tbuckley/cabot-search huggingface dataset:
Effect of continued immunotherapy on survival of extensive-stage small cell lung cancer: A retrospective analysis.
Authors: Zhuoran Sun, Yaru Tian, Shuangqing Lu, Hui Zhu
Journal: Journal of Clinical Oncology (2024)

e20114 Background: Immunotherapy has shown significant survival advantages in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC),and the second-line treatment options for ES-SCLC are gradually attracting wider attention. The aim of this study was to evaluate the clinical efficacy of continued immunotherapy as the second-line treatment for ES-SCLC. Methods: Between September 2020 and August 2023, the study included 207 patients diagnosed with ES-SCLC, all of whom progressed after first-line immunotherapy plus chemotherapy. The primary endpoints was progression-free survival (PFS) from the first disease progression to the second progression or date cutoff. And the second endpoints were overall survival(OS) from diagnosis to death or date cutoff and adverse events (AEs).OS and PFS were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: Overall, 124 patients were included in the continued immunotherapy group, and 83 patients in the control immunotherapy group. The basic characteristics of patients included age: 62.3% below 65 years old and 37.7% over or equal 65 years old; Most patients had KPS scores≥80 (85%),138 patients (66.7%) had baseline liver metastases, and 146 patients(70.5%) had baseline brain metastases.The continued second-line immunotherapy (including PD-L1 inhibitors and PD-1 inhibitors) did not prolong OS (median:18.03 vs. 21.34 months, HR=1.15,p=0.47) and PFS (median:4.30 vs. 4.43 months,HR=1.29,p=0.19) compared with the control. In the subgroup analysis, there were no significant differences in PFS among patients with partial response (PR, median:4.46 vs 4.43 months, HR=1.35,p=0.10) and stable disease (SD, median:4.75 vs 3.08 months HR=0.81, p=0.56), as well as in OS among patients with partial response (PR, median:18.43 vs 21.34 months, HR=1.15,p=0.53) and stable disease (SD, median:14.98 vs 17.80 months HR=0.95,p=0.90).I n the continued immunotherapy group, PFS was not significantly different between continued PD-L1 inhibitor group and PD-1 inhibitor group (median: 4.26 vs 4.59 months HR=1.04,p=0.17). There was no significant difference in adverse effects between the groups. Conclusions: Continued immunotherapy did not prove survival of ES-SCLC patients progressed after the standard first-line immunotherapy plus chemotherapy, neither efficacy nor type of immune checkpoint inhibitors produces benefit after progression in ES-SCLC patients.
Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies
Authors: Gonzalo P. Solis, Alexey Koval, Jana Valnohova, Arghavan Kazemzadeh, Mikhail Savitsky, Vladimir L. Katanaev
Journal: Journal of Clinical Investigation (2024)

GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein Gαo. Of >80 pathogenic mutations, most are single amino acid substitutions spreading across Gαo sequence. We perform extensive characterization of Gαo mutants showing abnormal GTP uptake and hydrolysis, and deficiencies to bind Gβγ and RGS19. Plasma membrane localization of Gαo is decreased for a subset of mutations that leads to epilepsy; dominant interactions with GPCRs also emerge for the more severe mutants. Pathogenic mutants massively gain interaction with Ric8A and, surprisingly, Ric8B proteins, delocalizing them from cytoplasm to Golgi. Of these two mandatory Gα-subunit chaperones, Ric8A is normally responsible for the Gαi/o, Gαq, and Gα12/13 subfamilies, and Ric8B solely for Gαs/olf. Ric8A/B mediate the disease dominance when engaging in neomorphic interactions with pathogenic Gαo through disbalancing the neuronal G protein signaling networks. As the strength of Gαo-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies. Our work discovers the neomorphic molecular mechanism of mutations underlying pediatric encephalopathies and offers insights to other maladies caused by G protein misfunctioning and further genetic diseases.
Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor
Authors: Ajit Regmi, Eitaro Aihara, Michael E. Christe, Gabor Varga, Thomas P. Beyer, Xiaoping Ruan, Emily Beebe, Libbey S. O’Farrell, Melissa A. Bellinger, Aaron K. Austin, Yanzhu Lin, Haitao Hu, Debra L. Konkol, Samantha Wojnicki, Adrienne K. Holland, Jessica L. Friedrich, Robert A. Brown, Amanda S. Estelle, Hannah S. Badger, Gabriel S. Gaidosh, Sander Kooijman, Patrick C.N. Rensen, Tamer Coskun, Melissa K. Thomas, William Roell
Journal: Cell Metabolism (2024)

