bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of ecosystem health and driving forces in response to landscape pattern dynamics: the Shibing Karst world natural heritage site case study
Authors: He Lixiang , Zhang Juan , Yu Bin , Hu Mengshan , Zhang Zihao
Published: June 2024

The Shibing Karst constitutes a pivotal component of the "South China Karst," and its ecosystem health integrity crucially influences the Outstanding Universal Value (OUV) of the corresponding Natural World Heritage (NWH). Consequently, robust ecosystem health assessment (EHA) is imperative for the judicious conservation and management of this heritage, as well as for the sustainable progression of the region. This research assessed the health of the Shibing Karst ecosystem from 2004 to 2020 by employing changes in landscape patterns through the Vigor-Organization-Resilience-Ecosystem Services (VORS) model. Spatial autocorrelation was employed to discern the spatial coherence and evolutionary patterns of ecosystem health, whereas a geo-detector ascertained the pivotal determinants impacting regional ecosystem vitality. The findings revealed that: (1) The landscape patterns distribution in the study area exhibited considerable constancy, primarily comprising forest land, with a rising trajectory in construction land and water, juxtaposed with a recession in shrubland, grassland, paddy land, and dryland expanses. (2) From 2004 to 2020, the ecosystem of the study area maintained its health and remained stable, with mean values of 0.8303, 0.7689, 0.6976, and 0.7824, respectively, showing an evolutionary trend of an initial downtrend trend followed by an upswing, with 2016 marking a pivotal juncture. (3) Spatial clustering analysis highlighted significant clustering characteristics of ecosystem health, with a nominal decrease in the Global Moran's I index from 0.666 to 0.665, which is indicative of a subtle decrease in clustering over time. High-high clustering areas were predominantly located within the World Heritage Site (WHS), while low-low clustering areas were mainly distributed in the southeastern part of buffer zone. (4) Land use and cover change (LUCC) and Ecosystem Services (ESs) were identified as the primary indexes of EHA, with Ecosystem Resilience (ER), Ecosystem Vigor (EV), and Ecosystem Organization (EO) exerting relatively mild influences. This study provides a scientific framework for policymakers in local governance to devise strategies for ecosystem conservation and management, enhances the analytical perspective on the integrity and conservation of Karst Natural World Heritage (KNWH).
Diabetes mellitus and hard braking events in older adult drivers
Authors: Liu Difei , Chihuri Stanford , Andrews Howard F. , Betz Marian E. , DiGuiseppi Carolyn , Eby David W. , Hill Linda L. , Jones Vanya , Mielenz Thelma J. , Molnar Lisa J. , Strogatz David , Lang Barbara H. , Li Guohua
Published: June 2024

Background

Diabetes mellitus (DM) can impair driving safety due to hypoglycemia, hyperglycemia, diabetic peripheral neuropathy, and diabetic eye diseases. However, few studies have examined the association between DM and driving safety in older adults based on naturalistic driving data.

Methods

Data for this study came from a multisite naturalistic driving study of drivers aged 65–79 years at baseline. Driving data for the study participants were recorded by in-vehicle recording devices for up to 44 months. We used multivariable negative binomial modeling to estimate adjusted incidence rate ratios (aIRRs) and 95% confidence intervals (CIs) of hard braking events (HBEs, defined as maneuvers with deceleration rates ≥ 0.4 g) associated with DM.

Results

Of the 2856 study participants eligible for this analysis, 482 (16.9%) reported having DM at baseline, including 354 (12.4%) insulin non-users and 128 (4.5%) insulin users. The incidence rates of HBEs per 1000 miles were 1.13 for drivers without DM, 1.15 for drivers with DM not using insulin, and 1.77 for drivers with DM using insulin. Compared to drivers without DM, the risk of HBEs was 48% higher for drivers with DM using insulin (aIRR 1.48; 95% CI: 1.43, 1.53).

Conclusion

Older adult drivers with DM using insulin appear to be at increased proneness to vehicular crashes. Driving safety should be taken into consideration in DM care and management.
Key ingredients for successful collaboration in health research: perspectives of patient research partners
Authors: Bruce Marcia , Yogaratnam Karthika , Suryaprakash Nitya , Barker Karis L. , Marshall Deborah A.
Published: June 2024

Background

There are increasing publications on meaningful collaboration between researchers and patient research partners (PRPs), but fewer publications of such work from the PRP perspective using an evaluation framework. Our aim is to present our own perspectives and reflections on meaningful collaboration as PRPs working on a qualitative research study.

Main body

We were part of a study team that comprised of PRPs, clinicians and academic researchers, and was led by a PRP. The team designed and conducted a qualitative study aimed at understanding how patients make decisions around tapering of biologics for inflammatory bowel disease. The study was conducted online. The PRP lead was trained in qualitative methodology through a one-year certificate program called Patient and Community Engagement Research offered through the University of Calgary Continuing Education. We had received patient-oriented research training and qualitative research training prior to this project. Team members were assigned tasks by our group lead based on member interests and willingness. Some group members were part of the Strategy for Patient-Oriented Research, Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects Network, one of five chronic disease networks in the Strategy for Patient Oriented Research initiative of the Canadian Institutes of Health Research. We describe the five key ingredients to successful collaboration based on our experiences and reflections utilizing the Experience-Reflection-Action Cycle as our framework. The five key ingredients that we identified were: inclusiveness, goal and role clarity, multi-level training and capacity building, shared decision making, and a supportive team lead.

