PRETEXT) IV tumors or those with positive annotation factors, standard management consists of intensive chemotherapy followed by surgical resection or orthotopic liver transplantation (OLT). Radiotherapy has traditionally been avoided because of the liver’s radiosensitivity and the risk of radiation-induced liver disease. Proton beam therapy (PBT), owing to its dosimetric advantage and ability to spare uninvolved liver parenchyma, may represent a potential local control strategy in selected pediatric patients for whom curative surgery or OLT is not feasible. Case Presentation. We describe five pediatric patients with advanced hepatoblastoma treated with proton beam therapy at our institution between February 2022 and January 2024. The cohort included three girls and two boys, with a median age of 3.0 years (interquartile range [IQR], 1.6–4.0) and a median alpha-fetoprotein level of 435,453 ng/mL (IQR: 7,668–1,276,681) at diagnosis. All patients were initially considered inoperable because of extensive hepatic involvement, inadequate future liver remnant, or multifocal disease, and OLT was not feasible owing to donor limitations or medical comorbidities. All received neoadjuvant chemotherapy using SIOPEL-based regimens, achieving partial tumor response. Tumors ranged from 5 to 12 cm and involved central hepatic segments, the portal region, or both lobes. PBT was delivered at a total dose of 50 GyE in 10–25 fractions as definitive or consolidative therapy, followed by surgical resection in three patients. Two patients additionally received targeted therapy and immunotherapy. At last follow-up, four patients were alive with no evidence of disease, while one patient died from tumor progression. Conclusions. These cases suggest that proton beam therapy may serve as a feasible liver-sparing local treatment option for selected pediatric patients with unresectable or residual hepatoblastoma when surgery or OLT is not possible. While limited by availability and cost, PBT may facilitate multimodal therapy and preserve future treatment options.

Background: The objective of this study was to evaluate the efficacy of mycophenolate mofetil (MMF) as a second- or third-line treatment for chronic immune thrombocytopenia (ITP).Methods: A cohort of 13 patients with chronic ITP, who had previously been treated with eltrombopag, corticosteroids, or both, without achieving an effective response, was administered mycophenolate mofetil at a daily dosage of 1000 mg. Platelet counts were monitored at the fourth and twelfth weeks of treatment.Results: In our study, 13 patients were included, consisting of 4 females (30.8%) and 9 males (69.2%). At the 12-week mark following the initiation of MMF therapy, three out of 13 patients achieved a complete response, three out of 13 patients achieved a partial response, and seven patients showed no response. (Fig.1). At the time of transitioning to Mycophenolate Mofetil (MMF), all patients had a platelet count below 30 × 10^9/L. Approximately 40% of patients experienced an increase in platelet counts to levels above 30 × 10^9/L.Conclusions: Mycophenolate mofetil may be considered a potential treatment option for patients with chronic ITP who are refractory to first- and second-line therapies.

Chimeric antigen receptor (CAR)-T cell therapy exerts limited therapeutic efficacy in solid tumors including digestive tract cancer (DTC), which is largely attributable to the suppressive tumor microenvironment (TME) and the functional deficits of CAR-T cells. Herein, we generated fourth-generation CAR-T cells engineered to target Claudin18.2 (CLDN18.2) with concurrent secretion of IL-7 and XCL1, which are designated as ExCAR-T cells (also named RD07 cells in a clinical trial). The preclinical results demonstrated the remarkable and enduring suppressive effects of ExCAR-T cells on DTC growth in murine models through activating both the inherent of the administered CAR-T cells and robust endogenous immune cells anti-tumor response. Furthermore, we performed a clinical investigation for previous systemic treatment failed patients with DTC. RD07 therapy was well tolerated, and 7 out of 10 patients exhibited tumor regression; this effect was particularly evident in patients exhibiting moderate to high CLDN18.2 expression (DCR of 100%). Finally, single-cell RNA (scRNA) sequencing combined with spatial landscape profiling revealed that RD07 has antitumor effects and activates endogenous immune cells within the TME. Concomitantly, enhanced cytotoxic activity of CAR-T cells and expanded T cell receptor (TCR) clonotypes were detected in patients with a partial response (PR). Taken together, present data demonstrate the therapeutic efficacy and safety of RD07 in our study and highlight its ability to both exert antitumor effects and remodel the TME. These findings support RD07 as an innovative CAR-T cell therapy for DTC.

