In FLAURA2 (NCT04035486) 1L osi with addition of platinum-pemetrexed chemotherapy (osi+CTx) showed significant PFS benefit vs osi alone (HR 0.62 [95% CI 0.49, 0.79] p<0.0001, per investigator) in EGFRm advanced NSCLC. Higher ≥Grade 3 (G3) AE rates were seen with osi+CTx vs osi, driven by well-recognised CTx-related AEs. We report additional safety analyses of specific AEs of interest from FLAURA2. Eligible pts (≥18 years with EGFRm advanced NSCLC, no prior tx for advanced NSCLC; stable CNS metastases allowed) were randomised 1:1 to osi+CTx (osi once daily [QD] + pemetrexed and cisplatin or carboplatin for 4 cycles every 3 weeks (Q3W) [induction], followed by osi QD + pemetrexed Q3W [maintenance]) or osi alone until disease progression/unacceptable toxicity/other discontinuation criteria. Safety was assessed via AE reporting (until 28 days after tx discontinuation) and clinical investigations. Data cutoff: 03 Apr 2023. The safety analysis set included pts who received ≥1 dose of study tx: osi+CTx n=276; osi n=275. In the osi+CTx arm, median duration of exposure was: osi 22.3, platinum CTx 2.8 and pemetrexed 8.3 months (mos). AE onset frequency and severity (osi+CTx arm) were highest during the induction period (∼0–<3 mos) and reduced over time during the maintenance period (>3 mos); ≥G3 AEs (64% overall for osi+CTx arm) reduced by approximately half from 49% (during 0–<3 mos) to 24% (during 3–‍<9 mos), and remained around this level for the rest of the tx period. The majority of ≥G3 AEs (osi+CTx arm) were haematological toxicities (neutropenia and anaemia), as expected from CTx-related AEs. AEs leading to osi discontinuation in the osi+CTx arm vs osi arm were 11% vs 6%; the most frequently reported events leading to discontinuation of osi in both arms were primarily those which mandated tx discontinuation by protocol, ILD (2% vs 2%) and pneumonitis (1% vs <1%). As expected, AE onset frequency and severity (osi+CTx arm) were highest during induction with clear reductions over time in the maintenance period. The addition of CTx had minimal impact on osi discontinuations. In FLAURA2, osi+CTx safety was consistent with the established profiles of osi and CTx, and manageable with standard medical practice.

We present Fermi Gamma-ray Burst Monitor (Fermi-GBM) and Swift Burst Alert Telescope (Swift-BAT) searches for gamma-ray/X-ray counterparts to gravitational wave (GW) candidate events identified during the third observing run of the Advanced LIGO and Advanced Virgo detectors. Using Fermi-GBM on-board triggers and sub-threshold gamma-ray burst (GRB) candidates found in the Fermi-GBM ground analyses, the Targeted Search and the Untargeted Search, we investigate whether there are any coincident GRBs associated with the GWs. We also search the Swift-BAT rate data around the GW times to determine whether a GRB counterpart is present. No counterparts are found. Using both the Fermi-GBM Targeted Search and the Swift-BAT search, we calculate flux upper limits and present joint upper limits on the gamma-ray luminosity of each GW. Given these limits, we constrain theoretical models for the emission of gamma-rays from binary black hole mergers.

Magnetars are neutron stars with exceptionally strong dipole magnetic fields which are observed to display a range of x-ray flaring behavior, but the flaring mechanism is not well understood. The third observing run of Advanced LIGO and Virgo extended from April 1, 2019 to March 27, 2020, and contained x-ray flares from known magnetar SGR 1935+2154, as well as the newly-discovered magnetar, Swift J1818-1607. We search for gravitational waves coincident with these magnetar flares with minimally modeled, coherent searches which specifically target both short-duration gravitational waves produced by excited f-modes in the magnetar's core, as well as long-duration gravitational waves motivated by the Quasi-Periodic Oscillations observed in the tails of giant flares. In this paper, we report on the methods and sensitivity estimates of these searches, and the astrophysical implications.