Conclusion

Overall, our experience was positive. With successful collaboration came an increased level of trust, commitment and performance. There is a need for more studies with diverse PRPs in different settings to validate and/or identify additional factors to improve collaboration in patient-oriented research.
Leveraging Electronic Health Record Data to Understand Gaps Underlying the Underdiagnosis of Lynch Syndrome
Authors: Maoz Asaf , Yurgelun Matthew B.
Published: June 2024

Using the electronic health record to address the underdiagnosis of Lynch syndrome
Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06).
Authors: Curigliano Giuseppe , Hu Xichun , Dent Rebecca Alexandra , Yonemori Kan , Barrios Carlos H. , O'Shaughnessy Joyce , Wildiers Hans , Zhang Qingyuan , Im Seock-Ah , Saura Cristina , Biganzoli Laura , Sohn Joohyuk , Levy Christelle , Jacot William , Begbie Natasha , Ke Jun , Patel Gargi Surendra , Bardia Aditya
Published: June 2024

LBA1000

Background: T-DXd is approved for HER2-low (IHC 1+ or 2+/ISH-negative) mBC after ≥1 line of chemotherapy (CT). DB-06 (NCT04494425) evaluated T-DXd in pts with HER2-low or -ultralow (IHC 0 with membrane staining), HR+ mBC after disease progression (PD) on endocrine-based therapy and no prior CT for mBC. Methods: Pts with HER2-low or -ultralow, HR+ mBC were randomized 1:1 to T-DXd 5.4 mg/kg or TPC. Pts had no prior CT for mBC, with ≥2 lines of ET for mBC, or 1 line of ET for mBC if PD occurred ≤24 months (mo) of adjuvant ET or ≤6 mo of ET+CDK4/6i for mBC. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in HER2-low. Key secondary endpoints were PFS in intent-to-treat (ITT = HER2-low and -ultralow) and overall survival (OS). Other endpoints included objective response rate (ORR) and safety. Results: As of Mar 18, 2024, 866 pts (HER2-low, n=713; HER2-ultralow, n=153) were randomized; 90.4% had prior CDK4/6i. TPC group pts were selected for capecitabine (59.8%), nab-paclitaxel (24.4%) or paclitaxel (15.8%). T-DXd significantly improved PFS vs TPC in HER2-low (HR, 0.62 [95% CI 0.51, 0.74], P<0.0001; median, 13.2 vs 8.1 mo). ITT and HER2-ultralow results were consistent with HER2-low (Table). Median treatment duration was 11.0 mo (T-DXd) vs 5.6 mo (TPC). OS was immature at first interim analysis (HER2-low HR, 0.83 [95% CI 0.66, 1.05], P=0.1181; median follow up, 18.6 mo). Grade (Gr) ≥3 drug-related adverse events occurred in 40.6% (T-DXd) vs 31.4% (TPC). Adjudicated interstitial lung disease / pneumonitis occurred in 49 (11.3%; 0.7% Gr 3/4, 0.7% Gr 5) vs 1 (0.2% Gr 2) pts receiving T-DXd vs TPC. Conclusions: T-DXd showed a statistically significant and clinically meaningful PFS benefit vs TPC (CT) in HER2-low mBC. HER2-ultralow results were consistent with HER2-low. Safety was in line with known profiles. DB-06 establishes T-DXd as a standard of care following ≥1 endocrine-based therapy for pts with HER2-low and -ultralow, HR+ mBC. Clinical trial information: NCT04494425 .[Table: see text]
Preventive effect of naldemedine for opioid-induced constipation in patients with cancer starting opioids: A multicenter, double-blinded, randomized, placebo-controlled, phase 3 trial.
Authors: Hamano Jun , Higashibata Takahiro , Kessoku Takaomi , Kajiura Shinya , Hirakawa Mami , Ariyoshi Keisuke , Oyamada Shunsuke
Published: June 2024

