tbuckley/cabot-search huggingface dataset:
Prognostic analysis of PD-1/CTLA-4 bispecific antibody combined with chemotherapy first-line treatment for recurrent or metastatic cervical cancer: A multicenter real-world study.
Authors: Jiwei Li, Tao Wu, Yuping Deng, Chao Xu, Yupeng Jiang, Wen Zou, Yeqian Feng, Lin Wu, Jingjing Wang
Journal: Journal of Clinical Oncology (2024)

e17520 Background: PD-1/CTLA-4 bispecific antibody, cadonilimab, has shown excellent efficacy in advanced cervical cancer patients who have previously received platinum containing chemotherapy. However, its effectiveness in first-line treatment remains unclear yet. This study aims to evaluate the efficacy, safety, and prognostic biomarker of cadonilimab combined with chemotherapy for the first line treatment of recurrent or metastatic cervical cancer. Methods: Information on patients with recurrent or metastatic cervical cancer who received chemotherapy combined with cadonilimab as first-line treatment at three cancer centers from July 2022 to September 2023 were collected. Patients have not received systemic chemotherapy previously and are not suitable for curative local treatment, received cadonilimab 10mg/kg Q3W for up to 17 cycles + chemotherapy for up to 6 cycles (paclitaxel 135-175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 10-15 mg/kg. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. RNA-seq was used to analyze differential expressed genes (DEGs) between PR+CR group and PD+SD group. Results: There are 52 patients enrolled, median age 56.5 years (39–87 years). The median follow-up time was 12 months (5–23 months). There were 29 cases of lung metastasis, 7 cases of liver metastasis, 11 cases of bone metastasis, 12 cases of pelvic metastasis, and 11 cases of lymph node metastasis. The median number of cycles of cadonilimab and chemotherapy were 8 and 5, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 91% and 72.5%, respectively. The objective response rate (ORR) was 75%.The expression of PD-L1 and bevacizumab had no effect on prognosis. The most common treatment-related adverse events (TRAEs) were neutropenia (78.2%), anemia (82.7%), thrombocytopenia (51.9%), thyroid dysfunction (50%), nausea and vomiting (88.5%), fatigue (71.2%). Grade 3 or 4 adverse events (AE) were reported in 36.5% patients, mainly hematological toxicity. The most significant differential pathways between PR+CR group and PD+SD group were adhesion, Hippo signaling pathway, NOD like receptor signaling pathway, programmed cell death, and secretory granules. Conclusions: Cadonilimab combined with chemotherapy ± bevacizumab as first-line treatment for recurrent or metastatic cervical cancer was effective and well-tolerant.
ITGB6 as an inhibitor of T-cell killing via modulation of paracrine TGFβ signaling in pancreatic ductal adenocarcinoma.
Authors: William J. MacDonald, Maximilian Schwermann, Praveen Srinivasan, Vida Tajiknia, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2024)

e16334 Background: Immunotherapy has experienced limited success in PDAC, with αPD-1 therapy being approved only in a subset that makes up &lt; 2% of all PDAC cancers. TGFβ is a contributor to T-cell suppression in the PDAC tumor microenvironment. However, the success of blocking TGFβ in preclinical models has failed to translate into the clinic due to the off-target effects of systemic TGFβ blockade. Integrin ITGB6 is an activator of the inert latent TGFβ into the active, immunosuppressive form. Consequently, inhibition of ITGB6 is a potent and targeted therapeutic approach for disrupting TGFβ to overcome T-cell suppression in PDAC. Methods: Analysis of TCGA molecular and survival data was performed to determine the specificity and prognostic value of ITGB6 in PDAC. Subsequently, candidate cell lines were screened for ITGB6 expression using flow cytometry to facilitate an in vitro model. Using a lentiviral system, PDAC cells were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown (KD) of ITGB6. Both KD and control shRNA cell lines were induced with doxycycline and subsequently co-cultured with TALL-104 T-cells. Furthermore, conditioned media was analyzed for secreted active TGFβ levels using a luciferase-based TGFβ reporter cell line. Finally, a clonogenic assay was performed to determine the autocrine effects