bluuebunny/crossref_metadata_2025 huggingface dataset:
The anti-CD20 antibody-drug conjugates TRS005 in relapse/refractory CD20-positive B-cell non-Hodgkin lymphoma: A multicenter, open-label, single-arm, phase I study.
Authors: Shi Yuankai , Li Zhiming , Qin Yan , Li Yufu , Zhou Keshu , Zhang Huilai , Li Ling , Jia Youchao , Tong Xiangmin , Liang Xinquan , Zhang Yongdong , Li Kunyan , Zhou Hui , Hou Shuling , Li Zengjun , Shuang Yuerong , Liu Peng , Gui Lin
Published: June 2024

3026

Background: TRS005 is a novel anti-CD20 antibody-drug conjugate targeting CD20 positive tumor cells to deliver MMAE into the cells via receptor-mediated endocytosis. The aim of this study was to evaluate the safety, pharmacokinetics, and anti-tumor activity of TRS005 in relapse/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Methods: This first-in-human, single arm, multicenter, phase I, dose-escalation and expansion study conducted at 28 hospitals in China. The eligible patient had histologically confirmed CD20 positive B-cell lymphoma and had failed ≥2 prior lines of standard treatment. The dose-escalation phase involved 6 dose cohorts (from 0.1mg/kg to 2.1mg/kg) following a 3+3 design. Patients received TRS005 intravenously on day 1 of each 21-day cycle for 6 cycles. The dose cohort in which partial response (PR) or complete response (CR) was observed entered the dose-expansion phase. The safety, tolerability and efficacy of TRS005 were evaluated every two cycles. The primary endpoints were safety and pharmacokinetics. Secondary endpoints were objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) assisted by investigators. Results: From Aug 24th,2020 to Oct 23th,2023, 130 R/R B-cell NHL patients received treatment. The dose limiting toxicity was observed in the first patient in the 2.1mg/kg dose group during the dose-escalation phase. 70 patients had R/R diffuse large B cell lymphoma (DLBCL). Of the 70 R/R DLBCL patients, the median age was 59 (25-83) years, 82.9% of patients were in stage III-IV and 98.6% of patients received at least 2 lines of treatment (except one patient who only received 1 line of previous treatment). Overall, 88.6% of patients experienced all grades adverse events (AEs). Treatment-emergent adverse events (TEAEs) of ≥grade 3 occurred in 65.7% of patients, hematologic TEAEs were the most common. Two patients withdraw the treatment due to TEAEs and no TEAE related death were observed. At the data cutoff date of Nov 17th, 2023, the median treatment duration was 4 (1-27) cycles. 58 patients were evaluated for efficacy and confirmed ORR was 46.6%, with a DCR of 75.9%. The highest ORR was seen in 1.8mg/kg dose cohort, with an ORR and DCR of 56.7% and 86.7%, respectively. The PFS was 5.6 (95% CI: 4.2-17.4) months and 12-month PFS was 35.1%. Conclusions: TRS005 is well-tolerated and exhibits encouraging anti-tumor efficacy in the treatment of R/R DLBCL. Clinical trial information: NCT05395533 . [Table: see text]
A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): Results of dose escalation.
Authors: Stockton Shannon , Shyr Cathy , Cecchini Michael , Aljumaily Raid , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad B. , Whisenant Jennifer , Ivy S. Percy , LoRusso Patricia , Das Satya , Gore Steven , Berlin Jordan , Beumer Jan Hendrik , Heumann Thatcher Ross
Published: June 2024

3076

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]
Biomarker discordance after neoadjuvant systemic therapy and associated patterns of recurrence.
Authors: Chong Esther G , Joung Bowon , Guo Mengni , Jeon Won Jin , Bera Kevin , Lee Jae , Moon Jin Hyun Floyd , Nagaraj Gayathri
Published: June 2024

