Search Results (113)

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

With the increasing detection of artemisinin resistance to front-line antimalarials in Africa and notwithstanding the planned roll-out of RTS’S and R21 in Africa, the search for new vaccines with high efficacy remains an imperative. Towards this endeavour, we performed in silico screening to identify Plasmodium falciparum gametocyte stage genes that could be targets of protection or diagnosis. Through the analysis we identified a gene, Pf3D7_1105800, coding for a Plasmodium falciparum subtilisin-like domain-containing protein (PfSDP) and thus dubbed the gene Pfsdp. Genetic diversity assessment revealed the Pfsdp gene to be relatively conserved across continents with signs of directional selection. Using RT qPCR and Western blots, we observed that Pfsdp is expressed in all developmental stages of the parasite both at the transcript and protein level. Immunofluorescence assays found PfSDP protein co-localizing with PfMSP-1 and partially with Pfs48/45 at the asexual and sexual stages, respectively. Further, we demonstrated that anti-PfSDP peptide-specific antibodies inhibited erythrocyte invasion by 20–60% in a dose-dependent manner, suggesting that PfSDP protein might play a role in merozoite invasion. We also discovered that PfSDP protein is immunogenic in children from different endemic areas with antibody levels increasing from acute infection to day 7 post-treatment, followed by a gradual decay. The limited effect of antibodies on erythrocyte invasion could imply that it might be more involved in other processes in the development of the parasite. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy. Full article

Background: Retinal vascular occlusion (RVO) and retinal artery occlusion (RAO) have been reported as rare adverse events following COVID-19 vaccination, raising concerns about vaccine safety. This review synthesizes cohort and case–control studies assessing the association between COVID-19 vaccines and RVO/RAO, while exploring potential pathophysiological mechanisms. Methods: We analyzed large-scale population-based studies from South Korea, Europe, and the TriNetX database, focusing on odds ratios (OR), hazard ratios (HR), and relative risks (RR) across mRNA and adenoviral vector vaccines. Pathological processes were hypothesized based on molecular and clinical evidence. Results: Studies investigating the association between COVID-19 vaccination and retinal vascular occlusion show conflicting results; some studies report no association (e.g., OR 0.93, 95% CI 0.60–1.45), others suggest reduced risk (e.g., OR 0.80, 95% CI 0.64–0.99), and one indicates increased risk over two years (HR 2.19, 95% CI 2.00–2.39). Adenoviral vector vaccines, particularly ChAdOx1, show higher RAO incidence in specific cohorts. Proposed mechanisms include vaccine-induced immune thrombotic thrombocytopenia (VITT) via anti-PF4 antibodies, spike protein-mediated endothelial dysfunction, and adjuvant-driven inflammation. Conclusions: While causality remains unproven, temporal heterogeneity and vaccine type-specific risks warrant further investigation. Longitudinal studies with robust controls are needed to clarify these associations in the post-pandemic context. Full article

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders. Full article

Background: Recently, the addition of anti-CD38 monoclonal antibodies (mAbs) to standard first-line triplet regimens, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and dexamethasone, has led to the introduction of quadruplets in clinical practice. Methods: A systematic search was conducted (end-of-search: 9 November, 2024) for clinical trials investigating first-line anti-CD38 mAb-based quadruplets in combination with a PI and an IMiD. Pooled proportions and effect-estimates along with 95% confidence intervals were calculated with common-effect and random-effects models and further subgroup and meta-regression analyses were performed. Results: The pooled 2-, 3- and 4-year progression-free survival (PFS) rates were 89%, 77% and 86%, respectively. Furthermore, patients treated with quadruplets demonstrated a 46% reduced risk for disease progression or death (HR = 0.54, 95% CI: 0.46–0.64) compared to those on triplets. Overall survival (OS) rates were consistently high, ranging from 83% to 96% between different regimens. High rates of deep responses that deepened over time were observed, with the pooled proportion of patients achieving at least complete response being 64%. Importantly, the pooled MRD negativity rate was 62%, whereas patients treated with quadruplet first-line therapy had 2.5 times the odds to be MRD negative at any point compared with those on triplets. Moreover, the odds for sustained 12-month MRD negativity were thrice as much with quadruplets compared to triplets. Finally, while no increase in serious adverse events was observed with quadruplet regimens compared to triplets, a 46% statistically significant increased risk for grade 3–4 neutropenia and thrombocytopenia was observed, along with a 14% increased risk for grade 3–4 infections. Conclusions: The addition of anti-CD38 mAbs to standard triplet regimens has shown particularly favorable outcomes, supporting their integration in the upfront treatment of patients with NDMM. However, close monitoring for hematological toxicity and infections is essential. Full article