Gravitational lensing by massive objects along the line of sight to the source causes distortions to gravitational wave (GW) signals; such distortions may reveal information about fundamental physics, cosmology, and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO-Virgo network. We search for repeated signals from strong lensing by (1) performing targeted searches for subthreshold signals, (2) calculating the degree of overlap among the intrinsic parameters and sky location of pairs of signals, (3) comparing the similarities of the spectrograms among pairs of signals, and (4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by (1) frequency-independent phase shifts in strongly lensed images, and (2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the nondetection of GW lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects.

With high integration of distributed energy resources (DERs), modern distribution networks are subject to optimal power flow (OPF) analysis. Conventional non-linear and linear OPF models suffer from either infeasibility or inaccuracy for large networks, and global optimality is not guaranteed. Addressing computational infeasibility and non-convexity for DERs integrated distribution networks, this article presents a novel approach for OPF analysis employing semi-definite programming (SDP). For the proposed SDP-OPF model, network power flow relations utilize a bus injection model (BIM) for single-phase networks and a branch flow model (BFM) for multi-phased unbalanced power distribution networks. The exactness and the global optimality of the proposed SDP-OPF model are illustrated in this article. The proposed models' performance is evaluated in multiple standard power distribution test cases with a wide range of DER integration. The simulation results are compared with a nonlinear programming (NLP) based and a second order cone programming (SOCP) based OPF models. The comparison and the result analysis demonstrate that the proposed approach yields a more robust solution with improved convergence and accuracy.

Gall bladder cancer (GBCA) is a common malignancy in eastern part of India[1]. Traditionally, the outcomes of GBCA are poor. There is paucity of data from western countries due to the rarity[2]. The standard treatment for localised GBCA is upfront radical cholecystectomy followed by adjuvant chemotherapy and/or chemoradiotherapy [3, 4]. The surgical expertise has improved significantly over time in major centres. Here we retrospectively analyse the outcomes of treatment of early stage GBCA from a the largest tertiary care hospital from western India. All the patients who were diagnosed with adenocarcinoma of gallbladder were identified. Those who underwent surgery and adjuvant treatment at our hospital were selected. All the baseline clinicopathological characteristics were retrieved from electronic medical records. The survival data was collected from follow up visits as well as telephonic calls. Simple proportions were used for baseline characteristics and Kaplan Meier method was used for survival analysis. A total of 161 patients were identified and data was captured from electronic medical records. The median age was 56 yrs with a range of 26 to 80yrs. There were 103 females and 58 males. All patients underwent radical cholecystectomy at our hospital. Primary TNM distribution were as follows: pT2: 111 (70.25%), pT3: 44 (27.85%) and pT4: 3 (1.90%). The nodal statuses were, pN0: 91(61.9%), pN1: 51 (34.69%) and pN2: 5 (3.4%). The median number of lymph nodes harvested were 9 (range 1-43). All patients underwent adjuvant treatment. Adjuvant single agent capecitabine was the majority, 102 (63%) followed by gemcitabine-based platinum doublet, 50 patients (31%). Some patients also received adjuvant concurrent chemoradiotherapy 4 (2.4%). No adjuvant was prescribed to 3 (1.9%) patients. Out of total numbers, 55 (34.16%) patients relapsed. Out of the relapses, 25 (44.5%) were local and 30 (54.5%) were distant metastatic. The median follow up were 49 months (IQR 23 -71 months) In this study, the 24 month relapse free survival was 72.7% (95% CI: 0.64 - 0.79) and the 24 month overall survival was 82.2% (95% CI: 0.74 - 0.87). Our data,which is one of the largest one from India, shows early stage gallbladder cancer has very good outcomes after radical surgery and adjuvant chemotherapy. There was a higher proportion of T2 and node-negative disease, which could have led to better survival compared to published literature.