3149

Background: Understanding and addressing intratumor heterogeneity in breast cancer (BC) is crucial for advancing research and improving patient outcomes. The identification of biomarkers for targeted therapies is complex when dealing with heterogeneous tumors, and this heterogeneity complicates cancer outcomes since it affects treatment response, and the development of resistance. Methods: A single institution retrospective review of patients with BC who received neoadjuvant systemic therapy (NAST) followed by definitive surgical resection from 2008 to 2022 was performed. Initial tumor biopsies were tested for hormone receptors (HR) [estrogen receptor (ER) and progesterone receptor (PR)], and HER2 status and repeated on the residual tumor tissue after NAST. HER2 status was categorized into HER2-negative, HER2-low, and HER2-positive and HR status was categorized into ER and/or PR positive or negative based on the 2023 ASCO-CAP guidelines. HER2 and HR concordance and discordance rates were obtained and patients who had disease recurrence were identified and analyzed using descriptive statistics and Fisher’s exact test. Results: 480 patients with BC received NAST, and 143 patients with residual disease had pre and post treatment biomarker data available for analysis with a median post-surgery follow up of 15.2 months. Discordance in either HER2 or HR status was identified in 50% (72/143) of samples. Out of 143 patients, 44 patients had disease recurrence in which 50% (22/44) of tumors exhibited biomarker discordance. Among the changes in biomarker status, a shift in PR expression occurred most frequently in 27% of tumors (12/44). A change from HER2-low to HER2-negative status, as well as changes in ER expression occurred in 11% of tumors (5/44). 14% (6/44) of tumors had changes in both HER2 and HR. In patients who did not have recurrence, 51% (50/99) of tumors exhibited biomarker discordance. A HER2-low to HER2-negative status occurred most frequently in 18% (18/99). A change in ER expression occurred second most frequently, in 14% (14/99) of tumors. There was no statistical significance of discordance rates in the recurrence group and non-recurrence group (p-value=0.96). Conclusions: Tumor heterogeneity plays a role in shaping the distinct tumor biology of each patient. While the rates of biomarker discordance were comparable between samples with and without recurrence, the importance of HR discordance in this group requires extensive long-term monitoring. Our research highlights the importance of biomarker changes in a curative setting. Considering the implications for treatment, further investigation into additional biological and tumor-related factors associated with recurrence is warranted. [Table: see text]
Botensilimab plus balstilimab in microsatellite stable metastatic colorectal cancer: Assessing efficacy in non-liver metastatic sites.
Authors: Fakih Marwan , Bullock Andrea J. , Schlechter Benjamin L. , Tsimberidou Apostolia Maria , Messersmith Wells A. , Pimentel Agustin , Balmanoukian Ani Sarkis , Sanborn Rachel E. , Segal Neil Howard , Bockorny Bruno , Sharma Sunil , Henick Brian S. , Chau Ian , Grossman Joseph Elan , Patel Jaymin M. , Wu Wei , Johnson Benny , Lenz Heinz-Josef , O'Day Steven , El-Khoueiry Anthony B.
Published: June 2024

3556

Background: Botensilimab (BOT) is an Fc-enhanced, multifunctional anti-CTLA-4 antibody with unique mechanisms of action. In microsatellite stable colorectal cancer (MSS CRC), previous I-O combinations have shown poorer responses in metastatic sites of disease outside of the lungs and lymph nodes, even in non-liver metastases (NLM) populations. Here we present updated efficacy data with longer follow-up from an expanded phase 1b study (NCT03860272) in patients with NLM MSS CRC treated with BOT and balstilimab (BAL; anti-PD-1). Methods: As of Nov 29, 2023, 77 patients with NLM MSS CRC (median follow-up 13.0 months [range 0.6–42.6]) with ≥6 months follow-up were included (intention to treat [ITT]; all treated); of these, 70 had ≥1 post-baseline scan (efficacy evaluable [EE]). Patients received BOT 1 or 2 mg/kg every 6 weeks (Q6W) and BAL 3 mg/kg every 2 weeks. Endpoints included RECIST 1.1 confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results: Median age was 56 years (range 36–82), 48% male, and median prior lines of therapy was 4 (range 1–10). ORR was 22% (17/77) and DCR was 73% (56/77), with the median DOR not reached (NR; 95% CI 5.7–NR). An additional response confirmed after the data cutoff (18/77; ORR 23%), with 11/18 responses ongoing. Subgroup analyses revealed that BOT and BAL showed comparable activity (ORR 18–33%) across metastatic sites outside of the lungs, including the peritoneum, soft tissue, pleura, and the brain (Table). One responder with an occult brain metastasis experienced pseudoprogression, followed by a complete systemic response to treatment in target lung lesions. No new safety signals were observed and updated safety and translational data will be presented. Conclusions: In summary, for MSS CRC, BOT and BAL is differentiated from previous I-O combinations by producing deep and durable responses even in difficult-to-treat metastatic sites. In NLM patients, responses were observed in 18–33% of sites of disease including the peritoneum, soft tissue, pleura, and the brain. These compelling results support further investigation in the fully enrolled, randomized, global phase 2 trial in MSS CRC (NCT05608044) and a planned global phase 3 trial. Clinical trial information: NCT03860272 . [Table: see text]
A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.
Authors: Lim Sung Hee , Saluja Ashok K , Hong Jung Yong , Kim Seung Tae , Lavania Shweta , Pandey Somnath , Gupta Vineet K , Velagapudi Mohana , Lee Jeeyun
Published: June 2024

