Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02.

INTRODUCTION: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results used for study enrollment. METHODS: This phase 2, open-label study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥ 1 systemic treatment or without alternative treatments. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: In total, 111 (41.6%) and 151 (56.6%) patients were enrolled with IHC 3+ and IHC 2+ tumors, respectively. In patients with IHC 3+ tumors, investigator-assessed confirmed ORR was 51.4% [95% confidence interval (CI) 41.7, 61.0], and median DOR was 14.2 months (95% CI 10.3, 23.6). In patients with IHC 2+ tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8 months (95% CI 4.5, 12.6). Safety was consistent with the known profile of T-DXd. CONCLUSION: In line with previously reported results, T-DXd demonstrated clinically meaningful benefit in patients with HER2-expressing tumors, with the greatest benefit in patients with IHC 3+ tumors. These data support the antitumor activity of T-DXd in HER2-expressing solid tumors, irrespective of whether patients are identified by local or central HER2 IHC testing.

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.

PURPOSE: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Catalytic Advantages of SO3H-Modified UiO-66(Zr) Materials Obtained via Microwave Synthesis in Friedel-Crafts Acylation Reaction.

The catalytic activity and stability of sulfonic-based UiO-66(Zr) materials were tested in the Friedel-Crafts acylation of anisole with acetic anhydride. The materials were prepared using microwave-assisted synthesis, producing microporous materials with remarkable crystallinity and physicochemical features as acid catalysts. Different ratios between both organic ligands, terephthalic acid (H2BDC) and monosodium 2-sulfoterephthalic acid (H2BDC-SO3Na), were used for the synthesis to modulate the sulfonic content. The sulfonic-based UiO-66(Zr) material synthesized with a H2BDC/H2BDC-SO3Na molar ratio of 40/60 exhibited the best catalytic performance in the acidic-catalyzed Friedel-Crafts acylation reaction. This ratio balanced the number of sulfonic acid sites and their accessibility within the UiO-66 microporous structure. The catalytic performance of this material increased remarkably at 200 °C, outperforming reference acids and commercial heterogeneous catalysts such as Nafion-SAC-13 and Amberlyst-70. Additionally, the best sulfonic-based UiO-66(Zr) material proved to be stable in four successive reaction cycles, maintaining both its catalytic activity and its structural integrity.

Physician-reported patient involvement and treatment decisions in first-line ovarian cancer in the USA and Europe.

OBJECTIVES: Real-world data evaluating how approvals of novel treatment regimens for ovarian cancer have impacted the treatment paradigm, including first-line maintenance, are lacking. This analysis aimed to describe treatment patterns for advanced epithelial ovarian cancer in Europe and the USA in the first-line maintenance setting. Patient characteristics, biomarker testing rates, and drivers of treatment choice were also evaluated. METHODS: A retrospective chart review study of electronic medical records in Europe and the USA was conducted for patients diagnosed with epithelial ovarian cancer (June 1, 2017-May 31, 2020), in line with Healthcare Market Research guidelines. Eligible physicians extracted data from electronic medical records by completing standardized patient record forms, including questions on patient involvement in treatment decisions. Patients with advanced (stage III/IV) disease were stratified by country and diagnosis date to provide information on treatment patterns. RESULTS: Patient record forms for 7072 patients with epithelial ovarian cancer were completed by 416 physicians; 5386 patients had stage III/IV ovarian cancer. Over time, the percentage of patients who were tested for BRCA mutations or homologous recombination deficiency increased. Patient preference was documented as a reason for treatment selection in approximately one-sixth of cases in the first-line adjuvant and first-line maintenance settings. The use of first-line maintenance poly(ADP-ribose) polymerase inhibitor monotherapy increased over time, while the use of vascular endothelial growth factor inhibitor monotherapy decreased. CONCLUSIONS: This real-world study showed that treatment patterns for advanced epithelial ovarian cancer varied by country. Rates of physician-reported patient involvement in treatment decisions in the first-line adjuvant and maintenance treatment settings for ovarian cancer were low, highlighting an unmet need for initiatives to improve patient involvement in shared decision-making regarding maintenance therapy selection.

SENECA study: staging endometrial cancer based on molecular classification.

OBJECTIVE: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. METHODS: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. RESULTS: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). CONCLUSIONS: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.

Photonic and Nanomechanical Modes in Acoustoplasmonic Toroidal Nanopropellers.