Objective: To investigate the clinicopathological features of primary pulmonary epithelioid hemangioendothelioma (PEHE). Method: Forty cases of PEHE were diagnosed from October 2010 to June 2024 at the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. A retrospective analysis was conducted on their histological features, imaging findings, immunohistochemical characteristics and molecular phenotypes. Subsequently, the clinicopathological features were summarized. The patients were followed up. Result: Of the 40 cases, there were 19 males and 21 females, age 52.5 (43.0, 62.0) years old. Most patients were admitted for respiratory symptoms, mainly cough (25/40) and expectoration (14/40). Computed tomography findings mainly showed multiple intrapulmonary nodules (33/40) and solitary nodules in 7 cases (7/40). Tumor maximum diameters ranged from 3 to 70 mm, with a median of 19 (12, 35) mm. Grossly, all lesions appeared as grayish-white nodules with ill-defined margins and mucoid cut surfaces. Microscopically, tumor cells showed centrifugal distribution around blood vessels, arranged in irregular nests; local mucoid degeneration and chondroid matrix were noted. Intracytoplasmic vacuoles with red blood cells were noted in some tumor cells, indicating primitive vascular lumen differentiation. At the molecular level, WWTR1-CAMTA1 gene fusion was identified in 36 cases and YAP1-TFE3 fusion in 4 cases. Immunohistochemical results showed diffuse positivity for CD31 (38/38), CD34 (36/40), ERG (40/40) and Fli-1 (40/40), and focal positivity for TFE-3 (4/34). Therapeutic responses of 40 patients were assessed using the Response Evaluation Criteria in Solid Tumors criteria: complete response in 4 cases (10.0%), partial response in 5 (12.5%), stable disease in 7 (17.5%), and progressive disease in 24 (60.0%). Conclusions: PEHE is a rare vascular-derived tumor, radiologically characterized by multiple bilateral pulmonary nodules. It has non-specific clinical manifestations; combined use of highly sensitive and specific endothelial markers and genetic testing helps reach the definitive diagnosis. PEHE has an overall indolent course, with long-term survival in some patients. However, multiple lesions, pleural invasion, and distant metastasis may be linked to worse prognoses.

Background/Objectives: Thrombocytopenia subsequent to antineoplastic therapies leads to bleeding complications, treatment delay or de-intensification, and platelet transfusion requirement. Evidence suggests that thrombopoietin receptor agonists (TPO-RAs) can restore platelet counts in this scenario. Avatrombopag (AVA) is an oral TPO-RA whose efficacy in treating thrombocytopenia in haematological malignancy has been barely addressed. We aimed to evaluate AVA's efficacy in improving platelet recovery and reducing transfusion requirement in haematological patients with thrombocytopenia. Methods: In this retrospective observational study, haematological patients who developed thrombocytopenia persisting for ≥3 weeks and were treated with AVA between November 2023 and December 2024 were recruited. Results: Twenty-three patients were recruited. Nineteen (82.6%) responded to AVA, most within the first 4 weeks: 10 (43.5%) and 9 (39.1%) achieved platelet counts ≥ 30 × 109/L (partial response) and ≥100 × 109/L (complete response), respectively. Response was always maintained for 30 days after AVA withdrawal. Transfusions were significantly fewer than in the previous period: 0 (0-8) vs. 11 (2-15), median (interquartile range [IQR]), p = 0.007. Once on treatment, 13 (56.5%) patients no longer required transfusion. No patient delayed or de-intensified chemotherapy. No safety concerns were reported. Conclusions: AVA shows promise in safely reducing thrombocytopenia-associated transfusion needs in haematological malignancy.