4033

Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B & C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 45-month (mo) follow-up from CheckMate 648.
Authors: Chau Ian , Ajani Jaffer A. , Kitagawa Yuko , Xu Jianming , Wyrwicz Lucjan S. , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez , Holtved Eva , Blum Murphy Mariela A. , Nathani Raheel , Hu Nan , Matsumura Yasuhiro , Kato Ken , Doki Yuichiro
Published: June 2024

4034

Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]
ctDNA analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib (LEN) or sorafenib (SOR) as 1L therapy.
Authors: Evans T.R. Jeffry , Kudo Masatoshi , Cheng Ann-Lii , Wyrwicz Lucjan S. , Ngan Roger KC , Blanc Jean-Frédéric , Baron Ari David , Vogel Arndt , Ikeda Masafumi , Piscaglia Fabio , Qin Shukui , Hoshi Taisuke , Tamaki Ryuji , Funahashi Yasuhiro , Okpara Chinyere E , Sagane Koji , Xing Dongyuan , Minoshima Yukinori , Finn Richard S.
Published: June 2024

4094

Background: In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC ( P<0.0001); OS was noninferior. In this post-hoc analysis, we determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes. Methods: In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review. Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test. Results: 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population. In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of <200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%). In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table). Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/ CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%). Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS. OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented. Conclusions: TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms. Clinical trial information: NCT01761266 . [Table: see text]
The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for advanced biliary tract cancer.
Authors: Ying Jieer , Xie Yanru , Xu Qi , Li Jingjing , Luo Cong , Zhang Lei , Wang Yonghui , Chen Li , Huang Jianhui , Li Wenting , Xia Yu
Published: June 2024

4095

Background: Despite that PD-1/L1 inhibitors combined with chemotherapy have been approved as first-line(1L) treatment for advanced biliary tract cancer (BTC), the overall survival benefit remains limited, particularly for patients with gallbladder cancer. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce complementary and synergistic anti-tumor effects through both pathways. This study aimed to evaluate the safety and efficacy of ivonescimab in combination with chemotherapy in advanced BTC. Methods: This was an open-label, multi-center phase II study in patients with unresectable locally advanced and metastatic BTC. Ivonescimab was administered every 3 weeks for up to 8 cycles, along with gemcitabine and cis-platinum. After that, ivonescimab monotherapy was given until disease progression or unacceptable toxicity. The primary endpoints were safety and objective response rate (ORR) by RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS), and overall survival (OS). Results: As of Nov 26, 2023, a total of 22 pts with advanced BTC were enrolled in the study. The median age was 65.0 years (range, 47-75), 81.8% of patients had ECOG of 1. All patients had initially unresectable disease status, 54.5% of patients had intrahepatic cholangiocarcinoma, 4.5% of patients had extrahepatic cholangiocarcinoma and 40.9% of patients had gallbladder cancer at baseline. The median follow-up time was 10.7 months, and the median exposure time of ivonescimab was 7.2 months. A total of 86.4% (19/22) of patients experienced at least one grade 3 or higher treatment-related adverse event (TRAE), but none led to discontinuation treatment or death. The most common grade 3/4 TRAEs with a frequency of at least 10% included white blood cell count decreased (50.0%), neutrophil count decreased (50.0%), anemia (40.9%), platelet count decreased (22.7%), and hypertension (13.6%). The ORR by investigator assessment was 63.6% (14/22) regardless of PD-L1 status, with an ORR of 77.8% (7/9) for gallbladder cancer patients specifically. The DCR was 100% (22/22). The median PFS was 8.5 months (95% CI, 6.8-9.9), with a 6-month PFS rate of 84.2% (95% CI, 58.7-94.6). The median OS was 16.8 months (95% CI, 9.8- NE), with a 9-month OS rate of 81.8% (95% CI, 58.5-92.8). Conclusions: Ivonescimab combined with chemotherapy as 1L treatment demonstrated promising efficacy in pts with advanced BTC. Further trials to validate the efficacy and safety are warranted. Clinical trial information: NCT05214482 .
Atezolizumab plus bevacizumab (A+B) as first-line systemic therapy for advanced hepatocellular carcinoma (HCC): A multi-institution analysis of patient outcomes based on Child Pugh (CP) and ALBI liver function.
Authors: Storandt Michael H. , Zemla Tyler J. , Patell Kanchi , Naleid Nikolas , Gile Jennifer , Tran Nguyen H. , Chakrabarti Sakti , Jin Zhaohui , Mahipal Amit
Published: June 2024