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.
Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation
Authors: Deborah Cook, Adam Deane, François Lauzier, Nicole Zytaruk, Gordon Guyatt, Lois Saunders, Miranda Hardie, Diane Heels-Ansdell, Waleed Alhazzani, John Marshall, John Muscedere, John Myburgh, Shane English, Yaseen M. Arabi, Marlies Ostermann, Serena Knowles, Naomi Hammond, Kathleen M. Byrne, Marianne Chapman, Balasubramanian Venkatesh, Paul Young, Dorrilyn Rajbhandari, Alexis Poole, Abdulrahman Al-Fares, Gilmar Reis, Daniel Johnson, Mobeen Iqbal, Richard Hall, Maureen Meade, Lori Hand, Erick Duan, France Clarke, Joanna C. Dionne, Jennifer L.Y. Tsang, Bram Rochwerg, Timothy Karachi, Francois Lamontagne, Frédérick D’Aragon, Charles St. Arnaud, Brenda Reeve, Anna Geagea, Daniel Niven, Gloria Vazquez-Grande, Ryan Zarychanski, Daniel Ovakim, Gordon Wood, Karen E.A. Burns, Alberto Goffi, M. Elizabeth Wilcox, William Henderson, David Forrest, Rob Fowler, Neill K.J. Adhikari, Ian Ball, Tina Mele, Alexandra Binnie, Sebastien Trop, Sangeeta Mehta, Ingrid Morgan, Osama Loubani, Meredith Vanstone, Kirsten Fiest, Emmanuel Charbonney, Yiorgos A. Cavayas, Patrick Archambault, Oleksa G. Rewa, Vincent Lau, Arnold S. Kristof, Kosar Khwaja, David Williamson, Salmaan Kanji, Eric Sy, Brittany Dennis, Steve Reynolds, Francois Marquis, François Lellouche, Adam Rahman, Paul Hosek, Jeffrey F. Barletta, Robert Cirrone, Mark Tutschka, Feng Xie, Laurent Billot, Lehana Thabane, Simon Finfer
Journal: New England Journal of Medicine (2024)

Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear.
PD-(L)1 inhibitors plus anlotinib: A superior option for second-line treatment of extensive-stage small cell lung cancer.
Authors: Jian Zhang, Yuping Sun, Qin ai Gao
Journal: Journal of Clinical Oncology (2024)

e20117 Background: To evaluate the efficacy of PD-(L)1 inhibitors plus anlotinib as the second-line therapy of extensive-stage small cell lung cancer (ES-SCLC) in the real-world. Methods: EL-SCLC (n = 389) patients who received second-line treatment at 3 cancer centers between January 2008 and January 2023 were retrospectively analyzed. All patients received PD-(L)1 inhibitors in combination with anlotinib and/or chemotherapy(I+A±C), or PD-(L)1 inhibitors in combination with chemotherapy(I+C), or chemotherapy alone (C) as the second-line therapy. The efficacy including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), as well as safety were compared among three groups. Results: The baseline clinical characteristics among 3 groups were largely balanced. Compared with I+C (ORR=17.6%, DCR=68.8%) and C (ORR=18.0%, DCR=53.9%), I+A±C treatment had significantly higher ORR (30.2%) and DCR (82.6%). In addition, treatment with I+A±C generated the longest mPFS (7.2 months) and mOS (33.5 months) compared to that with I+C (mPFS=4.6 months, mOS=19.0 months, both P &lt; 0.001) or C (mPFS=3.4 months, P &lt; 0.01; mOS=18.3 months, P=0.083). However, addition of chemotherapy upon I+A did’t impact PFS (7.2 vs. 7.1 months, P=0.431) and OS (NA vs. 33.5 months, P=0.598). Stratified analysis showed that patients with female gender and oligometastasis (≤ 3 metastasis sites) benefit more from I+A±C treatment compared to male patients and those with polymetastasis, respectively. In addition, the combination of anlotinib with PD-L1 inhibitors generated superior PFS compared to that with PD-1 inhibitors. In patients not receiving PD-(L)1 inhibitors in first-line therapy, I+A±C treatment showed better PFS. The incidence of ≥ grade 3 myelosuppression is much lower in I+A±C group than those in I+C and C groups (3.5% vs 11.2% vs 16.3%, P &lt; 0.01). However, I+A±C treatment generated a higher prevalence of immune-related pneumonia (2.3% vs 0% vs 0%, P &lt; 0.05) and hemoptysis (1.4% vs 0% vs 0.6%, P &lt; 0.05) compared with I+C and C. Conclusions: PD-(L)1 inhibitors plus anlotinib and/or chemotherapy has promising efficacy and manageable toxicity as second-line therpay of ES-SCLC.
The outcomes of atezolizumab therapy in combination with carboplatin and etoposide for small-cell lung cancer.
Authors: Sergey Kamishov, Mirzagaleb Tillyashaykhov, Abrorjon Yusupbekov, Shakhnoza Khamoydinovna Niyozova, Oleg Balenkov, Kamila Izrailbekova, Odiljon Kobilov, Meri Lipartiya, Dilshod Rafiev
Journal: Journal of Clinical Oncology (2024)

