Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer.

BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).

Retrospective multicenter study of elderly patients with platinum-sensitive relapsed ovarian cancer treated with trabectedin and pegylated liposomal doxorubicin (pld) in a real-world setting: a geico study.

BACKGROUND: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting. METHODS: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible. RESULTS: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%). CONCLUSIONS: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients.

Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

Integrating climate policies in the sustainability analysis of green chemicals.

New and enhanced processes will not be the only drivers toward a sustainable chemical industry. Implementing climate policies will impact all components of the chemical supply chain over the following decades, making improvements in energy generation, material extraction, or transportation contribute to reducing the overall impacts of chemical technologies. Including this synergistic effect when comparing technologies offers a clearer vision of their future potential and may allow researchers to support their sustainability propositions more strongly. Ammonia and methanol production account for more than fifty percent of the CO2 emissions in this industry and are, therefore, excellent case studies. This work performs a prospective life cycle assessment until 2050 for fossil, blue, wind, and solar-based technologies under climate policies aiming to limit the global temperature rise to 1.5 °C, 2 °C, or 3.5 °C. The first finding is the inability of fossil-based routes to reduce their CO2 emissions beyond 10% by 2050 without tailored decarbonisation strategies, regardless of the chemical and climate policy considered. In contrast, green routes may produce chemicals with around 90% fewer emissions than today and even with net negative emissions (on a cradle-to-gate basis), as in the case of methanol (up to -1.4 kg CO2-eq per kg), mainly due to the contributions of technology development and increasing penetration of renewable energies. Overall, the combined production of these chemicals could be net-zero by 2050 despite their predicted two to fivefold increase in demand. Lastly, we propose a roadmap for progressive implementation by 2050 of green routes in 26 regions worldwide, applying the criterion of at least 80% reduction in climate change impacts when compared to their fossil alternatives. Furthermore, an exploratory prospective techno-economic assessment showed that by 2050, green routes could become more economically attractive. This work offers quantitative arguments to reinforce research, development, and policymaking efforts on green chemical routes reliant on renewable energies.

Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.

Prognostic value of systemic inflammation response indexes obtained from the complete blood count in patients treated for advanced ovarian carcinoma in front line.

OBJECTIVE: Various systemic inflammation response indexes (SIRI) have repeatedly been described as prognostic factors in ovarian cancer. They have not been validated in prospective trials and published results are sometimes contradictory. We aimed to explore their role in a cohort of patients diagnosed with stage III and IV ovarian cancer treated at our institution. METHODS: We retrospectively examined the prognostic influence of the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), the red cell distribution width (RDW), and the mean platelet volume (MPV). RESULTS: A total of 77 patients were analyzed. NLR > 2.243 at diagnosis, NLR before primary surgery, MLR at diagnosis, PLR > 289.1 at diagnosis, and PLR at diagnosis were significant in univariate Cox regression for progression-free survival, but none of them retained their significance in the multivariate Cox regression analysis. For overall survival, NLR > = 2.53 at diagnosis, MLR > = 0.245 at diagnosis, and PLR > = 198.3 at diagnosis resulted significant in univariate COX regression; only PLR > = 198.3 at diagnosis retained its significance in the multivariate analysis. CONCLUSION: In our cohort, PLR > = 198.3 was an independent prognostic factor for worse OS. The definitive role of SIRI in ovarian cancer has not yet been established. If their value as prognostic factors could finally be established, they would become a simple and economical method to predict prognosis in patients with advanced ovarian cancer. Therefore, it is time to conduct prospective, multicenter studies with larger samples to definitively establish its role in ovarian cancer, if any.

Low phospholipid-associated cholelithiasis syndrome (LPAC), a not uncommon cause of biliary problems and hospital admissions.

BACKGROUND AND AIMS: Biliary diseases are a major source of morbidity and mortality for patients and a burden for the healthcare system. The genetic syndrome LPAC (low phospholipid-associated cholelithiasis) is a little known and rare entity whose treatment with bile salts avoids symptoms, admissions and the need for surgery. Our aim is to determine its incidence and characteristics in our center. METHODS: Prospective study between February 2021 and September 2022. LPAC was diagnosed if (at least two): onset of biliary problems <40 years of age, recurrence of symptoms after cholecystectomy, ultrasound image of hepatolithiasis (multiple echoic foci, comet-tail images, hepatolithiasis with acoustic shadow). Demographic, clinical, genetic (analysis of MDR3 gene mutations) and ultrasound characteristics were analyzed, as well as their incidence in hospital admissions for biliary causes. RESULTS: 36 patients with LPAC were identified. Of these, 6 were among 237 admissions for biliary causes in the previous 9 months, with an incidence of 2.5% (95%CI 1.17-5.41). By age subgroup, the incidence was 16.7% in those admitted <40 years and 9.1% in those <50 years. Considering women only, the incidence was 21% in those admitted <40 years and 15.8% in those <50 years. All patients remained asymptomatic after treatment with ursodeoxycholic acid and there were no new admissions. CONCLUSIONS: LPAC syndrome is not as uncommon as it may appear, especially in women <50 years of age admitted with biliary problems. Its correct diagnosis based on simple criteria would avoid a significant number of hospital admissions and unnecessary cholecystectomies.