4099

Background: A+B is standard of care for advanced HCC in the first line setting, although was only evaluated in patients with CP class A liver function in IMbrave150. We sought to determine outcomes of patients in the real-world setting. Methods: We conducted a multi-institution retrospective analysis of patients with HCC who received A+B as first-line systemic therapy between March 2018 and November 2023, at Mayo Clinic and University Hospitals Seidman Cancer Center. Treatment response was evaluated, and progression free survival (PFS) and overall survival (OS) were determined using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazard regression method. Results: Among patients with HCC (n=322), 226, 86, and 10 had CP-A, -B, and -C liver function, while 120, 177, and 25 had ALBI grade 1, 2, and 3 liver function. Median age was 66.5 years, 78.6% were male, and 82.6% were white. Liver disease causes included hepatitis B (5.3%) and C (34.8%), ethanol use (26.1%), and non-alcoholic steatohepatitis (15.5%). Macrovascular invasion was seen in 42.9%, and 30.4% had extrahepatic metastatic disease. Median OS for patients with CP-A5/6 was 21.6 months, B7 (n=49) was 9.1 months, and B8-C12 was 4.7 months ( p<0.0001). Median OS by ALBI grade was 34.9, 11.7, and 4.7 months for grades 1, 2, and 3. Median PFS was 8.9, 6.4, and 2.7 months for CP-A5/6, B7, and B8-C12 ( p<0.0001). Median PFS by ALBI grade was 11.0, 6.4, and 3.7 months for grades 1, 2, and 3 ( p=0.0001). Among patients with CP-A, those with ALBI grade 1 had mOS of 34.9 months versus 14.2 months for those with grade 2. Partial response was seen in 29.2%, 19.8% and 10.0% of patients with CP-A, -B, and -C, while 32.7%, 33.7%, and 40.0% had stable disease. In a univariate analysis, factors predictive of shorter OS included CP-B7 or CP-B8-C12, ALBI grade 2 or 3, hepatitis B, poorer ECOG performance status (PS), macrovascular invasion, non-white race, and lack of prior surgery or embolization. In multivariate analyses, CP score, ALBI grade, hepatitis B, ECOG PS, and macrovascular invasion were significantly associated with survival. There was significant interaction between CP and ALBI grade (Table). Conclusions: A+B remains a viable option in patients with CP-B7 liver function, although benefit is significantly less than those with CP-A. ALBI score has predictive value and can identify two prognostic groups among those with CP-A liver function. [Table: see text]
Clinical and translational results from REVOLUTION cohorts A (nivolumab + ipilimumab + chemotherapy) and B (hydroxychloroquine + ipilimumab + chemotherapy) in patients with previously untreated metastatic pancreatic adenocarcinoma.
Authors: O'Reilly Eileen M. , Wainberg Zev A. , Fisher George A. , Wolff Robert A. , Ko Andrew H. , O'Hara Mark H. , Spencer Christine N , Yu Jia Xin , Da Silva Diane M. , Padron Lacey J. , Lyman Jaclyn P. , Moore Jonni S. , Peng Brandon , Hoos William , O'Donnell-Tormey Jill , Boffo Silvia , Dugan Ute , Cabanski Christopher R , Amaravadi Ravi K. , Vonderheide Robert H.
Published: June 2024

4137

Background: Metastatic pancreatic adenocarcinoma (mPDAC) is largely refractory to treatment, including immunotherapy. However, recent developments in chemoimmunotherapy combinations show promise. Herein, we report results from the first 2 cohorts of REVOLUTION, an ongoing, adaptive platform study designed to assess the safety and antitumor activity of novel chemoimmunotherapy combinations in patients (pts) with untreated mPDAC. Methods: REVOLUTION (NCT04787991) is an open-label, non-randomized, exploratory platform trial. Pts were assigned by investigator choice to one of the enrolling cohorts. All pts in Cohorts A and B received 1000 mg/m2 gemcitabine, 125 mg/m2 nab-paclitaxel, and 2 doses of 1 mg/kg ipilimumab. In addition, pts received 360 mg nivolumab Q3W in Cohort A or 600 mg hydroxychloroquine BID in Cohort B. Primary endpoint: safety. Secondary endpoints: ORR, DCR, DOR, PFS, and OS. Exploratory endpoints: pharmacodynamics and association of tumor and blood biomarkers with clinical activity. Each cohort utilized a Simon two-stage design: n=15 in Stage 1 with expansion to Stage 2 (an additional n=15) based on the totality of safety, efficacy and biomarker analyses. Results: Both cohorts enrolled 15 pts each. Median treatment duration was 6.5 and 5.6 months (mo), and median study duration was 19.1 and 12.7 mo for A and B, respectively. All pts experienced a treatment-related adverse event (TRAE). Grade 3-4 TRAEs occurred in 60% of A (most common: decreased neutrophil count [n=4]) and 53% of B (most common: anemia [n=5], decreased neutrophil count [n=4]). In B, 2 pts discontinued due to AEs, with none occurring in A. One grade 5 TRAE (multiple organ dysfunction syndrome, deemed related to chemotherapy) occurred in B; none in A. Table shows efficacy results. Cohort A revealed increased activated/proliferating CD4 T cells, CD8 T cells, Tregs, and soluble PD-1 in circulation. Cohort B showed increases in activated/proliferating CD4 T cells and signs of autophagy inhibition. Preliminary multi-omic analyses that aim to associate biomarkers with clinical response will be presented. Conclusions: REVOLUTION cohorts A and B demonstrated antitumor activity in pts with mPDAC. Cohort B treatment, which included hydroxychloroquine, incurred more early discontinuations. As designed, neither cohort will advance to Stage 2, highlighting the need for further tailored therapeutic approaches in mPDAC. Clinical trial information: NCT04787991 . [Table: see text]
Genetic landscape of colorectal cancer (CRC) across genetic ancestries: Implications for early cancer detection (ECD).
Authors: Ioannidis Alexander , Srinivasan Preethi , Bristow Sara L. , Krinshpun Shifra , Shams Solari Omid , Rivero-Hinojosa Samuel , Aushev Vasily N. , Jurdi Adham A , Liu Minetta C. , Mitchell Bree , Aleshin Alexey , Reiter Johannes G. , Nakamura Yoshiaki , Yoshino Takayuki , Wall Jeffrey , Myer Parvathi , Bustamante Carlos D.
Published: June 2024