of TGFβ activation in PDAC. Results: ITGB6 is highly specific to PDAC and also shows upregulation in comparison to normal pancreatic tissue (FC 3.38, p &lt; 0.0001). Capan-2 cells were chosen as a model for high integrin PDAC (Capan-2 99.73% cells ITGB6+, negative control: HCT116WT 0.96% cells ITGB6+). Fluorescent microscopy of the co-culture revealed that the KD of ITGB6 increased T-cell killing over 24 hours (Capan-2 CTRL shRNA 7.71%±3.63 dead vs. Capan-2 ITGB6 shRNA 21.68%±4.57 dead, p &lt; 0.05). Media from ITGB6 KD cells contained significantly decreased TGFβ (+TGFβ: 673000 RLU vs. CTRL: 175500 RLU, p = 0.015). A clonogenic assay of Capan-2 cells treated with active-TGFβ demonstrates that PDAC cells resist the autocrine growth inhibitory effects of TGFβ through loss of SMAD4. TCGA survival data revealed ITGB6 as prognosis marker in PDAC (high ITGB6 median survival 16.79 mos, vs. low ITGB6 21.88 mos, HR = 2.730, p &lt; 0.004). Conclusions: Survival data that clearly demonstrates the poor prognosis of ITGB6 expression, as well as the presently proposed mechanism of immunosuppression, provide ample justification for deploying anti-ITGB6 combination therapies to in vivo studies that facilitate translation of our findings into therapeutic clinical trials.
Molecular and clinical features of pancreatic acinar cell carcinoma: A single institutional experience.
Authors: Ashwathy Balachandran Pillai, Mahmoud M.G. Yousef, Abdelrahman M.G. Yousef, Mark W. Hurd, Huamin Wang, Anirban Maitra, Jason Willis, John Paul Y.C. Shen, Shubham Pant, Brandon George Smaglo, Robert A. Wolff, Dan Zhao
Journal: Journal of Clinical Oncology (2024)

e16335 Background: Acinar Cell Carcinoma (ACC) accounts for around 1% of pancreatic cancer. The molecular and clinical features of acinar cell carcinoma are less characterized. We sought to evaluate the clinical and molecular features of patients with ACC at MD Anderson Cancer Center. Methods: Patients with ACC who had germline and/or somatic molecular testing at MD Anderson Cancer Center from 2008 to 2022 were identified retrospectively. After obtaining approval of approval of the institutional review board genomic alterations including germline or somatic BRCA mutations, KRAS mutation, demographic, clinical, and pathological information were extracted from institutional databases using the Palantir Foundry software platform (Syntropy); this included natural language processing with subsequent validation by manual chart review. Overall Survival (OS) was calculated from the date of diagnosis to death or last follow-up. The Kaplan-Meier method was used for survival analysis. Results: 16 patients were identified with molecular testing results available. There were 13 males and 3 females. The median age of diagnosis was 62.5 years (range 49 -72). 14/16 patients (87.5%) had metastatic disease, one (6.25%) patient had borderline resectable disease and one (6.25%) had localized resectable disease at initial diagnosis. Median OS was for 24 months for patients with metastatic disease. There were 2 patients with mixed pathology, 1 with acinar cell carcinoma with neuroendocrine features and the 2nd had mixed acinar cell-ductal carcinoma. 15/16 (93.75%) patients were tested for KRAS and all 15 were KRAS wildtype. Somatic mutations in DNA damage repair genes (BRCA2, PALB2) were present in 3 patients (25%) and 2 patients had germline mutation (BRCA and ATM) (16%) out of 12 patients tested for those genes. 6/16 (37.5%) patients were treated with FOLFIRINOX at first line. 3/6 (50%) of these patients had partial response, 2/6 (33%) had stable disease and only 1/6 (16%) had progression. 5 patients were treated with FOLFOX based regimen and 1/5 (20%) had response, 2/5 (40%) had stable disease and 2/5 (40%) had progression of disease. 5 patients were treated with gemcitabine-based regimen and only 1 had response which received gemcitabine/nab-paclitaxel combined with cisplatin. Conclusions: ACC were KRAS wild type and had higher rates of germline/somatic mutations in DNA damage repair genes. Better treatment outcome of FOLFIRNIOX/ platinum-based regimens was suggested based on this limited patient dataset. Larger studies are needed to further understand the molecular features of ACC and guide the treatment of this rare entity of pancreatic cancer.