LBA12014

Background: A peripherally acting μ-opioid receptor antagonist (PAMORA), such as naldemedine, could alleviate OIC in cancer patients. However, the evidence of PAMORA on OIC prevention in cancer patients starting opioid analgesia is limited. This clinical trial aimed to confirm the preventive effect of naldemedine for OIC in cancer patients who start daily strong opioid administration compared with placebo. Methods: We conducted a multicenter, double-blinded, randomized, placebo-controlled trial between July 2021 and May 2023 with four academic hospital in Japan (jRCTs031200397). Patients with cancer starting regular strong opioid for the first time for cancer pain, and age 20 years or older were included. The eligible patient was randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio. The protocol treatment period was 14 days after the start of naldemedine (or placebo) and the naldemedine group had Symproic at 0.2 mg once a day after breakfast for 14 days. The placebo group had the placebo once a day after breakfast for 14 days. The primary endpoint was the proportion of patients with a Bowel Function Index (BFI) of less than 28.8 on Day 14. We conducted the safety assessments with the number of all adverse events occurring during the protocol treatment period using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Japanese translation of Japan Clinical Oncology Group. Results: Of the 103 patients were assessed for eligibility, 99 patients were randomly assigned on a 1:1 basis to receive naldemedine (n = 49) or placebo (n = 50). The BFI score at Day 1 was 18.3±19.8 with naldemedine group and 18.2±20.0 with placebo. The proportion of patients with a BFI of less than 28.8 on Day 14 was significantly greater with naldemedine group (64.6% [31 of 48 patients]; 95% CI, 51.1% to 78.1%) than with placebo (17.0% [8 of 47 patients]; 95% CI, 6.3% to 27.8%) with a difference of 47.6% (95% CI, 30.3% to 64.8%, p< 0.0001). There was no statistical difference in the proportion of adverse events; abdominal distention, abdominal pain, diarrhea, bowel obstruction, and nausea. However, there was a significantly lower proportion of vomiting in patients treated with naldemedine. During the treatment period, none of patients treated with naldemedine had diarrhea, nausea, or vomiting as adverse events causally related to protocol treatment (0.0% [0 of 48 patients] v.s 34.0% [16 of 47 patients]. Conclusions: Naldemedine is a valuable option with proven efficacy in preventing OIC in cancer patients starting regular strong opioids. Clinical trial information: 031200397 .
Longitudinal circulating tumor DNA monitoring in predicting response to short-course neoadjuvant radiotherapy in locally advanced rectal cancer: Data from a phase III clinical trial (UNION).
Authors: Lin Zhenyu , Zhai Menglan , Yan Linghua , Zhang Tao
Published: June 2024

LBA3606

Background: The data presented here is from a multicenter, randomized, open-label, controlled Phase III clinical study evaluating the feasibility of short-course radiotherapy (shortRT) sequentially combined with camrelizumab and chemotherapy as neoadjuvant therapy (NAT) for locally advanced rectal cancer (LARC)(UNION). Our aim is to explore the value of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) in assessing the comparative efficacy of short-course and long-course chemoradiotherapy (CRT). Methods: A total of 244 plasma samples from 79 LARC patients, who underwent NAT prior to curative surgery, were collected at baseline (C1), on-NAT (C2), post-NAT (C3), and post-surgery (C4). Deep targeted panel sequencing of 556 cancer-related genes was performed. The changes in genomic features and ctDNA-MRD status during treatment were monitored, and the relationship between these changes and treatment response were explored. Results: During NAT, the ctDNA-MRD positivity rate showed significant declining trends. Patients with high baseline TMB tend to show a significant inclination towards major pathological response and tumor regression grade 0/1 after NAT, while there is no significant correlation observed between baseline ctDNA-MRD status and treatment response. Interestingly, compared to long-course radiotherapy, microsatellite instability is more pronounced after shortRT ( P=0.042), and ctDNA negativity is significantly associated with pathological complete response (pCR) ( P=0.022). Furthermore, both ctDNA clearance ( P=0.049) and MRD clearance ( P=0.015) after shortRT are significantly correlated with pCR. A risk scoring predictive model based on ctDNA-MRD was established, with achieving the highest C-index at the C2 time point. This model, combining MRD clearance and CEA, outperforms models using only MRD clearance (AUC=0.917, 95% CI=0.753 to 1.000) or only CEA (AUC=0.733, 95% CI=0.449 to 1.000), demonstrating superior performance in predicting pCR/non-pCR (AUC=0.983, 95% CI=0.937 to 1.000). Conclusions: These findings offers valuable insights into the dynamic landscape of NAT for LARC management and emphasize the potential of ctDNA-based MRD assessment as a valuable tool for tailoring treatment strategies. The differences observed between shortCRT and longCRT regimens underscore the need for personalized treatment approaches. Overall, our study contributes valuable insights into optimizing treatment decision-making and predicting treatment response in LARC patients, ultimately advancing the field of rectal cancer management.
Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW.
Authors: Galle Peter Robert , Decaens Thomas , Kudo Masatoshi , Qin Shukui , Fonseca Leonardo , Sangro Bruno , Karachiwala Hatim , Park Joong-Won , Gane Edward , Pinter Matthias , Tai David , Santoro Armando , Pizarro Gonzalo , Chiu Chang-Fang , Schenker Michael , He Aiwu Ruth , Wang Qi , Stromko Caitlyn , Hreiki Joseph , Yau Thomas
Published: June 2024