e15527

Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for adoption of and adherence to screening. As health disparities in the incidence of CRC across minority populations are known to exist, we evaluated the genomic landscape in patients with CRC across genetic ancestries. Methods: De-identified patients (N = 16,337) with stage I-IV CRC had personalized, tumor-informed commercial ctDNA testing (SignateraTM) based on whole exome sequencing. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR, n = 1697), Ashkenazi Jewish (ASJ, n = 1192), East Asian (EAS, n = 2247), European (EUR, n = 9726), Latino (LAT, n = 1291), and South Asian (SAS, n = 184) ancestries. Somatic driver mutations and pathogenic germline variants (PVs) in CRC-associated genes were evaluated. Somatic single nucleotide variants were used for mutational signature inference. Results: Across ancestries, 47-67% of the patients were male and most were aged > 50 years. Among 35 to 50-year-olds, microsatellite instability (MSI) rates were higher in LAT (12.9%, p = 0.04) and SAS (28.3%, p < 0.001) vs EUR (8.2%). Among > 50-year-olds, MSI rates were lower in AFR (10.7%, p < 0.001), EAS (7.9%, p < 0.001), and LAT (10.4%, p < 0.001) vs EUR (16.0%). The POLE signature was more common in AFR (2%, p = 0.001) vs EUR (1.1%). There were significant differences in the frequency of driver mutations and PV rates between non-EUR vs EUR ancestry groups (Table, *p < 0.05, **p < 0.001). Gene-level enrichment was observed in MLH1 for SAS (8.7%, p < 0.001) and LAT (1.8%, p = 0.03), CHEK2 for AFR (0.4%, p = 0.03) and EAS (0.1%, p < 0.001), and PMS2 (1.4%, p = 0.006) for AFR. Among patients aged ≤50 years, similar findings were observed, with differences driven by MSI rates and germline findings in Lynch syndrome (LS) genes. Conclusions: This is the first study to investigate genomic differences between multiple ancestry groups in the largest cohort to date, including EAS, LAT, and SAS populations. The differences observed between ancestries could provide insight into differences in both hereditary risk and subsequent tumor initiation and growth. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide the rationale for precision treatment based on ancestry. [Table: see text]
Upregulation of GREB1 in colorectal cancer ovarian metastases may be a potential therapeutic target.
Authors: Ruff Samantha M. , La Ferlita Alessandro , Palavalli Manoj , Chick Robert Connor , Beane Joal D. , Tsai Susan , Eng Oliver S. , Kim Alex
Published: June 2024