Background: Docetaxel is the standard of care for advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy and/or immunotherapy but is associated with modest clinical outcomes and considerable toxicity. Sacituzumab govitecan and datopotamab deruxtecan are trophoblast cell surface antigen (TROP)-2-directed antibody–drug conjugates (ADCs) that showed encouraging activity in pretreated patients with advanced NSCLC. This systematic review and pooled analysis aims to comprehensively assess the efficacy and safety of anti-TROP-2 ADCs compared to docetaxel in pretreated patients with advanced NSCLC. Methods: A systematic search through PubMed and EMBASE before 31 January 2025 was performed to identify eligible studies. Randomized controlled phase III trials comparing an anti-TROP-2 regimen to docetaxel in patients with pretreated advanced NSCLC were included. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs) were extracted from the identified trials. A pooled analysis of reconstructed patient data and meta-analysis employing the random-effect model were used to summarize the efficacy and safety outcomes. Results: Across the two trials included, 1207 patients were enrolled, 598 in the TROP-2 ADC arm and 609 in the docetaxel arm. Anti-TROP-2 treatment did not produce significant improvements in OS (HR: 0.90; 95% CI, 0.78–1.03; P = 0.13) and PFS (HR: 0.84; 95% CI, 0.68–1.02; P = 0.08), compared to docetaxel, even in patients with a nonsquamous histology (OS HR: 0.86; 95% CI, 0.73–1.01; P = 0.06; PFS HR: 0.76; 95% CI, 0.52–1.12; P = 0.17). Across the subgroup analyses, a statistically significant improvement in OS was observed in patients with actionable genomic alterations (AGAs) (HR: 0.63; 95% CI, 0.41–0.95; P = 0.03). Compared to docetaxel, the anti-TROP-2 regimen demonstrated a lower risk of developing grade ≥ 3 TRAEs (RR: 0.76; 95% CI, 0.55–1.05; P = 0.09). Conclusions: The anti-TROP-2 regimen showed a better safety profile but failed to demonstrate a relevant clinical improvement over docetaxel. Anti-TROP-2 ADCs could find a role in the management of patients with AGAs. Full article

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article

Treatment for relapsed/refractory multiple myeloma (RRMM) is complex, with several classes of drugs that can be combined into doublet, triplet, or quadruplet regimens. Real-world studies can help to determine the optimal treatment sequences and dosing through observed usage of drugs outside of clinical trials. Previous clinical trials have demonstrated high rates of durable responses in the treatment of patients with triple-class-exposed RRMM with regimens containing selinexor, a first-in-class, orally available selective exportin 1 inhibitor. This study analyzed real-world treatment patterns and survival outcomes using a nationwide electronic health record-derived, deidentified database of patients with RRMM treated with an eligible selinexor-containing, triplet-based regimen, including combinations with dexamethasone and pomalidomide, bortezomib, carfilzomib, or daratumumab. Patients had a real-world overall survival (rwOS) of 14.7 months (95% CI: 10.6, 20.9) and a derived progression-free survival (dPFS) of 4.7 months (95% CI: 3.4, 6.7). Patients with previous exposure to anti-CD38 monoclonal antibodies (mAbs) in the most recent regimen prior to the selinexor treatment had numerically higher survival outcomes (rwOS, 20.9; dPFS, 8.7 months). These data suggest that, in the real-world setting, the use of selinexor triplet regimens is effective in patients with RRMM, especially those with prior exposure to an anti-CD38 mAb in the immediate prior line of therapy. Full article

Background: Treatment of multiple myeloma has advanced tremendously with the approval of anti-CD38 antibodies. Their efficacy is impressive but still controversial in the 1q amplification subgroup (amp1q). This retrospective study aims to provide real-world data. Methods: This trial is analyzing 74 patients with relapsed/refractory multiple myeloma treated with CD38Abs at the Medical University of Innsbruck (2016–2023). High-risk (HR) cytogenetics according to R-ISS (t(4;14), t(14;16), t(14;20), del(17p)), the presence of amp(1q21), the frequency of two HR markers (double hit), and the high-risk criteria agreed at IMS 2024 (HR-IMS24) were considered. Results: The median age of the 74 patients (62.1% male) was 62 years, with a median follow-up of six years. Most patients received third-line therapy (37.8%). R-ISS HR was documented in 39.2% of patients, double hit in 13.5% of patients, and HR-IMS24 in 32.4% of patients, while amp1q was detected in 35.1% of patients. The median OS was 66 months (35–89), and the median PFS was 17 months (6.5–26.9). While neither R-ISS HR nor isolated amp1q had an impact on progression-free survival (e.g., amp1q 7.03: 1.95–22.44; p = 0.347), the occurrence of a double-hit pattern significantly impaired PFS and OS (6.2: 1.4–16.4 months; p = 0.044; OS, 42.8: 25.9–74.6 months; p = 0.035). Patients fulfilling the HR-IMS24 criteria (32.4%, 24 patients) also exhibited an impaired PFS and OS (7: 2.7–18.1 months, p = 0.023; 40.12: 21.1–74.5 months, p = 0.01). Conclusions: This retrospective study highlights the durable effect of daratumumab on cytogenetic abnormalities, particularly amp1q. However, patients who meet the criteria for double-hit myeloma or the high-risk IMS2024 criteria remain a difficult-to-treat patient population who require early access to new treatment approaches. Full article