LBA4008

Background: First-line therapies based on programmed death ligand 1 (PD-L1) inhibitors are standard of care (SOC) in uHCC and demonstrate improved outcomes over SOR; however, prognosis remains poor and there is an unmet need for alternative therapies with long-term benefits. Second-line NIVO + IPI demonstrated clinically meaningful efficacy and manageable safety in SOR-treated patients (pts) with HCC in CheckMate 040, leading to its accelerated approval in the United States. We report first results from the preplanned interim analysis of the phase 3, open-label, randomized CheckMate 9DW trial evaluating the efficacy and safety of NIVO + IPI vs LEN or SOR as first-line therapy for pts with uHCC (NCT04039607). Methods: Adult pts with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5–6, and ECOG performance status 0–1 were included. Pts were randomly assigned 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles) followed by NIVO 480 mg Q4W or investigator’s choice of LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: In total, 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated in the LEN/SOR arm, 275 (85%) received LEN. After a median (range) follow-up of 35.2 (26.8–48.9) months (mo), median OS was 23.7 mo with NIVO + IPI vs 20.6 mo with LEN/SOR (HR, 0.79; 95% CI, 0.65–0.96; P = 0.0180) (Table), with respective 24-mo OS rates (95% CI) of 49% (44–55) vs 39% (34–45). ORR was higher with NIVO + IPI (36%) vs LEN/SOR (13%; P < 0.0001); complete response was observed in 7% of pts with NIVO + IPI vs 2% with LEN/SOR. Median DOR was 30.4 mo with NIVO + IPI vs 12.9 mo with LEN/SOR (Table). A summary of treatment-related adverse events (TRAEs) is shown in the Table. Conclusions: NIVO + IPI demonstrated statistically significant OS benefit vs LEN/SOR in pts with previously untreated uHCC, as well as higher ORR and durable responses with a manageable safety profile. These results support this combination as a potential new first-line SOC for uHCC. Clinical trial information: NCT04039607 . [Table: see text]
Rates of pathologic complete response (pCR)after neoadjuvant datopotamab deruxtecan (Dato): Results from the I-SPY2.2 trial.
Authors: Meisel Jane Lowe , Khoury Katia , Chien Amy Jo , Wallace Anne M. , Arora Mili , Rozenblit Mariya , Williams Nicole Olivia , Nanda Rita , Borges Virginia F. , Stringer-Reasor Erica Michelle , Boughey Judy Caroline , Nangia Chaitali , Vaklavas Christos , van 't Veer Laura , DeMichele Angela , Hylton Nola , Yee Douglas , Yau Christina , Esserman Laura ,   ISPY2 Investigators
Published: June 2024

LBA509

Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) evaluating novel experimental regimens in the neoadjuvant breast cancer setting. The novel therapy is given as first in a sequence (Block A), followed by standard chemo/targeted therapies (Block B/C) if indicated. The goal is to identify agents that lead to pCR after novel targeted agents alone, or in sequence with optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to classify patients by subtype: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3 and S4 were eligible for assignment to Dato in Block A. Patients (pts) were followed by MRI during treatment (at 3, 6 and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early, otherwise they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 103 pts were randomly assigned to the Dato arm between August 2022 and August 2023. All patients have proceeded beyond Block A; 33 went to surgery after Dato alone. The efficacy results for Dato as a stand-alone therapy are summarized in Table. Conclusions: Dato monotherapy was active, particularly in the HR-HER2- signature, but did not meet the pre-specified threshold for graduation in I-SPY 2.2. Clinical trial information: NCT01042379 . [Table: see text]
A phase III randomized, double-blinded, placebo-controlled study of suvemcitug combined with chemotherapy for platinum-resistant ovarian cancer (SCORES).
Authors: Yuan Guangwen , Wu Lingying , Li Qingshui , Lou Ge , Li Jundong , Liu Xiaowei , Wang Danbo , Yang Chen , Sun Shuguang , Zhang Jiajing
Published: June 2024

LBA5516

Background: Suvemcitug is a new-generation recombinant humanized anti-VEGF rabbit monoclonal antibody. In the previous P1b study, Suvemcitug demonstrated its favorable safety profile and efficacy signals when combo with chemotherapy in platinum-resistant ovarian cancer (PROC). SCORES is the first randomized, double-blind, placebo-controlled phase III clinical trial to confirm the efficacy of Suvemcitug combo with chemo in PROC, whether or not previously received antiangiogenic agents or PARP inhibitors. Methods: Eligible patients had progressed during platinum-based therapy or within 6 months after ≥4 cycles of platinum-based therapy with at least one measurable lesion. After the investigators chose chemotherapy (CT) (weekly paclitaxel 80 mg/ m2 d1, 8, 15 & 22 q4w, pegylated liposomal doxorubicin 40 mg/m2 d1 q4w or topotecan 4 mg/m2 d1, 8 & 15 q4w), patients were randomly assigned (2:1) to either Suvemcitug (1.5 mg/kg q2w) or placebo combine with CT until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent review committee (BIRC) according to the RECIST 1.1. Key secondary end point is the overall survival (OS). Results: A total of 421 patients were enrolled between June 2021 and June 2023 in China. As the data cut off of the primary efficacy analysis (8 December 2023), 197 PFS events (70.1%) in Suvemcitug arm and 111 PFS events (79.3%) in placebo arm had occurred with the median follow-up of 14.36 and 14.26 months, respectively. The median PFS by BIRC was 5.49 months in Suvemcitug arm versus 2.73 months in placebo arm (hazard ratio[HR] 0.46, p<0.0001). OS data are immature. 42.7% and 50.7% of patients are deceased in Suvemcitug arm or placebo arm respectively, and there is a trend of OS benefit trend: median OS 16.07 months vs. 14.88 months, HR 0.79, p=0.1244. Efficacy results are summarized below. Treatment-emergent adverse events (TRAEs) occurred in all patients in Suvemcitug arm, with the most common being neutrophil count decreased, white blood cell count decreased and platelet count decreased. No Suvemcitug-related grade 5 TEAE occurred. Conclusions: To the best of our knowledge, this is the first double-blinded phase III study demonstrated promising antitumor activity of anti-angiogenic agent in patients with PROC. The improvement in PFS, ORR and DCR gained by adding Suvemcitug to single-agent CT was observed with no new safety concern. Clinical trial information: NCT04908787 . [Table: see text]
PRGN-2012, a novel gorilla adenovirus-based immunotherapy, provides the first treatment that leads to complete and durable responses in recurrent respiratory papillomatosis patients.
Authors: Norberg Scott , Gulley James L. , Schlom Jeffrey , Lankford Amy , Semnani Roshanak , Shah Rutul R. , Brough Douglas E , Sabzevari Helen , Allen Clint
Published: June 2024