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, ultimately releasing the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it regulates gene expression. This review mainly aims to evaluate γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, with a focus on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard therapies. Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following PRISMA guidelines. The review included preclinical in vitro and in vivo studies, as well as clinical trials, investigating GSIs, either as monotherapy or in combination with other treatments, in TNBC, metastatic melanoma, PDAC, gastric cancer, and NSCLC. Exclusion criteria included duplicates, non-English articles, studies published before 2010, studies on non-cancer conditions, research unrelated to NOTCH signaling, and studies outside the selected cancer types. Overall, 69 articles were included and categorized into the five types of cancer analyzed (20 on NSCLC, 22 on TNBC, 11 on metastatic melanoma, 7 on GC, and 9 on PDAC). Of these, 60 studies corresponded to preclinical research in the types of cancer, and 9 studies corresponded to clinical trials in the types of cancer except for GC. Two independent authors screened and extracted relevant data, with disagreements resolved by the corresponding author. Findings were synthesized qualitatively across cancer types under study. Results. This review summarizes therapeutic advances involving GSIs in cancers driven by oncogenic NOTCH signaling, based on the 69 articles included. Preclinical studies show that GSIs synergize with chemotherapy and radiotherapy, particularly in NSCLC, melanoma, and TNBC, and block EMT, overcome therapeutic resistance, and improve prognosis. Commonly used GSIs include DAPT and RO4929097, which enhance the efficacy of agents, such as gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib, and crizotinib (NSCLC), and 5-FU (gastric cancer, TNBC). Promising strategies include combining GSIs with SAHA, ATRA, CB-103, and other NOTCH signaling targeting molecules, either alone or with chemo- and radiotherapy. Clinical trials with GSIs, however, remain limited. RO4929097 is the most extensively tested GSI in clinical settings. PDAC trials combining GSIs with gemcitabine showed no benefit; melanoma trials yielded modest outcomes; and TNBC trials demonstrated partial responses to GSIs but overall low efficacy and significant adverse events. Discussion and Conclusions. Despite encouraging preclinical evidence, clinical trials with GSIs have underperformed, largely due to tumor heterogeneity, dosing limitations, and the non-selective nature of γ-secretase inhibition. Other NOTCH inhibitors, such as DLL4 antibodies, also resulted in partial responses and secondary effects. Future strategies should prioritize receptor-specific NOTCH inhibitors, patient stratification based on NOTCH pathway activation, and optimized combination regimens. Emerging approaches include integrating immunotherapy with advanced technologies such as CRISPR, CAR-T cells, and bispecific antibodies, as well as targeted delivery systems to enhance efficacy and reduce toxicity. Additional research directions include addressing the tumor microenvironment and EMT-driven resistance, elucidating the mechanisms of immune evasion, and inhibiting tumor angiogenesis. Finally, leveraging artificial intelligence and big-data-driven personalized medicine, including sex-specific considerations, will be essential for improving patient outcomes.