Non clear cell renal cell carcinoma (nccRCC) refers to a rare diverse heterogeneous group of tumors; usually treated with immunotherapy (IO) and or tyrosine kinase inhibitors (TKI). Prospective large-scale data from Asia specific countries is limited. We aimed to present the demographic profile and treatment outcome of nccRCC patients from single centre in India. This is a retrospective study on patients with metastatic nccRCC treated at Tata Medical Centre, Kolkata-West Bengal from 2012-2022. Demographic profiles, histologic subtypes, treatment details, response to therapy (by RECIST v1.1) and survival status were captured from electronic medical records of hospitals up till March 2023. Progression free survival (PFS) and Overall survival (OS) were estimated using Kaplan Meier method. A total of 89 patients were screened;24 excluded due to inadequate records. 65 patients were included in analysis, with a median age at diagnosis of 59 years (range 20-84). Histologic subtypes comprised 43% (n=28) papillary, 31%(n=20) clear cell with mixed histology, 3%(2) sarcomatoid & 23%(15) others including chromophobe, oncocytoma. The most common site of metastasis was lung 62% (n=40).15% presented with haematuria and 62%(n=40) underwent cytoreductive nephrectomy. Majority received pazopanib 46% (n=30) then chemotherapy 20% (n=13) including bevacizumab plus erlotinib, sunitinib 15%(10), cabozantinib 14%(9). Only 3(5%) received IO plus TKI combination. The best response was CR in 1.5%, PR 20%, SD 51% & PD 23% as per RECIST v1.1. Total 17 (26%) patients required dose reduction & interruption due to adverse effects & 33% received second-line therapy with nivolumab,axitinib & everolimus were commonly used. After a median follow up of 44 months; median PFS was 13 months (95%CI 7.2-18.9) & median OS was 17 months (95%CI 12.1-22.1). Regression analysis identified better outcome for PFS & OS with sarcomatoid subtype & those underwent prior nephrectomy. The overall response and survival was quite impressive in comparison with published data; despite limited number of cases treated with IO due to its cost.This study also highlighted better survival with sarcomatoid subtype and prior nephrectomy.

In the power distribution systems, optimal power flow (D-OPF) is formulated as a non-convex and non-linear programming (NLP) problem. Convex relaxation and linear approximation models have been increasingly adopted to achieve computational efficiency for D-OPF. Despite the benefits of scalability and global optimality, each method is based on certain assumptions, performs differently, and may lead to solutions that are physically not meaningful. In this context, this work numerically evaluates the relative performance of second-order cone programming (SOCP), semi-definite programming (SDP), and linear programming (LP) formulations of D-OPF in terms of their feasibility, optimality, and scalability with respect to NLP-based formulations. We also compare the bus injection (in bus voltage and current variables) and branch flow (in active and reactive power flow variables) based on NLP formulations. The performance is evaluated using small (123-node), medium (730-node), and large (2522-node) sized distribution feeders. Case studies, which are backed up by visualization of the analytical models for the solution space to the extent possible, show that (1) the feasibility and exactness of relaxed D-OPF formulations depend upon the problem type, (2) some NLP formulations are computationally more tractable than others, (3) different NLP formulations can converge to different local solutions, and (4) the approximate linear model may underestimate or overestimate the cost function (depending upon the problem type) and may lead to AC-infeasible solutions.

With the high penetration of distributed generations (DGs), modern distribution systems require novel and efficient optimal power flow (OPF) models. This paper proposes a second-order cone programming (SOCP) based AC-OPF model for three-phase radial power distribution networks. Mutual coupling effects are generally ignored in the existing multi-phase SOCP AC-OPF models. To overcome this critical issue, the proposed SOCP-OPF model introduces a coupling coefficient for the mutual coupling effects on the three-phase unbalanced lines. The derivation of the coupling coefficients has been illustrated with the required proof that the relaxation is tight and the solution from the proposed OPF model is optimal for an unbalanced multi-phase distribution network. The SOCP-OPF model is evaluated on several IEEE standard distribution networks without and with high penetration of Distributed Energy Resources (DERs). It has been shown that the proposed OPF model provides an optimal global solution for convex objective functions. Also, this OPF model is scalable and computationally efficient compared to Nonlinear Programming (NLP) and other convex OPF models.