e15596

Background: Classification of ovarian metastases (OM) in colorectal cancer (CRC) as peritoneal metastasis (PM) remains controversial. Moreover, OM demonstrate resistance to systemic therapy, suggesting distinct molecular tumorigenesis. Gene expression profiling and transcriptomic analysis was performed to distinguish OM, PM, and primary CRC (pCRC) and identify potential therapeutic targets. Methods: RNA sequencing was performed on tissue from the Total Cancer Care database. Raw counts were scaled in reads per million to filter out low-expressed genes. Afterward, raw counts of retained genes were normalized in trimmed mean of M-values and then log2-transformed using the Limma R package. Genes with a |Log2FC| > 0.58 and an adjusted p-value < 0.05 were considered dysregulated. In silico motif enrichment analysis of estrogen receptor 1 (ESR1) on growth regulating estrogen receptor binding 1 (GREB1) was conducted via the FIMO program. Results: There were 115 patients with tissue from OM (n = 6), PM (n = 4), and pCRC (n = 105). The average age was 58 years and most patients were male (57.4%), Caucasian (89.5%), and had microsatellite stable disease (69.6%). Most patients underwent cytotoxic chemotherapy (67%), while fewer underwent targeted therapy (38.3%) or radiation therapy (27.8%). The median overall survival for the pCRC, OM, and PM populations was 7.1, 3.4, and 4.0 months, respectively. Among upregulated genes, LAMC3, SCUBE1, and GREB1 had the highest differential expression in OM compared to PM and PEG3, C7, and GREB1 had the highest differential expression in OM compared to pCRC (all p < 0.001). Among downregulated genes, IGLC1, IGHG2, and IGHG1 had the greatest differential expression in OM compared to PM and IGHG1, IGKV4-1, and MMP12 had the greatest differential expression in OM compared to pCRC (all p < 0.001, Figure 1). GREB1 was upregulated in OM compared to both PM and pCRC. There are two estrogen response element (ERE) sites within the promoter region of GREB1. ESR1 transcription factor was shown to bind to these ERE (p < 0.001). Conclusions: Transcriptomic analysis demonstrated clear molecular distinction between OM, PM and pCRC. Differences in gene expression profiling suggest distinct underlying mechanisms of metastasis. We identified a significant upregulation of GREB1 in OM compared to PM and pCRC. GREB1 contains both ERE and ESR1 in the upstream promoter regions implying potential upstream transcription regulation mediated by ESR1. GREB1 is a potential novel, hormonal target in treatment of OM in CRC. Continued analysis is ongoing to identify other potential targets.
Phase 1b study evaluating the efficacy and safety of ABBV-400, a c-Met–targeting antibody-drug conjugate, in select advanced solid tumor indications.
Authors: Perets Ruth , Sharma Manish , Strickler John H , Golan Talia , Hollebecque Antoine , Henner William , Vasilopoulos Athanasios , Morrison Thiele Gladys , Burns Michael Charles , Harding James J.
Published: June 2024

TPS3162

Background: c-Met (MET protein) is commonly overexpressed in a number of tumors, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), biliary tract cancers (BTC), esophageal squamous cell carcinoma (ESCC), breast cancer (BC), and head and neck squamous cell carcinoma (HNSCC). Patients with c-Met–overexpressing tumors represent an underserved population, with the need for more effective c-Met–targeting therapies to become available. ABBV-400 is an antibody-drug conjugate, consisting of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Initial results from the ongoing first-in-human study (NCT05029882) of ABBV-400 in patients with advanced solid tumors indicate a tolerable safety profile, with a maximum tolerated dose of 3 mg/kg once every 3 weeks (Q3W), and promising antitumor activity, with an overall response rate of 24.4% (1). Herein, we describe a signal-seeking study evaluating ABBV-400 treatment in patients with select solid tumors. Methods: Multicenter, open-label, phase 1 signal-seeking study(NCT06084481). Eligible patients (≥18 years) have confirmed locally advanced/metastatic disease measurable per RECIST v1.1 and Eastern Cooperative Oncology Group performance status ≤1. Approximately 220 patients are planned for enrollment across 7 cohorts (HCC, n=40; PDAC, n=40; BTC, n=20; ESCC, n=40; triple-negative BC, n=20; hormone receptor-positive/HER2-negative BC, n=20; HNSCC, n=40). The primary objectives are to assess efficacy and safety/tolerability of ABBV-400 in each tumor indication. Secondary objectives include the evaluation of pharmacokinetics (PK) and immunogenicity of ABBV-400. Pharmacodynamic (PD) and biomarker analyses are exploratory endpoints. Patients receive intravenous ABBV-400 at 3 mg/kg Q3W until disease progression, intolerable toxicity, or any other per-protocol discontinuation criteria. c-Met expression will be assessed retrospectively by immunohistochemistry. The maximum treatment duration is 2 years. Tumor assessments are performed at screening and every 6 weeks from the first dose of study drug, with objective response rate as primary efficacy endpoint and duration of response, clinical benefit rate, progression-free survival, and overall survival as secondary efficacy endpoints. Safety evaluations include adverse events monitoring (graded according to the NCI CTCAE, v5.0), physical examinations, vital sign measurements, ECG variables, and clinical laboratory testing. Blood samples for PK, PD, and biomarker analysis are collected at designated time points throughout the study. Enrollment started in November 2023. As of 19 January 2024, 24 patients have been enrolled. 1. Sharma et al. JCO 2023;41[16 suppl]:3015. Clinical trial information: NCT06084481 .
Diabetic nephropathy in patients with type 2 diabetes mellitus and its correlation with diabetic retinopathy
Authors: Benevides Damasceno Márcia , Martins Ferreira Juliana de Lucena , Da Silva Rodrigues Raquel Ádria , Rodrigues Riedel da Costa George
Published: June 2024