Teclistamab is the first approved anti-BCMA bispecific antibody for patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM), based on the results of MajesTEC-1 clinical trial. Here, we first report the findings from REALiTEC, a retrospective observational study of patients who received teclistamab outside of clinical trials in Europe and Israel. The study included 113 patients from 23 sites in eight countries, with most (88.5%) accessing the medication through pre-approval access programs. The median age was 66 years, and patients had a median of 6 prior lines of therapy. Notably, 78.8% were triple-class refractory, 44.2% penta-class refractory, and 35.4% had previous anti-BCMA treatment. Overall response rate (ORR) was 60.2%, with 52.2% of patients achieving a very good partial response or better (≥VGPR). After a median follow-up of 20.7 months, median duration of response (DoR) was 20.3 months, median progression-free survival (PFS) was 9.7 months, and median overall survival (OS) was 26.3 months. Patients attaining ≥VGPR experienced longer DOR (median 26.1 months), with 12-month PFS and OS rates of 71.2% and 83.1%, respectively. Subgroup analyses demonstrated consistent outcomes across different patient groups, even in those with historically poorer outcomes. Most common adverse events were infections (all grade: 70.8%), cytokine release syndrome (55.8%), neutropenia (35.4%), and anaemia (25.7%), with no new safety signals identified. Infection rates decreased over time, and immunoglobulin replacement therapy was used in up to 60% of patients. REALiTEC corroborates the efficacy observed in MajesTEC-1, supporting teclistamab as an effective treatment option in heavily pre-treated RRMM patients.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and has poor immunogenicity, warranting the use of vaccines to guide and recruit the immune response. Building on prior efforts to achieve clinical immunotherapeutic responses against PDAC, we conducted a phase II study (NCT03190265) that combined attenuated mesothelin (MSLN)-secreting listeria vaccine (CRS-207) and GM-CSF-secreting allogeneic whole-cell vaccine (GVAX) along with checkpoint inhibition. Patients with metastatic PDAC who progressed on chemotherapy were enrolled in one of two treatment arms in a randomized fashion. CRS-207 was given with anti-PD-1 (nivolumab) and anti-CTLA4 (ipilimumab) with (arm A) or without (arm B) GVAX. The primary endpoint was the objective response rate (ORR), and the secondary endpoint was safety. Fifty-seven patients received at least one dose of treatment, with two partial responses (4% ORR), in both arm B. The response rates were not significantly different between the two arms. Related grade ≥3 adverse events were seen in 39 (68%) patients, including 33 events attributed to CRS-207. Mass cytometry analysis of serially obtained biospecimens demonstrated treatment-induced promotion of T-cell memory and infiltration into the tumor microenvironment (TME). Peptide-specific T-cell expansions in vitro, followed by T-cell receptor sequencing, revealed clones specific to MSLN and mutant KRAS within the tumor. Accompanying these antitumor T-cell responses was significant enrichment of myeloid cells. High myeloid and regulatory T-cell signatures correlated with poor responses. We conclude that GVAX/CRS-207 plus nivolumab and ipilimumab successfully generates and expands T-cell clones specific to MSLN and mutant KRAS within the PDAC TME, but immunotherapy-induced myeloid cell enrichment remains a barrier to greater efficacy. See related article by Sidiropoulos et al., p. 399.

Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.

Objective: To evaluate the efficacy and safety of avelumab maintenance therapy in patients with metastatic urothelial carcinoma (UC) in real-world practice. Methods: This ambispective study included patients with metastatic UC and measurable tumor lesions, without progression during and after first-line platinum-based chemotherapy (CHT), who received avelumab maintenance therapy (800 mg IV every 2 weeks). The primary endpoint of the study was overall survival (OS). Results: The study included 110 patients, with a predominance of men (81 %). The median age of all patients was 65 (range, 36–84) years. With a median follow-up of 11.9 months, the median OS was not reached; the one-year OS was 78.7 %. The median progression-free survival (PFS) was 9.5 months (95 % CI, 7.8–11.2 months). The objective response rate (ORR) to first-line chemotherapy was 48.2 %. Of the 97 patients with an evaluated objective response, 38 (39.2 %) demonstrated additional objective responses to avelumab therapy (16 complete and 22 partial responses). Grade 3 adverse events during avelumab therapy were observed in 11.8 % of patients. Conclusions: The efficacy and safety of avelumab maintenance therapy in real-world practice are comparable to those in the pivotal study.

To evaluate the clinical outcome of calcium electroporation in treating canine superficial solid tumors using 1 or 2 treatment sessions and to assess the associated adverse events and effects on quality of life. 4 client-owned dogs were treated between February 2021 and May 2022. This prospective, randomized case series included an oral malignant melanoma, 2 digital melanomas, and a subcutaneous mast cell tumor. Tumors were treated once or twice and monitored for ≥ 180 days (median follow-up, 705 days; range, 180 to 870 days). Tumor response, tumor volume, adverse events, pain scores, and quality of life were recorded. 2 dogs received a single treatment, and 2 dogs received 2 treatments. At day 180, the overall response rate was 75% (1 complete response, 2 partial responses, and 1 progressive disease). Three dogs had no clinical evidence of progression at the time of writing (570 to 870 days posttreatment). Among responders, tumor volume reduction at day 180 ranged from 85% to 100%. No serious adverse events occurred. Transient muscle contractions during pulse delivery and mild swelling with erythema were noted in all dogs for 1 to 3 days. One dog developed a self-limiting grade 1 ulcer that had resolved by day 14. Pain scores remained low, and owners consistently reported good quality of life. Calcium electroporation has the potential of being a chemotherapy- and surgery-free local ablative treatment option. Although limited by small case numbers, the findings in this study support further evaluation of calcium electroporation for the treatment of malignant tumors in dogs.