e20115 Background: Nearly two-thirds of patients with small-cell lung cancer (SCLC) are diagnosed at an advanced stage, associated with a poor prognosis and extremely low 5-year survival. Platinum-based chemotherapy with etoposide remains the standard treatment for such patients. In recent years, immune checkpoint inhibitors have shown improved outcomes for patients with advanced-stage SCLC. In Uzbekistan, there is currently insufficient research on atezolizumab for this oncological condition. Methods: The retrospective study included 34 patients with previously untreated stage IV SCLC and distant metastases in the central nervous system, lungs, lymph nodes, and liver. The patients underwent treatment from July 2022 to October 2023. The average age of the patients was 67.4±8.2 years, with 21 (61.8%) males and 13 (38.2%) females. The patients were divided into two groups: The 1st group comprised 14 (41.2%) individuals who received four 21-day cycles of carboplatin (AUC 5 mg/mL/min intravenously on day 1) + etoposide (100 mg/m² intravenously on days 1-3) + atezolizumab (1200 mg intravenously on day 1). Subsequently, they underwent maintenance therapy with atezolizumab until unacceptable toxicity or disease progression. The 2nd group consisted of 20 (58.8%) patients who underwent standard platinum-based chemotherapy (carboplatin + etoposide) following the same regimens. Immunohistochemical analysis was conducted using the Ventana BenchMark Ultra automatic stainer with Ventana PD-L1 SP263 monoclonal antibodies. Results: The median overall survival (OS) in the 1st patient group was 11.2 months (95% CI: 9.4-12.6), while in the 2nd group, it was 9.7 months (95% CI: 8.3-11.6). The median progression-free survival (PFS) in the 1st group was 4.8 months (95% CI: 3.9-5.3), and in the 2nd group, it was 4.1 months (95% CI: 3.1-4.6). The objective response rate in the 1st group was 41.2%, and in the 2nd group, it was 37.5%. An analysis of PD-L1 expression was conducted on both tumor cells (TC) and infiltrating immune cells (IC). The prevalence of PD-L1 expression ≥1% on TC or IC was 48.3%, while the prevalence of PD-L1 expression ≥5% was 17.4%. Among 5 patients in the 1st group with tumors showing PD-L1 expression ≥5% on TC or IC, the median OS was 15.6 months (95% CI: 11.2-17.1), compared to 8.4 months (95% CI: 7.3-9.6) in 8 patients in the 2nd group with a similar level of PD-L1 expression. The use of atezolizumab did not impact the toxicity of the administered chemotherapy. Conclusions: Adding atezolizumab to standard platinum-based chemotherapy in the first-line treatment of metastatic SCLC improves both OS and PFS in patients without increasing the toxicity of the treatment. The therapeutic benefit of atezolizumab is more pronounced in patients with elevated PD-L1 expression in tumor tissue.
Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity
Authors: Rebecca B. Delconte, Mark Owyong, Endi K. Santosa, Katja Srpan, Sam Sheppard, Tomi J. McGuire, Aamna Abbasi, Carlos Diaz-Salazar, Jerold Chun, Inez Rogatsky, Katharine C. Hsu, Stefan Jordan, Miriam Merad, Joseph C. Sun
Journal: Immunity (2024)
A phase II, open-label, efficacy and safety of olaparib with bevacizumab (SUKSES-B2) in biomarker matched relapsed or refractory small cell lung cancer.
Authors: Sehhoon Park, Jiyeon Kim, Peter G. Mortimer, Heejung (Rosa) Kim, Hyun Ae Jung, Jong-Mu Sun, Woong-Yang Park, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Se-Hoon Lee
Journal: Journal of Clinical Oncology (2024)