LBA6015

Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and, although rare, transformation into malignant cancer. There are no approved therapeutics. RRP is currently managed with frequent ablative procedures that can lead to irreversible laryngotracheal scarring and disability. PRGN-2012 is a gorilla adenovirus-based gene therapy/immunotherapy designed to generate HPV6/11-specific T cell immunity. The FDA has granted PRGN-2012 Breakthrough Therapy Designation for the treatment of RRP recognizing that this single arm study can serve as pivotal to support a licensing application. Methods: This pivotal trial (NCT04724980) evaluates the safety and efficacy of PRGN-2012 in patients with RRP requiring a minimum of 3 surgeries in the 12 months prior to treatment. Eligible patients received 4 subcutaneous (SC) injections of PRGN-2012 at dose level (DL) 1 (1x1011 Particle Units (PU) per injection; n=3) or DL2 (5x1011 PU per injection; n=35) over 12 weeks. The primary endpoint was the rate of complete response (CR), defined as no requirement for surgery in the 12 months following completion of treatment. Other key endpoints include duration of response, change in extent of papilloma growth (anatomic Derkay score) and vocal function. Results: PRGN-2012 was well-tolerated, with no serious adverse events, grade > 2 treatment-related adverse events, or early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. PRGN-2012 treatment at DL2 significantly (p<0.0001) decreased the requirement for surgery, with a median number of surgeries in the 12 month period decreasing from 4 (3-10) prior to treatment to 0 (0-7) surgeries post-treatment. Approximately 90% of patients experienced a decrease in the number of surgeries in the 12 months post-treatment compared to pre-treatment with PRGN-2012. The primary endpoint evaluation demonstrated a confirmed complete response in 17/31 (55%) of evaluable patients. The median duration of complete response has yet to be reached with a median follow up of 15 months (12 - 30) at the time of data cutoff (March 6, 2024). Additionally, PRGN-2012 treatment resulted in a significant reduction in Derkay score, improvement in vocal function and generation of HPV-specific immune responses. Conclusions: These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult RRP patients. These findings support PRGN-2012 as a potential therapeutic option for this patient population where no FDA-approved therapeutics exist. Clinical trial information: NCT04724980 .
Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816.
Authors: Spicer Jonathan , Girard Nicolas , Provencio Mariano , Wang Changli , Mitsudomi Tetsuya , Awad Mark M. , Vokes Everett E. , Taube Janis M. , Lupinacci Lorena , Saylors Gene B. , Tanaka Fumihiro , Liberman Moishe , Lee Sung Yong , Alexandru Aurelia , D’Arcangelo Manolo , Tran Phuong , Mahmood Javed , Gharpure Vishwanath Suresh , Bhingare Apurva , Forde Patrick M.
Published: June 2024