Objective: the present study aimed to evaluate the prevalence of diabetic nephropathy and diabetic retinopathy, in addition to the associations that can be established between these microvascular complications of diabetes mellitus. Methods: this was a retrospective study, a systematic review without meta-analysis. The authors used the Pubmed and SciELO databases to search the terms “diabetic nephropathy”, “diabetic retinopathy” and “type 2 diabetes”, including publications dated 2011 to 2021. Results/Discussion: the results presented were a synthesis of patients with both pathologies and their correlations, in addition to associated laboratory changes and agreement between the stages or severity of both conditions. Conclusions: DN and DR are pathologies that are directly interconnected and cause repercussions for patients.
Metaphors and allusions to ancient writers and the Bible in Ioannis Apocaukos’ epistles relevant to medical and paramedical issues
Authors: Diamandopoulos Athanasios
Published: June 2024

Ioannis Apocaukos (1153/60 - 1235) was a famous Metropolitan of Naupactus, today a minor town in Southwestern Greece, but then one of the strongest Seats of the Orthodox Church in the Balkans. He was a prolific writer, and apart from many theological works he wrote extensively on political, social and medical matters. In the fashion of Byzantine epistolographers, he excelled in correspondence with numerous illustrious personalities of his area and era. A frequently recurring topic was his illness, described in a flamboyant language. In his letters, he used direct or indirect metaphors and allusions to passages from prominent religious or secular authors of antiquity. In this paper, we tried to trace the obscure threads joining his references to medical and paramedical issues with poets, historians, orators, philosophers and clergymen of the past. We identified nineteen and commented extensively upon them.
Case Report: Callosal disconnection syndrome manifesting as mixed frontal-callosal-posterior alien hand syndrome following extensive corpus callosum infarct
Authors: Zainudin Muhamad Faizal , Soo Kar Chuan , Nyein Yin Khin
Published: June 2024

Alien hand syndrome (AHS) is a rare neurological phenomenon first described by Van Vleuten over a century ago. The most widely recognized variants in literature are frontal, callosal, and posterior AHS. AHS due to the corpus callosum lesion can occur alone or as part of callosal disconnection syndrome (CDS). This report presents a unique CDS case manifesting clinical features from all three AHS variants, resulting from an extensive corpus callosum infarct. Our patient exhibited various clinical features from the three AHS variants, which include grasping, groping, and difficulty releasing objects from the hand (anterior); intermanual conflict (callosal); arm levitation, mild hemiparesis, and hemisensory loss (posterior). Additionally, the extensive disruption of the corpus callosal fibers produced neurological manifestations of CDS, such as cognitive impairment, ideomotor and constructional apraxia, behavioral disorder, and transcortical motor aphasia. We employed a range of rehabilitation interventions, such as mirror box therapy, limb restraint strategy, verbal cue training, cognitive behavioral therapy, bimanual hand training, speech and language therapy, and pharmacological treatment with clonazepam. The patient showed almost complete resolution of CDS and AHS features by nine months post-stroke Our case report highlights distinctive clinical variations of AHS and the challenging correlation between clinical manifestations and neuroanatomical substrates. Future studies are necessary to explore the intricate neural connections and the precise function of the corpus callosum. This can be achieved by combining comprehensive neuropsychological testing with diffusion tensor tractography studies. It is also essential to develop a validated tool to standardize AHS assessment. Finally, the scarcity of evidence in rehabilitation interventions necessitates further studies to address the wide knowledge gap in AHS and CDS management.
Climate migrations as a subject of the American national security policy
Authors: Anita Adamczyk , Mrozowska Sylwia
Published: June 2024

This article draws attention to the growing importance of climate migration as a subject of national security. The United States of America (USA) was cited as a global leader upon which the international community places its hopes in combating climate change. With this in mind, an analysis was conducted on the institutional and normative actions of the American administration during the presidency of Joe Biden, which were a direct response to the effects of the climate crisis. These actions show the increased involvement of the USA administration in trying to define climate migration as a serious national security problem. In the article, we argue that with the change in the presidency in 2021, there was an increased commitment to climate migrants accompanied by a growing awareness of climate change. In the analysis of the cognitive problem, research methods characteristic of the following sciences were used: political (decision-making method), legal (dogmatic method), and historical sciences. The article is descriptive and explanatory.
Zawartość wybranych składników odżywczych w różnych częściach liści aloesu zwyczajnego (Aloe vera (L.) Burm. f.)
Authors: Różańska Jolanta
Published: June 2024