White blood cell kinetics in patients with gynecologic cancer receiving mecapegfilgrastim prophylaxis: A multicenter real-world study.
Authors: Yong Chen, Liang Chen, Gang Li, Li Zuo, Gang Cheng, Nong Xu, Chenyu Mao, Peng Shen, Minbin Chen, Yanhong Wang, Zhanggui Wang, Rusen Zhao, Jun Bie, Weie Zheng, Haijiao Yan, Guifang Zhang, Zhe Yang, Ningling Zhang, Rui-Hua Xu, Xin Huang
Journal: Journal of Clinical Oncology (2024)

e17502 Background: Some studies have indicated that using granulocyte-colony stimulating factor (G-CSF) following chemotherapy in patients with solid tumors may increase the risk of excessive white blood cell (WBC) elevation. In this real-world study, we aimed to assess the changes in WBC counts after prophylactic administration of 6 mg mecapegfilgrastim (a long-acting G-CSF) in multiple chemotherapy cycles among Chinese gynecological cancer patients, with a particular focus on those with low body weight (≤50 kg). Methods: A multicenter prospective cohort study was conducted involving gynecological cancer patients who received at least two consecutive chemotherapy cycles with mecapegfilgrastim 6 mg (administered 24 hours post-chemotherapy) between October 2019 and November 2021. Absolute WBC and absolute neutrophil counts (ANC) were recorded at baseline and on the 7th and 14th days of each cycle. Results: A total of 256 gynecological cancer patients completing 2-4 treatment cycles, including 86 with cervical cancer, 136 with ovarian cancer, and 34 with endometrial cancer, were analyzed. Of them, 58 had a pre-chemotherapy body weight of ≤50 kg, and 198 had a body weight of &gt;50 kg. The majority of patients received taxane-based chemotherapy regimens with a cycle duration of ≥14 days. For day 7 post-chemotherapy WBC counts, data were collected from 535 cycles, including 125 cycles in the ≤50 kg group and 410 cycles in the &gt;50 kg group. Elevated WBC counts (&gt;10.0×10^9/L) were observed in 56 cycles (44.8%) in the ≤50 kg group and 177 cycles (43.2%) in the &gt;50 kg group. On day 14 post-chemotherapy, data from 505 cycles, comprising 115 cycles in the ≤50 kg group and 390 cycles in the &gt;50 kg group, indicated elevated WBC counts in 27 cycles (23.5%) in the ≤50 kg group and 63 cycles (16.2%) in the &gt;50 kg group. In the ≤50 kg group, 3 cases (5.2%) experienced an ANC &lt;0.5×10^9 /L, with no febrile neutropenia observed. In the &gt;50 kg group, 11 cases (5.6%) experienced an ANC &lt;0.5×10^9 /L, with 1 patient (0.51%) experiencing febrile neutropenia. Conclusions: In patients with low body weight (≤50 kg), the administration of 6 mg mecapegfilgrastim effectively stabilizes WBC elevation, exhibiting a favorable safety and efficacy profile. This regimen ensures the timely and appropriate progression of patients to subsequent cycles of chemotherapy. WBC counts in patients. [Table: see text]
Cadonilimab safety and efficacy in recurrent or metastatic cervical cancer: First real-world experience from a Chinese multicenter study.