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.

Dacomitinib, an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), is approved in advanced non-small cell lung cancer (NSCLC) with mutated EGFR. Literature on real world experience of dacomitinib is lacking, especially in patients (pts) with brain metastasis and uncommon EGFR mutation. This is single centre retrospective study of EGFR mutated advanced NSCLC pts treated with dacomitinib between July’19 and Feb’23. Clinicopathologic features, treatment details, toxicity and treatment outcome were recorded. Total 111 pts were treated with median age of 62 years (range: 39-82). ECOG performance status (PS) was 1 in 65 pts, 2 in 37 pts and 3 in 9 pts. 42 (38%, n=96) pts had brain metastasis and 21 pts received WBRT. Type of mutations was Del 19 in 66 pts, L858R in 35 pts, G719X in 4 pts, G719X and S768I in 2 pts, L861Q in 2 pts, and Del 19 + L858R, Exon 20ins + L858R in one patient each. Starting dose of dacomitinib was 45 mg in 43 pts and 30 mg in 68 pts (61%). Intracranial response (n=27) was – CR in 2 pts, PR in 18 pts, SD in 5 pts, and PD in 2 pts. 41 out of 52 pts underwent re-biopsy on progression, 17 pts had EGFR T790M mutation and 3 had small cell transformation. After a median follow-up of 19 months (95 CI: 14.4-23.2), the median PFS was 21.5 months (95% confidence interval [CI]: 18.7 – 26.2) and median overall survival (OS) was 31.2 months (95 CI: 23.4 – not reached). PFS was inferior in pts with brain metastases (p=0.003) and 30 mg starting dose (p=0.004), but not OS and neither with type of mutation or dose modification. 81(73%) pts had any grade of toxicity and 53 pts (47%) had any grade 2 & 3 toxicity. Total 25 pts (23%) required dose modification (Table).Table: 1339PVariablesGroupsHRPProgression-free survivalBrain metastasesAbsent (n=54)1Present (n=42)2.90.003Not known (n=15)1.40.53Type of mutationDel 19 (n=69)1L858R (n=34)1.60.12Uncommon mutation (n=8)1.50.47Starting dose of dacomitinib30 mg (n=68)145 mg (n=43)0.90.004Dose modificationNot required (n=88)1Required (n=23)0.60.14Overall survivalBrain metastasesAbsent (n=54)1Present (n=42)1.60.22Not known (n=15)0.80.7Type of mutationDel 19 (n=69)1L858R (n=34)1.50.32Uncommon mutation (n=8)1.60.48Starting dose of dacomitinib30 mg (n=68)145 mg (n=43)10.8Dose modificationNot required (n=88)1Required (n=23)0.90.9 Open table in a new tab To best of our knowledge, this is largest real-world study of dacomitinib in mEGFR advanced NSCLC. Dacomitinib is active in pts with brain metastasis, uncommon EGFR mutation, in patients with poor PS, and at 30 mg starting dose. Dacomitinib showed very good PFS with manageable safety profile.