e20118 Background: The treatment of relapsed or refractory small-cell lung cancer (SCLC) remains challenging due to a paucity of effective options and its rapid proliferation coupled with a high rate of genomic alterations in the DNA damage response (DDR) pathway. The SUKSES-B2 study is designed to assess the efficacy and safety of a PARP inhibitor combined with a VEGF inhibitor within a biomarker-focused umbrella framework. Methods: In this open-label, phase II, multi-cohort umbrella trial, patients received 300mg of olaparib every 12 hours and 15mg/kg of bevacizumab on day 1 of a 21-day cycle. The biomarker based inclusion criteria for SUKSES-B2 arm were as follows: (1) SLFN11 positivity, (2) POU2F3 positivity, (3) DDR pathway alterations, or (4) ATM deficiency. A total of 25 evaluable patients were targeted for recruitment, with the primary endpoint being the objective response rate (ORR). Concurrent biomarker studies were also conducted. Results: Between August 2021 and September 2023, twenty-five patients were enrolled at Samsung Medical Center, South Korea. The median age was 67 (range: 49-80), with the cohort being predominantly male (n = 24) and smokers (n = 23). The Eastern Cooperative Oncology Group Performance Status was 0 (n = 1) or 1 (n = 24) for all participants. Patients were identified to possess following biomarkers: ATM loss (n = 1), SLFN11 expression (n = 18), POU2F3 expression (n = 1), and co-expression of SLFN11 &amp; POU2F3 (n = 5). The ORR was 12.0%, with 3 partial responses. Median progression-free survival was 1.31 months (95% CI: 1.28-5.28) and overall survival was 7.80 months (95% CI: 5.21-9.87). All responders demonstrated 3+ SLFN11 expression with ASCL1 expression. The disease control rate was 48.0%, including nine patients with stable disease, showcasing a PFS range of 2.1 to 6.8 months. Among the patients with stable disease, four patients exhibited tumor volume reductions of 4% to 17%. Drug-related adverse events (AEs) included grade 3 anemia (n = 4) and febrile neutropenia (n = 1); however, the majority of AEs were grade 1 or 2 and were managed with standard treatments. Conclusions: The combination of olaparib and bevacizumab has shown clinical benefits in a subset of patients, particularly those with SLFN11 expression, and was generally well-tolerated. The observed extended duration of response in certain patients suggests the need for further studies. Clinical trial information: NCT04939662 .
Therapeutic stratification for small cell lung cancer with multiplexed proteomic analysis.
Authors: Tae Jung Kim
Journal: Journal of Clinical Oncology (2024)

e20130 Background: Even with standard platinum doublet therapy, most patients with small-cell lung cancer (SCLC) survive less than 1 year. For those with refractory or relapsed disease, second-line, single-agent chemotherapy is recommended. Pre-treated SCLC patients can opt for clinical trials of agents such as temozolomide, fluorouracil (5FU), and antibody-drug conjugates (ADC) targeting the proteins DLL3, CD56, or TROP2. Some of these therapies have produced responses in untreated SCLC. To assess the proportions of patients who would be likely to respond to these therapies, we profiled protein targets in clinical tumor biopsies of SCLC using quantitative mass spectrometry. Methods: Archived tumor samples from 99 SCLC patients were microdissected and solubilized for proteomic quantification of 58 therapeutically relevant biomarkers. In each sample, quantities of tumor protein were compared with pre-defined thresholds based on evidence from clinical studies or quantification limits of proteomic assays. Prevalence and protein expression levels in SCLC were compared with those of other cancer indications analyzed in the same clinical laboratory. Results: 15 of 83 (18%) SCLC tumors had low or absent MGMT protein expression ( &lt; 200 attomoles per microgram [amol/ug]), indicating likely response to temozolomide. 14 of 88 (15%) overexpressed TYMP protein ( &gt; 1335 amol/ug), suggesting a likely response to 5FU. Except for one patient, likely responder to temozolomide or 5FU were mutually exclusive. The prevalence of quantifiable levels of the ADC markers DLL3, TROP2, and CD56 were 43%, 49%, and 97%, respectively. The SCLC tumors expressed a wide range of DLL3 protein (range: 101 – 1201 amol/ug); median expression in SCLC was 2 times higher than in pediatric neurological cancers, while median expression of TROP2 was lower in SCLC than in other indications. CD56 protein levels in SCLC were similar to other indications, but with higher prevalence in SCLC. Conclusions: In patients with SCLC, clinical proteomics identified protein targets of multiple approved and investigational therapies. Multiplexed clinical proteomic testing revealed additional treatment options in SCLC patients, which may be useful in first-line or later-line settings.
Correlation between multiorgan immune-related adverse events and clinical outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with chemo-immunotherapy.
Authors: Federico Monaca, Martin Igor Gomez-Randulfe Rodriguez, Emanuele Vita, Antonia Cosmai, Sara Polidori, Alessio Stefani, Guido Horn, Luca Mastrantoni, Antonio Vitale, Jacopo Russo, Denis Occhipinti, Alessandro Scala, Paola Troisi, Ettore D'Argento, Mariantonietta Di Salvatore, Giampaolo Tortora, Raffaele Califano, Emilio Bria
Journal: Journal of Clinical Oncology (2024)