Authors: Yang Sun, Jian Chen, Haijuan Yu, RenLiang Fan, Li Liu, Weixiong Xiao, Rong Lin, DeZhao Chen, Xiaoying Weng, Fengfang Shen, Shaoyu Wang, Qihua Tian, Wei Zeng, Rong Lian
Journal: Journal of Clinical Oncology (2024)

e17510 Background: Cadonilimab, a bi-specific antibody that simultaneously targets PD-1 and CTLA-4, was approved on 29 June 2022 in China for the treatment of recurrent or metastatic cervical cancer (R/M CC) in patients who have progressed following platinum-based chemotherapy. The COMPASSION-03 trial recently demonstrated promising tumor response rates with cadonilimab in R/M CC patients. This study aims to assess the efficacy and safety of cadonilimab in a real-world clinical setting in China. Methods: This multicenter retrospective study enrolled 102 patients with R/M CC, who received at least one cycle of cadonilimab at seven medical centers from July 2022 to October 2023. Among these, 94 patients were administered 10 mg/kg of cadonilimab once every 3 weeks on day 1, while 8 patients received 6 mg/kg every 2 weeks on day 1. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and the disease control rate (DCR) of the overall patients, as well as toxicity, were evaluated. Results: The study included patients with squamous cell carcinoma (73 patients), adenocarcinoma (20), adenosquamous carcinoma (5), and small cell neuroendocrine carcinoma (4). The median age was 54 years, ranging from 28 to 83. Initially, most patients presented with advanced disease: stage IIIB (8 patients), stage IIIC (24), and stage IV (43). The Eastern Cooperative Oncology Group (ECOG) performance status was 0, 1, 2, and 3 for 150, 12, 6, and 3 patients, respectively. Cadonilimab was administered as first, second, and third line or beyond in 35 (34.3%), 31 (30.4%), and 36 (35.3%) patients, respectively. Treatment regimens included cadonilimab monotherapy (13.7%), combined with chemotherapy (33.3%), chemoradiotherapy (19.6%), anti-angiogenesis therapy (11.8%), chemotherapy and anti-angiogenesis therapy (7.8%), chemoradiotherapy and anti-angiogenesis therapy (10.8%), and surgery plus chemoradiotherapy (2.9%). After a median follow-up of 10.2 months, median PFS and OS were not reached. Among the 93 patients (88.2%) with evaluable efficacy, 8 were CR, 32 were PR, 32 were SD, and 22 were PD. The ORR reached 43.0% and the DCR reached 77.4%. Adverse events were reported by 88.2% of patients, with 31 (30.4%) experiencing grade 3-4 immunotherapy-related adverse effects, mainly decreased white blood cell count(21 patients, 20.6%),, anaemia (6, 5.9%), infection (4, 3.9%), and increased alanine aminotransferase (3, 2.9%). Treatment discontinuation or reduction due to toxicity occurred in 17 patients (16.7%). There were no treatment-related deaths. Conclusions: Cadonilimab demonstrates efficacy and safety for patients with recurrent/metastatic cervical cancer in a real-world setting.
Survival in cervical cancer IIb-IVA subjected to postchemo-radiotherapy surgery in Ecuador.