LBA8010

Background: The phase 3 CheckMate 816 study established neoadjuvant NIVO + chemo as a standard of care for eligible pts with resectable NSCLC. Here, we report the 4-year survival update from this study, representing the longest follow-up among all global phase 3 studies evaluating neoadjuvant or perioperative immunotherapy-based treatments. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC v7) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized 1:1 to receive NIVO 360 mg + chemo Q3W or chemo alone Q3W for 3 cycles, followed by surgery. Event-free survival (EFS) and pathologic complete response (pCR; both per blinded independent review) were primary endpoints and were both statistically significant. Overall survival (OS) was a key secondary endpoint. Exploratory analyses included efficacy by pCR status and extent of resection. Results: At the 23 Feb 2024 database lock (median follow-up, 57.6 mo), NIVO + chemo continued to improve EFS vs chemo (median, 43.8 mo vs 18.4 mo; HR [95% CI], 0.66 [0.49–0.90]); 4-year EFS rates were 49% vs 38%. EFS favored NIVO + chemo vs chemo regardless of whether pts had lobectomy or pneumonectomy (Table), with 56%–57% vs 40%–43% of pts without disease recurrence at 4 years. NIVO + chemo also continued to show OS improvement vs chemo (HR [98.36% CI], 0.71 [0.47–1.07]; P = 0.0451; median OS was not reached [NR] in both arms, and the significance boundary was not met at this interim analysis). An OS improvement of 13% was sustained over time for NIVO + chemo vs chemo; 4-year OS rates were 71% vs 58%. Pts in the NIVO + chemo arm who had pCR continued to have improved OS vs those who did not (HR [95% CI], 0.08 [0.02–0.34]); 4-year OS rates, 95% vs 63%); a similar trend was seen in the chemo arm, although few pts had pCR with chemo (n = 4). No new safety signals were observed at this update. Additional survival analyses in pt subgroups and by ctDNA levels will be presented. Conclusions: In this 4-year analysis from CheckMate 816, neoadjuvant NIVO + chemo sustained EFS and OS separation vs chemo over time and demonstrated the long-term survival benefit of having pCR in pts with resectable NSCLC. These data provide the first understanding of the long-term benefits of neoadjuvant immunotherapy when added to chemo, reinforcing neoadjuvant NIVO + chemo as a standard of care, and providing a benchmark to assess the benefits of all perioperative immunotherapy-based treatments. Clinical trial information: NCT02998528 . [Table: see text]
IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Authors: Wakelee Heather A. , Altorki Nasser K. , Zhou Caicun , Csőszi Tibor , Vynnychenko Ihor O. , Goloborodko Oleksandr , Rittmeyer Achim , Reck Martin , Martinez-Marti Alex , Kenmotsu Hirotsugu , Chen Yuh-Min , Chella Antonio , Sugawara Shunichi , Fu Chenqi , Ballinger Marcus , Deng Yu , Srivastava Minu K , Bennett Elizabeth , Gitlitz Barbara Jenifer , Felip Enriqueta
Published: June 2024

LBA8035

Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]
KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.
Authors: Gregorc Vanesa , González-Cao Maria , Salvagni Stefania , Koumarianou Anna , Gil-Bazo Ignacio , Maio Michele , Viteri Santiago , Majem Margarita , Gutiérrez Vanesa , Bernabe Caro Reyes , Sanmamed Miguel F. , Zhu Huaqiang , Shen Haige , Wang Yu , Rosell Rafael
Published: June 2024

LBA8511

Background: Fulzerasib (GFH925), a KRAS G12C inhibitor, showed substantial efficacy in previously treated NSCLC patients (pts) as monotherapy. Activation of epidermal growth factor receptor (EGFR) is identified to be one of the dominant mechanisms for KRAS inhibition resistance. Preclinical evidence showed synergistic activity in KRAS G12C mutant NSCLC modeling using fulzerasib in combination with cetuximab. Here we report the first results for a KRAS G12C inhibitor combined with an anti-EGFR antibody in NSCLC pts as front-line treatment. Methods: KROCUS (NCT05756153) was an open-label, single-arm, multi-center, Phase II study with the primary objective to evaluate the efficacy of fulzerasib in combination with cetuximab in pts with previously untreated advanced NSCLC harboring KRAS G12C mutation. Secondary objectives included safety/tolerability, pharmacokinetics and biomarkers. Pts were enrolled to receive fulzerasib (oral, 600 mg BID) and cetuximab (intravenous, 500 mg/m2, every two weeks [Q2W]) combination treatment in a 28-day cycle. Results: As of Jan. 30, 2024, a total of 27 pts (median age: 68 yrs old; 55.6% female) were treated, 11 (40.7%) with baseline brain metastases. Of 20 pts who had at least one post-treatment tumor assessment, ORR was 80.0% (95% CI: 56.3, 94.3, including one CR), of whom eight pts had ≥ 50% tumor shrinkages in the target lesions. Disease control rate (DCR) was 100% (95% CI: 83.2, 100.0). Five out of seven pts (71.4%) with brain metastases achieved PRs. Nine pts with baseline PD-L1 expression tested (six TPS≥1% and three TPS <1%) all achieved PRs. The overall safety profile of the combination was favorable. Treatment-related adverse events (TRAEs) of any grade occurred in 21 (77.8%) pts. 5 pts (18.5%) experienced G3 TRAEs and no G4 or 5 TRAEs. Three pts (11.1%) had dose reduction/interruption with fulzerasib due to TRAEs but no pts discontinued treatment while one pt (3.7%) had dose reduction/interruption and three (11.1%) discontinued cetuximab due to TRAEs. Table 1 shows the most common TRAEs or G3 TRAEs. Conclusions: The preliminary data from ongoing KROCUS study has demonstrated very promising efficacy and favorable safety profile of fulzerasib + cetuximab in the first line setting of KRAS G12C mutated NSCLC. More data will be generated to provide clinical evidence supporting this combination as a potential frontline therapy. Clinical trial information: NCT05756153 . [Table: see text]
A utilização do gênero como categoria epistemológica para as ciências sociais e humanas
Authors: Gondim Yuri , Simões Sales Tainah
Published: June 2024