Patient care and access to clinical trials in gynaecological oncology: global implications of the early phase of the COVID-19 pandemic.

PURPOSE: Our prospective international survey evaluated the impact of the early phase of the COVID-19 pandemic on the management gynaecological malignancies from the multidisciplinary physicians' perspective with particular focus on clinical infrastructures and trial participation. METHODS: Our survey consisted of 53 COVID-related questions. It was sent to healthcare professionals in gynaecological oncology centres across Europe and Pan-Arabian region via the study groups and gynaecological societies from April 2020 to October 2020. All healthcare professionals treating gynaecological cancers were able to participate in our survey. RESULTS: A total of 255 answers were collected from 30 countries. The majority (73%) of participants were gynaecological oncologists from university hospitals (71%) with at least an Intensive Care Unit with cardiopulmonary support available at their institutions. Most institutions continued to perform elective surgeries only for oncological cases (98%). Patients had to wait on average 2 weeks longer for their surgery appointments compared to previous years (range 0-12 weeks). Most cases that were prioritised for surgical intervention across all gynaecological tumours were early-stage disease (74%), primary situation (61%) and good ECOG status (63%). The radicality of surgery did not change in the majority of cases (78%) across all tumour types. During the pandemic, only 38% of clinicians stated they would start a new clinical trial. Almost half of the participants stated the pandemic negatively impacted the financial structure and support for clinical trials. Approximately 20% of clinicians did not feel well-informed regarding clinical algorithm for COVID-19 patients throughout the pandemic. Thirty percent stated that they are currently having trouble in providing adequate medical care due to staff shortage. CONCLUSION: Despite well-established guidelines, pandemic clearly affected clinical research and patientcare. Our survey underlines the necessity for building robust emergency algorithms tailored to gynaecological oncology to minimise negative impact in crises and to preserve access to clinical trials.

Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells.

Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.

Gold trifluoromethyl complexes as efficient regioselective catalysts in alkyne hydration.

Gold (III) complexes containing trifluromethyl ligands are efficient catalyst in the hydration of alkynes, operating at low catalyst loadings, without additives, using environmentally friendly solvents and at mild conditions (60 ºC). Hydration of terminal and internal alkynes provide the corresponding ketones in quantitative yields without special precautions as dry solvents or inert atmospheres. Remarkably, hydration of asymmetric internal alkynes proceeds with moderate to notable regioselectivities, providing mixtures of the two possible isomers with ratios up to 90:10.

Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study.

OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.

Protocol for acquisition of images and measurement of transabdominal ultrasound pancreatic two-dimensional shear wave elastography (2D-SWE). / Protocolo de adquisición de imágenes y medición de la elasticidad pancreática mediante elastografía por onda de cizallamiento bidimensional (2D-SWE) transabdominal.

INTRODUCTION: Transabdominal ultrasound (TU) pancreatic 2D-SWE elastography is a developing technique that needs to be protocolized. OBJECTIVES: Establish a protocol for image acquisition and measurement of TU pancreatic - 2D-SWE elastography and estimate the minimum number of measurements to be performed. MATERIALS AND METHODS: Ten measurements of pancreatic elasticity were taken in healthy volunteers using TU-2D-SWE, following a strict protocol for image acquisition and measurement. RESULTS: The 70% of the participants were women, with an average age, weight, and BMI of 49.5±15.7 years, 65.9±11.9kg, and 24.5±4.2kg/m2, respectively. Measurements were taken from the body (70%), tail (16.7%), and pancreatic head (13.3%). The median mean velocity and elasticity were 1.46±0.25cm/sec and 6.46±2.87KPa, respectively. The ROI depth was 4.12±1cm and the SP-ROI distance was 5.2mm on average. There were no statistically significant differences between the 10 measurements. The reliability analysis of the measurements showed high internal consistency and repeatability. Taking 5-6 measurements ensured high concordance with the ten reference measurements. The measurements were significantly lower when the SP-ROI values were intermediate (0.3-0.6cm). The measurement accuracy was higher when performed at a depth less than 4.8cm. CONCLUSION: To measure pancreatic elasticity using TU-2D-SWE, we propose a strict protocol for image acquisition and measurement, taking a minimum of 5 measurements in the best visualized and accessible pancreatic portion, and preferably at a depth of less than 4.8cm.

Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations.

Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.

The Future of Chemical Sciences is Sustainable.

Chemistry, a vital tool for sustainable development, faces a challenge due to the lack of clear guidance on actionable steps, hindering the optimal adoption of sustainability practices across its diverse facets from discovery to implementation. This Scientific Perspective explores established frameworks and principles, proposing a conciliated set of triple E priorities anchored on Environmental, Economic, and Equity pillars for research and decision making. We outline associated metrics, crucial for quantifying impacts, classifying them according to their focus areas and scales tackled. Emphasizing catalysis as a key driver of sustainable synthesis of chemicals and materials, we exemplify how triple E priorities can practically guide the development and implementation of processes from renewables conversions to complex customized products. We summarize by proposing a roadmap for the community aimed at raising awareness, fostering academia-industry collaboration, and stimulating further advances in sustainable chemical technologies across their broad scope.