Authors: José Luís Reyes, Walter Morquecho, Mario Argüello, Fausto Emiliano Pulla, Mayra Santacruz, Elizabeth Graciela Veliz, Carlos Jose Alarcon, Jenniffer Stefania Plaza, Nery Abdon Rivadeneira
Journal: Journal of Clinical Oncology (2024)

e17517 Background: Cervical cancer (CC) is one of the leading causes of cancer death in the world. The objective of the present study is to determine the overall survival (OS), survival by age group, and histological type in patients with locally advanced CC undergoing salvage surgery after chemo-radiotherapy (CTx-RTx). Methods: A retrospective observational analytical study was carried out on patients with locally advanced CC with stages IIB-IVA who received CTx-RTx treatment from January 2010 to December 2014 with follow-up until August 2023 in SOLCA-Guayaquil. The SPSSv29 statistical program was used to analyze survival curves with the Kaplan-Meier estimator and Log-Rank test. Results: Of a total of 1909 patients, 1581 were excluded because they did not meet eligibility criteria. 328 received CTx-RTx, and 23 underwent rescue surgery. The average survival result is 107 months (m). In survival by histological type, 11 patients presented squamous cell carcinoma (SCC) and 12 adenocarcinoma (AC), with the mean survival for SCC 111 months and for AC 94 months, however in the Log-Rank statistical test (p: 0.672) was not significant, which is why it is estimated that survival is similar in the two histological types (graph 2). In the calculation of survival by age in m (every ten years), in the first group of 30-39 years, it is 98.1 m, 40-49 years 118.8 m, 50-59 years 98.6 m, 60 or more years, it is 56 m; however, in the Log-Rank statistical test (p = 0.317), it is not significant by age group. Conclusions: Of the 23 patients with a mean age of 48 years and a follow-up of 168 months, 13 (56%) are alive. Regarding survival by histological type and age group, there was no significant difference in survival with these results. [Table: see text]
The efficacy and safety of donafenib-containing regimens as first-line therapy for hepatocellular carcinoma (HCC): A multicenter retrospective study.
Authors: Qingqiao Zhang, Guowen Yin, Qingyu Xu, Jinchang Xiao, Bin Shen, Guofeng Chen, Genshan Zhang, Wei Feng, Yong Yang, Jianping Hu, Chenghu Wang
Journal: Journal of Clinical Oncology (2024)

e16243 Background: HCC is a common malignant tumor worldwide, safer and more potent treatments are desperately needed to increase the survival rates of HCC patients. Some studies have shown that transcatheter arterial chemoembolization/hepatic arterial infusion chemotherapy (TACE/HAIC) combined with systemic therapies shows potential synergistic effects in patients with HCC, the ZGDH3-III RCT's findings showed that donafenib(D) is highly safe and effective as first-line treatment for uHCC. This study aimed to evaluate the efficacy and safety of donafenib-containing regimens (D+TACE/HAIC, D+TACE/HAIC+ICI, D+ICI, D) as first-line systemic treatments for HCC patients in the real world. Methods: We retrospectively analyzed patient data from January 2022 to December 2023 in seven Chinese institutions with first-line therapeutic regimens based on donafenib. Donafenib-based treatments were administered to eligible patients until the point of disease progression, death, or intolerable toxicity. We examined the progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) per the modified Response Evaluation Criteria in Solid Tumors, and safety (CTCAE5.0). Results: There were 102 patients in this study (Table). The median age was 60 years (IQR: 52, 68) at the data cut-off in January 2024, with 87.3% of the population being male and 78.4% having HBV infection. Most patients received D+TACE/HAIC therapy (59.8%), D+TACE/HAIC+ICI therapy (35.3%), or other treatments. Median PFS and OS not yet been achieved, respectively, the 12-month PFS and OS rates were 87.0% (95%CI: 79.7%-95.0%) and 91.4% (95%CI: 84.9%-98.4%). The ORR was 68.6% and DCR was 88.2%, with complete response in 14 patients, partial response in 56 patients, stable disease in 20 patients, and progressive disease in 12 patients. Among the population, 51 patients (50.0%) had treatment-related adverse events (TRAE) of any grade, and the incidence of grade 3 TRAE was 13.7% (14/102), none of the patients experienced grade 4 or 5 TRAE. Conclusions: These results preliminarily showed that donafenib-containing treatment regimens exhibited encouraging efficacy and favorable safety profile in patients with HCC. [Table: see text]
Effect of regulatory B cell expansion on tissue-resident T<sub>PH</sub> cells immune evasion in hepatocellular carcinoma.