Celem pracy była ocena zawartości: suchej masy, popiołu, białka oraz błonnika pokarmowego w całych liściach oraz skórce i miąższu liści aloesu zwyczajnego Aloe vera (L.) Burm. f. Najwięcej suchej masy występowało w skórce liści aloesu (średnio 3,41%), a najmniej było jej w miąższu (średnio 0,62%). Odwrotnie było w przypadku wody – najwięcej zanotowano jej w miąższu aloesu, najmniej zaś w skórce liści. Zawartość popiołu w liściach aloesu zależała od części liścia: najwięcej popiołu stwierdzono w skórce (0,6 g·100 g-1), zaś najmniej w miąższu (0,16 g·100 g-1). Zawartość białka w badanych częściach liścia wynosiła w całych liściach 20,9 g·100 g-1, w miąższu 10,8 g·100 g-1, a w skórce 18,8 g·100 g-1. Średnia zawartość błonnika pokarmowego w próbkach całych liści aloesu wynosiła 24 g·100 g-1.
The influence of nitrogen fertilizer treated with low-temperature, low-pressure glow plasma on the growth and quality of selected species
Authors: Ciesielski Wojciech , Girek Tomasz , Oszczęda Wiktor , Oszczęda Zdzisław , Pisulewska Elżbieta , Tomasik Piotr
Published: June 2024

Water treated with low-pressure glow plasma of low frequency takes unique properties which might be utilized as a novel, beneficial nitrogen fertilizer. That assumption is tested in this report. Thus, plantations of dill (Anethum graveolens) var. Moravan, grass Universal (5% westerwold ryegrass (Lolium multiWorum), 20% tall fescue (Festuca arundinacea), 40% perennial ryegrass (Lolium perenne), 35% red festuce (Festuca rubra) and strawberry ((Fragaria) var. Senga Sengana were watered with that nitrogen fertilizer (LPGPAm) prepared of 1% ammonia solution in tap water treated for 30 min with plasma generated at 38oC at 5x10-3 mbar, 800 V, 50 mA and 10 kHz frequency. Watering lasted from August 1th (sowing) till September 30th (harvesting) 2023 in a greenhouse.The effect of the use of watering plants with LPGPAm was checked involving the following parameters: plant height, mass of stems, total mass of crops, content of fat, proteins, carotenoids, ascorbic acid, sulphur content chlorophyll, content of dry mass, and ash and bioaccumulation of cations and anions.
Prozdrowotne właściwości gryki zwyczajnej (Fagopyrum esculentum Moench)
Authors: Zarzecka Krystyna , Ginter Agnieszka , Gugała Marek , Mystkowska Iwona
Published: June 2024

W pracy przedstawiono pochodzenie gryki zwyczajnej (Fagopyrum esculentum Moench) i jej wartości odżywcze. Omówiono skład chemiczny nasion, właściwości prozdrowotne owoców oraz możliwości wykorzystania rośliny w przemyśle spożywczym (w postaci kaszy, mąki, płatków, pieczywa, makaronów, ciastek), farmaceutycznym i ziołolecznictwie (w postaci herbatek i preparatów ziołowych, suplementów diety). Przedstawiono walory zdrowotne miodu gryczanego oraz wykorzystanie łuski gryczanej – będącej produktem ubocznym przetwarzania spożywczego gryki – do wypełniania poduszek, materacy przeciwodleżynowych, rogali, opasek czy siedzisk, które mają działanie terapeutyczne. Gryka to cenna roślina rolnicza ze względu na niewielkie wymagania glebowe, wysoką odporność na choroby i szkodniki oraz dużą wydajność miodową z 1 ha; ponadto wzbogaca bioróżnorodność pól.
Cives Romanae. Roman Women as Citizens during the Republic
Authors: Lacorte Silvia , Rosillo López Cristina
Published: June 2024

This book goes beyond simplistic considerations, still occasionally found in popular and academic books, which merely state that, in Rome, men were citizens and women were not or, at best, were second-class citizens. Roman women were citizens and their civic roles and public presence are essential for gaining a better understanding of the Roman Republic. This monograph offers nineteen studies on Roman citizen women during this period, their roles in the public sphere and their place in the community and the res publica to which they belonged. It includes a variety of perspectives, discourses and nuances regarding the question of how women acted as citizens, in order to work towards a historical discourse that places men and women on an equal footing, considering the latter as historical actors as relevant as the former, and which incorporates gender issues into the narrative.