Non-conventional resonances, both acoustic and photonic, are found in metallic particles with a toroidal nanopropeller geometry, which is generated by sweeping a three-lobed 2D shape along a spiral with twisting angle α. For both optical and acoustic cases, the spectral location of resonances experiences a red-shift as a function of α. We demonstrate that the optical case can be understood as a natural evolution of resonances as the spiral length of the toroidal nanopropeller increases with α, implying a huge helicity-dependent absorption cross-section. In the case of acoustic response, two red-shifting breathing modes are identified. Additionally, even a small α allows the appearance of new low-frequency resonances, whose spectral dispersion depends on a competition between the length of the generative spiral and the pitch of the toroidal nanopropeller.

Magneto-optical Particles in Isotropic Spinning Fields Mimic Magnetic Monopoles.

In contrast with the typical electric currents accelerated under the influence of a Coulombic force, there are only a few condensed matter examples of particles experiencing a force proportional to a constant, external magnetic field. In this Letter, we present a new alternative, based on an isotropic radiation spinning field and the magneto-optical effect, in which a particle is propelled by a magnetic field just like a magnetic monopole will do. This is a purely nonreciprocal effect as the reciprocal equivalent (a chiral dipole), despite presenting a dichroic response, does not experience any force when illuminated by the spinning field. The "magnetic charge" induced by impinging radiation on the magneto-optical dipole is found to depend linearly on the helicity of the field. In addition, this artificial monopole experiences a dichroic permanent optical torque and does not interact with an external electric field.

Patterns of initial ovarian cancer recurrence on niraparib maintenance monotherapy in patients with no baseline evidence of disease after first-line chemotherapy: An ad hoc subgroup analysis of PRIMA/ENGOT-OV26/GOG-3012.

OBJECTIVES: Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). METHODS: PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. RESULTS: Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1-2). In total, 93.2% (177/190) of patients developed 1-3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. CONCLUSIONS: Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy.

Tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy.

PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

Efficient Self-Condensation of Cyclohexanone into Biojet Fuel Precursors over Sulfonic Acid-Modified Silicas: Insights on the Effect of Pore Size and Structure.

Mesoporous silica materials with different pore structures and sizes have been used for supporting aryl sulfonic acid catalytic sites via a postsynthetic grafting approach. The synthesized materials have been evaluated in the solventless acid-catalyzed self-condensation of cyclohexanone (CHO) to obtain the corresponding C12 adducts. These compounds display great potential as oxygenated fuel precursors as they can be transformed into jet fuel range alkanes in a subsequent hydrodeoxygenation process. In this work, the synthesized catalysts have displayed high selectivity values toward monocondensed compounds (>95%), thus limiting the formation of undesired heavier condensation products, together with CHO conversion values in the range 20-40% after 2 h of reaction at 100 °C. The structural and textural properties of the supports play an important role in the catalytic performance. Moreover, the activity per acid center is correlated with the textural properties of the supports, indicating that a lower surface density of the anchored aryl sulfonic groups affords an improvement in their specific activity. Finally, the benefit of using supports with large pore sizes and open structures, which limit the fouling of the catalysts by organic deposits, is demonstrated in a stability and reusability test.

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.

Active learning streamlines development of high performance catalysts for higher alcohol synthesis.

Developing efficient catalysts for syngas-based higher alcohol synthesis (HAS) remains a formidable research challenge. The chain growth and CO insertion requirements demand multicomponent materials, whose complex reaction dynamics and extensive chemical space defy catalyst design norms. We present an alternative strategy by integrating active learning into experimental workflows, exemplified via the FeCoCuZr catalyst family. Our data-aided framework streamlines navigation of the extensive composition and reaction condition space in 86 experiments, offering >90% reduction in environmental footprint and costs over traditional programs. It identifies the Fe65Co19Cu5Zr11 catalyst with optimized reaction conditions to attain higher alcohol productivities of 1.1 gHA h-1 gcat-1 under stable operation for 150 h on stream, a 5-fold improvement over typically reported yields. Characterization reveals catalytic properties linked to superior activities despite moderate higher alcohol selectivities. To better reflect catalyst demands, we devise multi-objective optimization to maximize higher alcohol productivity while minimizing undesired CO2 and CH4 selectivities. An intrinsic trade-off between these metrics is uncovered, identifying Pareto-optimal catalysts not readily discernible by human experts. Finally, based on feature-importance analysis, we formulate data-informed guidelines to develop performance-specific FeCoCuZr systems. This approach goes beyond existing HAS catalyst design strategies, is adaptable to broader catalytic transformations, and fosters laboratory sustainability.

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.).

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.

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.

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.

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.

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.