O artigo trata da relevância da utilização do gênero, enquanto categoria epistemológica, na reflexão sobre fenômenos sociais e jurídicos. A análise das diferentes privações que obstam o livre desenvolvimento das pessoas em países como o Brasil passa pela constatação da existência de diversas formas de dominação, estereótipos e desigualdades que desafiam a atuação de docentes, alunos e pesquisadores comprometidos com o impacto de suas intervenções em suas comunidades. Neste artigo, por necessidade de corte epistemológico, analisar-se-á especificamente a questão de gênero. Entende-se que, entre as inúmeras contribuições do feminismo para o repensar da história das ciências sociais e humanas, a epistemologia feminista se põe como essencial contribuição para a percepção do mundo como ele realmente é, o que inclui uma análise crítica sobre os campos social, moral, político e jurídico.
Morphological study of the popliteus muscle-tendon complex in formalin embalmed adult cadavers
Authors: Vadgaonkar Rajanigandha , Tonse Mamatha , Blossom Vandana , Kalluraya P. Gopal Govind , Murlimanju B.V.
Published: June 2024

Background The dimensions of popliteus muscle and its tendon are subjected to variability in the origin, mode of insertion, innervation patterns and vascular supply. The aim of this study was to measure the length, thickness and width of the popliteus muscle and its tendon at its different parts. The objectives were to study the topographic anatomy of the neurovascular structures of the popliteus and also to determine the dimensions of the popliteo-fibular ligament. Methods This descriptive cross sectional institutional based study included 50 formalin embalmed adult lower limb specimens. The measurements were performed by using the digital Vernier caliper. Results The length of the popliteus muscle belly along the upper and lower border were 44.2±6.63 mm and 89.26±14.41 mm, width of the muscle belly at midpoint, musculotendinous junction and insertion were 28.45±6.85 mm, 11.7±3.5 mm and 75.95±10.7 mm. The thickness of muscle belly at the midpoint was 2.55±0.55 mm. The length of popliteal tendon, width at origin and at musculotendinous junction were 24.85±2.15 mm, 7.55±1.55 mm and 8.5±1.15 mm. The thickness of tendon of popliteus was 2.6±0.75 mm. The length of nerve to popliteus was 50.44±8.66 mm and its origin was located 27.54±6.18 mm from the intercondylar line. The distance of origin of medial and lateral geniculate arteries from the intercondylar line were 26.26±10.47 mm and 20.76±5.19 mm. The distance of division of popliteal artery was 49.44±16.26 mm from the intercondylar line. The length and width of the popliteo-fibular ligament was 17.84±3.43 mm and 7.36±1.9 mm individually. Conclusions This study offered detailed morphometric data of the popliteus and it is believed that the data of this anatomical research is enlightening to orthopedic surgeons particularly in the field of arthroscopic and plastic surgery. The data can be considered as the database from our population.
Juan Gorgues y Lerma. Estudio historiográfico de la fraseología en Lluvia de refranes (1879).
Authors: Martín Cuadrado Carmen
Published: June 2024

Este artículo pretende acercarse a la obra de Juan Gorgues y Lerma, intelectual costumbrista que se dedicó a la labor de recopilación de paremias, pero cuyas aportaciones han quedado desatendidas en la investigación, pues han sido eclipsadas por los autores más representativos de la centuria decimonónica. Tras mostrar los pocos datos biográficos que se conocen acerca de Gorgues y Lerma y el contexto en el que compuso su repertorio, se presenta el análisis de la obra Lluvia de refranes (1879), una clasificación de las unidades fraseológicas incorporadas en su repertorio y el estudio de las series textuales con el fin último de contribuir al estudio de la historia de la fraseología y de la historiografía española en el siglo xix.
Percepción y reconocimiento de la diversidad lingüística del español por parte de jóvenes universitarios vietnamitas.
Authors: Ngân Võ Ngọc Kim
Published: June 2024

En el presente artículo se analiza la percepción y el reconocimiento de la diversidad lingüística por parte de los estudiantes de los últimos dos cursos del grado de Estudios Hispánicos de la Universidad de Ciencias Sociales y Humanidades de Ciudad Ho Chi Minh (Vietnam), en el marco del proyecto PRECAVES XXI (proyecto para el estudio de las creencias y actitudes hacia las variedades cultas del español del siglo xxi). Para ello se llevó a cabo una evaluación del conocimiento de variedades en dos fases —por medio de la encuesta de PRECAVES XXI— con una actuación didáctica entre ambas fases. La encuesta de PRECAVES XXI permite el estudio del conocimiento de variedades de español de forma directa a través de las dieciséis grabaciones de dos tipos de discurso (espontáneo o leído) de ocho variedades del español: castellana, andaluza, canaria, mexicana, caribeña, andina, rioplatense y chilena. Como conclusión principal constatamos la dificultad de estos alumnos en la identificación exacta de variedades, puesto que solo muestran, tras la actuación didáctica, mejora en la identificación genérica, especialmente con la distinción entre variedades conservadoras e innovadoras
Desde adentro y hacia todas las direcciones: en defensa y por la preservación de la vida, la semilla y el ambiente sano (Mocoa, Putumayo)
Authors: Jiménez Reinales Nathaly , Arias Naranjo María Angélica
Published: June 2024