Real world Indian data with maintenance Poly ADP Ribose Polymerase 1 Inhibitors (PARPi) in newly diagnosed advanced ovarian cancer (AOC) are lacking. The purpose of this study was to evaluate optimal dosing, safety and efficacy of olaparib or rucaparib maintenance plus minus bevacizumab in germline BRCA mutations or HRD-positive AOC patients. This was a retrospective study from Tata Medical Center, Kolkata, West Bengal, India; included patients with stage III & IV (AJCC 7th) AOC between 2020- 2023. All data captured from electronic medical records of hospital up till June 2023. Either standard dose or reduced dose of tablet olaparib (450mg/day orally) or rucaparib (600mg/day orally) plus minus injection bevacizumab (7.5 mg/kg IV q 3weekly) was offered as a front-line maintenance therapy after completion of surgery and platinum based chemotherapy without any residual disease. Out of 89 screened patients, 41 received therapy with a median age at diagnosis 57 years (range 41-74). 98% had high grade serous histology with 61% stage III and 39% stage IV diseases. 28(68%) patients had germline BRCA mutations and 13(32%) HRD-positive (high genomic scar score). 34(82%) patients received maintenance bevacizumab up to one year along with PARPi. The duration of exposure of PARPi ranged from 2-24 months and 63% patients started with reduced dose. Dose reductions due to adverse effects (AEs) seen in 42%. With a median follow up of 32 months (95% CI 22.04-41.95); two years predicted progression free survival (PFS) of the entire cohort was 84%, no difference in PFS between standard dose and reduced dose group (30 vs 35 months; log rank p=0.67). There was no significant difference in PFS among olaparib and rucaparib (NR vs 35 months; log rank p=0.20). The most common ≥ grade III AEs (CTCAE V.5) were anemia (24%), thrombocytopenia (7%), fatigue (22%), diarrhea (2%) and transamnitis (5%). We found that lower doses of PARPi were equally efficacious with good tolerance in comparison with standard dose and can be offered as first-line maintenance therapy in AOC patients with germline BRCA mutation or HRD positive in a resource-limited setting.

Dacomitinib, a second-generation, irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), provided statistically significant progression-free survival improvement over gefitinib in treatment-naive patients with advanced EGFR mutation–positive non-small cell lung cancer (NSCLC) in a global phase 3 study (ARCHER 1050; NCT01774721). Here, we report interim analysis of ARIA, a non-interventional study of dacomitinib’s real-world (RW) utilization and associated clinical outcomes in Asian patients with advanced EGFR mutation–positive NSCLC. This longitudinal, multicenter cohort study collected prospective and retrospective data from patients with advanced EGFR mutation–positive NSCLC who were treated with first-line (1L) dacomitinib based on routine practices and their best interest. Study objectives were to describe patient demographics and clinical characteristics, treatment patterns of dacomitinib use, and RW outcomes of 1L dacomitinib. 300 patients from China (n=262), India (n=24), and Malaysia (n=14) were enrolled and included in the analysis. Starting dose was 30 mg once daily (QD) in 159 patients (53%), 45 mg QD in 138 (46%), and other doses in 3 (1%). As of Jan 31, 2023, 81 patients (27.0%) had dose decreases, 13 (4.3%) dose increases, 35 (11.7%) interruptions, and 107 (35.7%) permanently discontinued dacomitinib. Six (2.0%) permanent treatment discontinuations were due to treatment-related toxicities. 1L dacomitinib safety and treatment outcomes are shown in the table.Table: 1337PSafety and treatment outcomes of 1L dacomitinibITT populationTotal (N=300)Duration of 1L dacomitinib treatment, median (IQR), months13.1 (11.8)Patients with any TRAEs, n (%)121 (40.3)Most common TRAEs, n (%)Rash74 (24.7)Diarrhea65 (21.7)Paronychia43 (14.3)TTF, median (95% CI),a months21.4 (17.3-35.9)rwPFS, median (95% CI),a months25.3 (20.1-NR)1L, first line; IQR, interquartile range; ITT, intention to treat; NR, not reached; rwPFS, real-world progression-free survival; TRAE, treatment-related adverse event; TTF, time to treatment failure. a Calculated using the Kaplan-Meier method to obtain 95% confidence interval. Open table in a new tab 1L, first line; IQR, interquartile range; ITT, intention to treat; NR, not reached; rwPFS, real-world progression-free survival; TRAE, treatment-related adverse event; TTF, time to treatment failure. a Calculated using the Kaplan-Meier method to obtain 95% confidence interval. To our knowledge, this is the largest RW study conducted for dacomitinib. Interim analysis shows efficacy of 1L dacomitinib; safety data in the RW setting were generally consistent with dacomitinib’s known safety profile. These results support 1L dacomitinib use in patients with advanced EGFR mutation–positive NSCLC.