Authors: Siqi Li, Haoyuan Yu, Mengchen Shi, Zhixing Liang, Kun Li, Yongwei Hu, Mingshen Zhang, Yang Yang, Linsen Ye
Journal: Journal of Clinical Oncology (2024)

e16252 Background: Within pathologically inflamed nonlymphoid tissues, T PH cells are uniquely positioned to stimulate B cell responses and antibody production. The phenotype, function and clinical relevance of T PH cells in hepatocellular carcinoma (HCC), however, are presently unknown. Methods: Flow cytometry was used to quantify the expression, phenotype and function of T PH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. T PH cells, CD19 + B cells and T FH cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays. Results: T PH cells highly infiltrated in tumor tissues, which influenced tumor sizes and early recurrence predictions and decreased survival times. The tumor-infiltrated T PH cells showed unique ICOS hi CXCL13 + IL-21 - MAF + BCL-6 - factors and triggered naïve B cell differentiation into regulatory B cells. Triggering PD-1 induced the production of CXCL13 by T PH cells, which then suppressed tumor-specific immunity and promoted disease progression. Conclusions: Our study reveals a novel regulatory mechanism of T PH cell-regulatory B cell mediated immunosuppression and provides an important perspective for the differentiation balance between protumorigenic T PH cells and antitumorigenic T FH cells in the HCC microenvironment.
Vaginal Progesterone for Pregnancy Prolongation After Arrested Preterm Labor
Authors: Zohar Nachum, Yael Ganor Paz, Manal Massalha, Malak Wated, Noa Harel, Enav Yefet
Journal: JAMA Network Open (2024)

Importance Women with arrested preterm labor (APTL) are at very high risk for spontaneous preterm delivery (SPTD), the leading cause of neonatal mortality and morbidity. To date, no maintenance therapy has been found to be effective for pregnancy prolongation. A few clinical trials with considerable methodological limitations have demonstrated some efficacy for 400 mg vaginal micronized progesterone (VMP) in women with APTL. Objective To investigate the effectiveness of daily 400 mg VMP for the prolongation of pregnancy after APTL. Design, Setting, and Participants This randomized clinical trial was conducted between December 19, 2018, and February 27, 2023, in 3 university-affiliated medical centers in Israel. Participants included women with singleton and twin pregnancies after APTL following tocolysis at 24 weeks 0 days to 34 weeks 0 days’ gestation. Women with a history of preterm delivery or asymptomatic cervical shortening in the current pregnancy were excluded. Interventions Participants were randomly allocated to receive VMP 200 mg twice a day or no treatment until 36 weeks 6 days’ gestation. Main Outcomes and Measures The primary end points were mean number of days from study enrollment to delivery and the rate of SPTD prior to 37 weeks’ gestation. Results A total of 129 participants were enrolled (65 in the VMP group and 64 in the no-treatment group). Mean (SD) age was 27.6 (5.1) years. Between the VMP and no-treatment groups, there was no difference in pregnancy prolongation (mean [SD], 40.0 [17.8] vs 37.4 [20.3] days; P = .44) and the rate of SPTD (16 [25%] vs 19 [30%]; relative risk, 0.8; 95% CI, 0.5-1.5; P = .52). In twin pregnancies, including 12 and 15 pairs in the VMP and no-treatment groups, respectively, VMP prolonged pregnancy (mean [SD], 43.7 [18.1] vs 26.1 [15.2] days; P = .02), postponed the delivery week (36.5 [1.4] vs 34.7 [2.2] weeks; P = .01), shortened the length of stay in the neonatal intensive care unit (4.9 [10.6] vs 13.2 [18.5] days; P = .03) and overall hospital stay (8.3 [9.6] vs 15.1 [17.2] days; P = .03), and was associated with a higher birth weight (2444 [528] vs 2018 [430] g; P = .01). Conclusions and Relevance These findings show that VMP given in a dosage of 200 mg twice a day following APTL is not an effective treatment to prolong pregnancy or prevent SPTD. However, VMP demonstrated beneficial effects in twin pregnancies, warranting further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT02430233