La apuesta por una globalización que promueve la mercantilización a través de acuerdos comerciales como instrumentos de poder hegemónico hace que, en Colombia, por ejemplo, el Estado no haya favorecido el desarrollo rural ni protegido la diversidad biocultural de los territorios. La normatividad y la voluntad política de los últimos gobiernos continúan priorizando la explotación minera y la agricultura inspirada en la revolución verde, y obstaculizan con ello los procesos de recuperación ambiental y la protección de la diversidad biocultural; especialmente, en territorios donde el conflicto armado ha vulnerado la calidad de vida de los habitantes. Este capítulo resalta la importancia del trabajo socioambiental en materia de autonomía alimentaria que desde el municipio de Mocoa, en el departamento del Putumayo, se ha venido reconfigurando por la necesidad de recrear condiciones favorables para la población y el territorio. Los sistemas agroalimentarios con enfoque agroecológico responden de forma sostenible, saludable y sustentable a la crisis ambiental que se deriva, entre otros, de la falta de garantías en el abastecimiento de alimentos sanos, la preservación de las semillas nativas y criollas y una consistente asociatividad.
Educación en agroecología. Estrategia para lograr la vida querida en contextos rurales
Authors: Angarita Leiton Arlex
Published: June 2024

El contexto rural configura el entramado en el cual se desen- vuelve la vida de todos los seres que lo habitan, incluido el ser humano. Lo rural es mucho más que producción agropecuaria, y en este sentido, urgen la creación y la puesta en marcha de propuestas y modelos educativos desde los cuales se pueda hacer una comprensión holística, que permitan el desarrollo de estrategias tendientes a su potencialización como escenario de vida, producción y conservación. En un proceso de construcción participativo con actores de la región sur de Bolívar, en Colombia, se ha identificado la educación en agroecología como la propuesta a través de la cual es posible la formación de personas profesionales que puedan permanecer en el territorio logrando las transformaciones sociales que permitan alcanzar la vida querida. Para ello, se ha estructurado una propuesta de educación concebida en clave de formación, producción y convivencia que armoniza y permite una forma equilibrada y digna de vida, basada en el reconocimiento y el respeto por la vida en todas sus manifestaciones.
Comparisons of Two-Stage Models for Flood Mitigation of Electrical Substations
Authors: Austgen Brent , Kutanoglu Erhan , Hasenbein John J. , Santoso Surya
Published: June 2024

We compare stochastic programming and robust optimization decision models for informing the deployment of ad hoc flood mitigation measures to protect electrical substations prior to an imminent and uncertain hurricane. In our models, the first stage captures the deployment of a fixed quantity of flood mitigation resources, and the second stage captures the operation of a potentially degraded power grid with the primary goal of minimizing load shed. To model grid operation, we introduce adaptations of the direct current (DC) and linear programming alternating current (LPAC) power flow approximation models that feature relatively complete recourse by way of an indicator variable. We apply our models to a pair of geographically realistic flooding case studies, one based on Hurricane Harvey and the other on Tropical Storm Imelda. We investigate the effect of the mitigation budget, the choice of power flow model, and the uncertainty perspective on the optimal mitigation strategy. Our results indicate the mitigation budget and uncertainty perspective are impactful, whereas choosing between the DC and LPAC power flow models is of little to no consequence. To validate our models, we assess the performance of the mitigation solutions they prescribe in an alternating current (AC) power flow model.

History: Accepted by Pascal Van Hentenryck, Area Editor for Computational Modeling: Methods & Analysis.

Funding: This work was supported by the Energy Institute, The University of Texas at Austin.

Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2023.0125 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2023.0125 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Case Article—Budding with ERP: Information and Operations Management Challenges in a Nascent Industry
Authors: Jat Mohsin , Monette Jason , Kang Parminder Singh
Published: June 2024

The role of analytics in operations and supply chain management (OSCM) has gained significant importance due to the decision-making complexities in the current business environment. The effectiveness of most analytical approaches, in turn, relies on access to timely and accurate data and information. Hence, it is essential for OSCM students to understand the underlying processes and dynamics of information management, for which enterprise resource planning (ERP) systems have become a standard. This case study can be a useful resource for introducing the critical interface between OSCM and information systems. The case study aims to facilitate learning on (1) the limitations of a rudimentary and disconnected information system, (2) the benefits and challenges of ERP implementation, and (3) the important steps to ensure a successful implementation of an ERP system. It provides an interesting context of a fast-growing agribusiness producing regulated products in Canada. The case study has been used in OSCM and management information systems (MIS) courses in two Canadian public Universities.

Funding: This work was supported by Mitacs [Grants IT28747 and IT32722].

Supplemental Material: The Teaching Note and data files are available at https://www.informs.org/Publications/Subscribe/Access-Restricted-Materials .