Introduction. Prognosis and response to treatment in Multiple Myeloma (MM) patients are profoundly influenced by genetic and cytogenetic alterations, either primary and secondary. The gold standard in clinical practice to detect these alterations is represented by fluorescence in situ hybridization (FISH) on purified or enriched plasma cells. Current guidelines recommend routine use of FISH to identify the following key high-risk prognostic markers: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) and/or del(1p). In this context, aberrations involving the MYC family oncogenes [C-MYC (8q24) and, to a lesser extent, N-MYC (2p24)], are crucial progression events but are not currently evaluated in the clinical routine.Methods. Conventional cytogenetic analysis was done using G-banding (GTG) on whole bone marrow cells. FISH was performed on isolated PC initially with standard probes from MM panel, followed by the MYC probe after evidence of karyopypic alterations involving MYC loci.Results. The clinical and therapeutic results in three patients with MYC rearrangements at the conventional cytogenetic analysis followed by FISH confirmation with specific MYC probes are reported. Clinical data of the three patients are reported in the Table. Conventional cytogenetic analysis revealed C-MYC rearrangements in two cases (pt 1 and 2) and N-MYC rearrangement in one case (pt 3). These rearrangements were confirmed by FISH. From a prognostic point of view, according to the International Scoring System (ISS) classification one out three patients (pt 1) was at low-risk, while according to the Revised ISS (R-ISS) all three patients were at intermediate risk. All three patients were treated frontline with standard VTD scheme: pt 1 achieved a very good partial response (VGPR) but relapsed after 36 months and became resistant thereafter, pt 2 achieved a VGPR but had an early relapse and became resistant after a 2nd short partial response, pt 3 remained always in stable disease during three different lines of therapy with subsequent progression.Conclusions. Cytogenetic risk assessment is essential to identify high-risk abnormalities. While C-MYC and N-MYC play a key role among the genes involved in progression in about 15% of patients with MM and are associated with an unfavorable outcome, their evaluation is not considered in the standard FISH analysis and in the standard high-risk classification: as a consequence, their role is underestimated in the current clinical practice. Our three cases highlight the bad prognosis of patients carrying MYC alterations: it should be emphasized that these alterations would have not reported if only the conventional FISH panel on plasma cells had been used. Therefore, the inclusion of MYC rearrangements in the FISH panel is essential for a comprehensive and timely risk assessment in MM, reducing the proportion of patients with the so called “functional high-risk”.

Introduction. Fixed-duration Rituximab (R) and Venetoclax (Ven) therapy has improved outcomes in chronic lymphocytic leukemia (CLL), achieving a 7-year overall survival of 69.6% and effective MRD eradication. Accurate minimal residual disease (MRD) assessment is essential to monitor treatment response. The “Dedalus” protocol compared MRD detection by flow cytometry (MFC) and next-generation sequencing (NGS) in relapsed/refractory CLL patients treated with R-Ven and explored correlations with clinical outcomes and immune changes.Methods. Twenty-two patients underwent MRD assessment using ERIC-compliant MFC and Lymphotrack NGS (sensitivity 10−5). Advanced ultrasound monitored treatment response. MRD and immunological parameters were evaluated at 1, 6, 12, and 18 months or upon treatment discontinuation.Results. Twenty patients achieved complete remission (CR), with MRD undetectable in 15 at first assessment by both methods. In two partial response cases, NGS detected residual IgH clonality (3–45 clonal cells per 106) missed by MFC (Figure 1). Detection thresholds were 10-4 (MFC) and 10-5 (NGS). Venetoclax caused sustained B cell depletion and reduced CD4+ T cells, altering the CD4/CD8 ratio in 25% of patients. NGS results correlated more closely with clinical outcomes, especially in low-level residual disease.Conclusions. R-Ven is highly effective in achieving durable remissions in relapsed CLL. While MFC is accessible and cost-effective, NGS offers superior sensitivity and better correlation with outcomes. Future studies should evaluate digital PCR for IgH rearrangements as a non-invasive MRD biomarker and further investigate Venetoclax’s immunomodulatory effects.