The CF3 Group as a Synthon of the CF+ Unit in Palladium Chemistry.

The homoleptic trifluoromethyl-palladium(II) complex [Pd(CF3)4]2- (1) is shown to be highly active towards amines. Thus, when treated with primary amines RNH2, it readily undergoes aminolysis of one of the CF3 ligands affording the isocyanide complexes [(CF3)3Pd(CNR)]- (R=aryl). In this process the original CF3 group undergoes total defluorination. Interestingly, the reaction of 1 with secondary amines R2NH proceeds with loss of just two F-substituents, whereby the Fischer-type fluoroaminocarbene complexes [(CF3)3Pd(CFNR2)]- are formed (R=Et, Ph). The reaction of 1 with diamines affords different [(CF3)3Pd(NHC)]- complexes containing sterically non-demanding NHC ligands. Representative examples of various topologies are reported based on the common imidazolidin-2-ylidene or benzimidazolin-2-ylidene rings as well as the expanded-ring perimidin-2-ylidene. This metal-tailored synthetic route, where a CF3 group acts as a pre-carbenic unit, is unprecedented in the vast NHC-chemistry. It takes place under very mild conditions and is envisaged to be extensible to other non-isolable NHC ligands. The key difluorocarbene intermediate [(CF3)3Pd(CF2)]- is experimentally detected.

Pyrazolate-Bridged NHC Cyclometalated [Pt2] Complexes and [Pt2Ag(PPh3)]+ Clusters in Electroluminescent Devices.

The ionic transition metal complexes (iTMCs) [{Pt(C∧C*)(µ-Rpz)}2Ag(PPh3)]X (HC∧C* = 1-(4-(ethoxycarbonyl)phenyl)-3-methyl-1H-imidazole-2-ylidene, X = ClO4/PF6; Rpz = pz 1a/2a, 4-Mepz 1b/2b, and 3,5-dppz 1c/2c) were prepared from the neutral [{Pt(C∧C*)(µ-Rpz)}2] (Rpz = pz A, 4-Mepz B, and 3,5-dppz C) and fully characterized. The "Ag(PPh3)" fragment is in between the two square-planar platinum units in an "open book" disposition and bonded through two Pt-Ag donor-acceptor bonds, as shown by X-ray diffraction (dPt-Ag ∼ 2.78 Å, 1a-1c). 195Pt{1H} and 31P{1H} NMR confirmed that these solid-state structures remain in solution. Photoluminescence studies and theoretical calculations on 1a, were performed. The diphenylpyrazolate derivatives show the highest photoluminescence quantum yield (PLQY) in the solid state. Therefore, 2c and its neutral precursor C were selected as active materials on light-emitting devices. OLEDs fabricated with C showed a turn-on voltage of 3.2 V, a luminance peak of 21,357 cd m-2 at 13 V, and a peak current efficiency of 28.8 cd A-1 (9.5% EQE). They showed a lifetime t50 of 15.7 h. OLEDs using 2c showed a maximum luminance of 114 cd m-2, while LECs exhibited a maximum luminance of 20 cd m-2 and a current efficiency of around 0.2 cd A-1, with a t50 value of 50 min.

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma.

Introduction: The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2. Methods: We compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 versus IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines. Results: The IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h. Conclusion: CB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

Progression-free survival and safety at 3.5 years of follow-up: results from the randomized phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer - a plain language summary.

What is this summary about? This PLSP provides a short summary of an original scientific article that presented results from the PRIMA study after 3.5 years of follow-up time. The original article was published in the European Journal of Cancer in 2023.The PRIMA study included adult patients with newly diagnosed advanced high-risk ovarian cancer whose tumors shrunk or became undetectable after treatment with chemotherapy with or without surgery. The PRIMA study evaluated how well the drug niraparib, also known as Zejula, worked at delaying or preventing ovarian cancer from coming back (recurring) or getting worse (progressing) compared with placebo (a substance with no effects that a doctor gives to a patient instead of a drug). The first results from the PRIMA study were published in 2019, when patients had participated in the PRIMA study for about 1.2 years.The article this PLSP is based on reports longer-term data from the PRIMA study, when patients had participated in the PRIMA study for about 3.5 years. Patients were monitored (or followed) for a longer time to understand how well niraparib continued to work and to evaluate whether the safety of niraparib changed with additional time being monitored.What were the results? Patients who took niraparib had more time before their cancer came back or got worse than patients who took placebo. In terms of safety, no new types of side effects with niraparib treatment were observed with additional time being monitored as part of the PRIMA study.What do the results mean? These results support that niraparib remains an important treatment option to help delay the cancer from coming back or getting worse in patients with newly diagnosed advanced ovarian cancer that responded to initial treatment.Clinical Trial Registration: NCT02655016 (PRIMA study) (ClinicalTrials.gov).