e20129 Background: The addition of immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy (CT-IO) has changed the first-line (1L) treatment landscape of extensive-stage small-cell lung cancer (ES-SCLC). Although ICIs improve survival, they can trigger immune related adverse events (irAEs). Notably, a correlation between irAEs and improved survival (OS) has been observed in several solid tumours including NSCLC. The impact of multiorgan irAEs in ES-SCLC treated with 1L CT-IO remains less clear. Methods: We retrospectively reviewed pts with ES-SCLC who received 1L CT-IO from November 2019 to September 2023 across 2 European centres. Demographic and clinical data were collected and analysed. We evaluated the correlation between irAEs (single and multiorgan) and OS. Results: A total of 217 pts were included. Median follow-up in censored pts was 13.2 m. Overall response rate was 75.1%, median PFS was 6.2 months (m) (95% CI, 5.8 - 6.7), and median OS 10.9 m (95% CI, 9.3 - 12.4). Single-organ any grade irAEs were reported in 58 pts (26.7%), while multi-organ irAEs occurred in 18 pts (8.3%). Clinicopathological characteristics stratified by irAEs are shown in the table. The most commonly affected organs were skin (n=25, 11.5%) and the digestive system (n=15, 6.9%). Treatment discontinuation rate due to irAEs was 11.1% (n=26). Median PFS in pts with multiorgan vs single vs no irAEs was 16.7m, 9.0m and 5.5m, respectively. Median OS was not reached, 17.9m and 8.2m, respectively. The multivariate analysis including irAEs as a time-varying covariate confirmed the association between irAEs and improved PFS (HR 0.38; 95% CI, 0.28 - 0.50, p&lt;0.001) and OS (HR 0.37; 95% CI, 0.27-0.52, p&lt;0.001). Conclusions: Our cohort shows that the incidence of irAEs in this setting is similar to previous real-world studies and that multiorgan irAEs were significantly associated with longer PFS and OS. Further research is needed to characterize the profile of irAEs associated with improved outcomes and to understand the role of concurrent therapeutic interventions. [Table: see text]
Cisplatin versus carboplatin in small cell lung cancer (SCLC): Single-center experience.
Authors: Serife Sivridemir, Efe Hasdemir, Mehmet Nezir Ramazanoglu, Aydan Farzaliyeva, Samed Rahatli, Arzu Oguz, Zafer Akcali, Ozden Altundag
Journal: Journal of Clinical Oncology (2024)

e20116 Background: The current standard of care for the treatment of SCLC is concurrent chemoradiatiotherapy for patients with limited-stage and chemoimmunotherapy for extensive-stage SCLC. Cisplatin is the preferred platinum agent in both settings. Although cisplatin constitutes the standard treatment with level one evidence, carboplatin is preferred in daily practice due to its more reliable toxicity profile. Methods: To investigate carboplatin is not inferior to cisplatin in both settings we retrospectively analyzed our data between 2011-2021. The results were given HR, 95% CI, and p-value. Kaplan-Meier survival analyses with log-rank tests were performed to examine and compare OS. Results: Overall 113 patients were analyzed. 62 (54.9%) patients received carboplatin+etoposide and 51 (45.1%) patients had cisplatin+etoposide. Median age was 70 vs 59.5 in carboplatin and cisplatin patients, respectively (p &lt; 0.001). Multivariate analyses showed that patients who received carboplatin had worse ECOG PS (p = 0.011). Median OS in both groups (Carbo vs Cis) were similar in limited stage (29.37 vs 27.77 mos p = 0.52) and extensive stage (10.79 vs 9.83 mos p = 0.64). Conclusions: Although cisplatin is still a backbone drug in both limited and extensive stage SCLC, carboplatin is a preferable drug due to its similar survival and tolerable toxicity advantage.