Introduction: Heparin-induced thrombocytopenia (HIT) is an autoimmune life-threatening prothrombotic syndrome associated with low platelet count after heparin exposure. Spontaneous heparin-induced thrombocytopenia (S-HIT) is an even less frequent variant of HIT, with only a handful of reports available in the literature, where unexplained thrombocytopenia and/or thrombosis without recent heparin exposure occurs in the setting of positive anti-PF4 antibodies. Case Presentation: We report a case of S-HIT associated with pulmonary artery embolism, left internal jugular vein, and cerebral vein sinus thrombosis complicated with ipsilateral acute intracerebral hemorrhage. Discussion: It is important to highlight that in patients with otherwise unexplained thrombocytopenia and prior exposure to an inflammatory process, S-HIT should be on the differential. Conclusions: Recognition and avoidance of heparin exposure is the most important aspect of S-HIT, as the management is otherwise similar to HIT. Full article

Osimertinib has been the standard treatment for advanced Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) for many years. However, even with remarkable response rate, progression-free survival (PFS) and survival benefit as compared to the old generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, treatment outcomes for these subsets of patients remain a challenge. Recently, in order to go beyond osimertinib, new treatment strategies have been developed. In particular, in the FLAURA 2 phase III randomized trial, the combination of platin-based chemotherapy and osimertinib showed impressive PFS benefits as compared to single-agent osimertinib. Furthermore, in the MARIPOSA phase III randomized study, the combination of the anti-EGFR and anti-MET monoclonal antibody amivantamab combined with the new anti-EGFR TKI lazertinib demonstrated remarkable PFS benefit as compared to single agent osimertinib. This paper will discuss these new treatment options and potential selection criteria for personalized treatment of patients. Full article

Background/Objectives: Vascular endothelial growth factor (VEGF)-A promotes an immunosuppressive tumor microenvironment, potentially affecting the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody therapy. VEGF₁₂₁ and VEGF₁₆₅, VEGF-A isoforms, promote and inhibit tumor growth, respectively. Additionally, VEGF-A levels differ depending on whether they are measured in serum or plasma. However, whether the serum or plasma levels of total VEGF-A (tVEGF-A) or its isoforms are the most suitable for predicting anti-PD-1/PD-L1 antibody therapy efficacy remains unclear. Methods: Eighty-six patients with non-small-cell lung cancer (NSCLC) who were treated with anti-PD-1/PD-L1 antibody monotherapy between December 2015 and December 2023 were retrospectively enrolled. The association between the serum and plasma levels of tVEGF-A and its isoforms (VEGF₁₂₁ and VEGF₁₆₅) and treatment outcomes was analyzed. Results: The median progression-free survival (PFS) was 2.9 months, and the objective response rate (ORR) was 23.3%. PFS was significantly shorter in patients with higher tVEGF-A serum levels (≥484.2 pg/mL) than in those without (median PFS 2.1 vs. 3.7 months, p = 0.004). In contrast, plasma tVEGF-A levels could not be used to stratify PFS. Therefore, the serum levels of VEGF-A isoforms were measured. Patients with higher VEGF₁₂₁ serum levels (≥523.5 pg/mL) showed both significantly shorter PFS (median PFS 2.3 vs. 3.3 months, p = 0.022) and a lower ORR (9.7% vs. 30.9%, p = 0.033) than those without. Multivariate Cox and logistic regression analyses showed that higher levels of serum VEGF₁₂₁ were significantly associated with shorter PFS and a lower ORR. Conclusions: Serum VEGF₁₂₁ levels may be useful in predicting anti-PD-1/PD-L1 antibody monotherapy efficacy. Full article

Background/Objectives: Anti-CD20 monoclonal antibodies combined with alkylator-based chemotherapy enhance survival in chronic lymphocytic leukemia (CLL). However, the risks of infection and bone marrow suppression may mean that new, targeted therapies are more appropriate for some patients than fludarabine–cyclophosphamide–rituximab (FCR). In the Republic of Korea, where insurance limits coverage to novel agents, FCR therapy should be carefully considered for patients with CLL. Methods: Using clinical data from 144 FCR-treated patients with CLL, we retrospectively analyzed clinical characteristics impacting survival outcomes, the impact of cytopenia after FCR, and the durable remission status in terms of measurable residual disease (MRD). We compared the impact of bicytopenia with those of other hematologic conditions. Results: The 5-year overall survival (OS) and 5-year progression-free survival (PFS) for all patients were 84.4% and 68.3%, respectively. FCR-treated patients in the bicytopenia and TP53-positive groups exhibited poor OS and PFS; in particular, the bicytopenia group often experienced prolonged anemia and thrombocytopenia (6–12 months). The responder group achieved sustained remission for a median of 5 years for MRD negativity. Conclusions: In bicytopenia, FCR can induce prolonged cytopenia, making it difficult to switch to second-line therapy or complete cycles of chemoimmunotherapy, directly affecting poor survival outcomes. The cautious application of FCR therapy in CLL without bicytopenia or TP53 positivity can achieve long-term remission. Full article