This paper proposes a fully decentralized distributed convex optimal power flow model for inverter-based distributed energy resources (DERs) integrated electric distribution networks based on Semi-Definite Programming (SDP) and alternating direction method of multipliers (ADMM) namely (SDP D-ADMM). The proposed approach is based on the SDP relaxed branch flow model of distribution networks within an auto-tuned accelerated decentralized ADMM architecture. The approach is based on dividing the power grid network into subproblems representing individual areas by interchanging minimum network information. In the proposed model the requirement of a central processor is also waived thus making the proposed approach more robust toward cyber-attacks. The effectiveness and scalability of the proposed method are validated by implementing modified IEEE 123 and IEEE 8500 bus systems with different levels of DER penetration. It has been observed that the proposed architecture outperforms other distributed optimization variants in terms of accuracy, global optimality, scalability, and computational time.

We present a search for dark photon dark matter that could couple to gravitational-wave interferometers using data from Advanced LIGO and Virgo's third observing run. To perform this analysis, we use two methods, one based on cross-correlation of the strain channels in the two nearly aligned LIGO detectors, and one that looks for excess power in the strain channels of the LIGO and Virgo detectors. The excess power method optimizes the Fourier Transform coherence time as a function of frequency, to account for the expected signal width due to Doppler modulations. We do not find any evidence of dark photon dark matter with a mass between $m_{\rm A} \sim 10^{-14}-10^{-11}$ eV/$c^2$, which corresponds to frequencies between 10-2000 Hz, and therefore provide upper limits on the square of the minimum coupling of dark photons to baryons, i.e. $U(1)_{\rm B}$ dark matter. For the cross-correlation method, the best median constraint on the squared coupling is $\sim2.65\times10^{-46}$ at $m_{\rm A}\sim4.31\times10^{-13}$ eV/$c^2$; for the other analysis, the best constraint is $\sim 2.4\times 10^{-47}$ at $m_{\rm A}\sim 5.7\times 10^{-13}$ eV/$c^2$. These limits improve upon those obtained in direct dark matter detection experiments by a factor of $\sim100$ for $m_{\rm A}\sim [2-4]\times 10^{-13}$ eV/$c^2$, and are, in absolute terms, the most stringent constraint so far in a large mass range $m_A\sim$ $2\times 10^{-13}-8\times 10^{-12}$ eV/$c^2$.

We present directed searches for continuous gravitational waves from the neutron stars in the Cassiopeia A (Cas A) and Vela Jr. supernova remnants. We carry out the searches in the LIGO data from the first six months of the third Advanced LIGO and Virgo observing run, using the Weave semi-coherent method, which sums matched-filter detection-statistic values over many time segments spanning the observation period. No gravitational wave signal is detected in the search band of 20--976 Hz for assumed source ages greater than 300 years for Cas A and greater than 700 years for Vela Jr. Estimates from simulated continuous wave signals indicate we achieve the most sensitive results to date across the explored parameter space volume, probing to strain magnitudes as low as ~$6.3\times10^{-26}$ for Cas A and ~$5.6\times10^{-26}$ for Vela Jr. at frequencies near 166 Hz at 95% efficiency.

Colo rectal cancer is the third most common cancer in the world. Clinical data on localized colon cancer and treatment outcome is scarce in the literature. This is a real-world study of the clinical profile and treatment patterns and outcomes of patients with nonmetastatic colon cancer from India. Here we report our experience in this patient population.