tbuckley/cabot-search huggingface dataset:
Age and body composition of patients receiving treatment for locally advanced esophageal cancer.
Authors: Ansley Beth Ricker, Jordan Robinson, Reilly Shea, Katelyn Cockerham, Matigan Simpson, Malcolm Hart Squires, Jonathan C. Salo
Journal: Journal of Clinical Oncology (2024)

e16094 Background: Standard of care for locally advanced esophageal cancer consists of chemoradiation (chemoRT) followed by esophagectomy. Fewer patients in older populations with locally advanced esophageal cancer undergo esophagectomy when compared to their younger counterparts. Furthermore, frail patients frequently forgo surgery after chemoRT. The current study examined the relationship between age, body composition, and treatment decision-making in locally advanced esophageal cancer. Methods: Patients with clinical stage T2-4, N0-2, and M0 adenocarcinoma or squamous cell carcinoma of the mid or distal esophagus diagnosed between 2010-2021 were included from 11 hospitals across our healthcare system. Treatment decision-points included receipt of chemoRT versus non-curative therapy, unresectable disease after chemoRT defined by metastatic disease or upper mediastinal lymphadenopathy, and receipt of surgery stratified by histology. Sociodemographic data including age, race, sex, insurance status, socioeconomic status, body composition data from CT imaging (skeletal muscle gauge [SMG]), and outcome data were collected. Skeletal Muscle Gauge was calculated as the product of skeletal muscle cross-sectional area at L3 normalized for height and muscle density. Fisher's exact test was used for categorical variables and Kruskal-Wallis for continuous variables. Results: 513 patients were included in the analysis, of which 399 (78%) had adenocarcinoma and 114 (22%) had squamous cell carcinoma. Median age was 66. Of the 513 patients, 472 (92%) underwent chemoRT (366 [78%] adenocarcinoma, 106 [22%] squamous cell carcinoma). Patients who were over the age of 75 were less likely to undergo chemoRT when compared to their younger counterparts (85% vs. 94%, p = 0.002). After the completion of chemoRT, 419 (89%) patients were deemed resectable, 330 adenocarcinoma and 89 with squamous cell carcinoma. Among resectable patients with adenocarcinoma, those &gt; 75 years old and lower SMG were less likely to receive surgery (p &lt; 0.001 and p =0.001). Age and body composition associated with lower receipt of surgery in locally advanced esophageal cancer patients was significant on both univariate and multivariate analyses. Conclusions: Patients over 75 are less likely to undergo chemoRT and surgical resection for locally advanced esophageal cancer. Among patients with resectable disease who have completed chemoRT, those with unfavorable body composition as measured by low SMG on CT imaging are also less likely to undergo surgical resection. These measures may be helpful in surgical decision-making in patients with locally-advanced esophageal cancer. Further study is warranted to more precisely define the relationship between age, body composition, and risk of surgery in esophageal cancer.
Immune checkpoint inhibitor plus chemotherapy versus chemotherapy alone in HER2-negative advanced gastric or gastroesophageal junction cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: João Pedro Oliveira, Isadora Mamede Mendes da Silva, Caio Dabbous de Liz, Melissa Maia, Audrey Cabral Ferreira de Oliveira, Ana Caroline Fonseca Alves
Journal: Journal of Clinical Oncology (2024)

e16052 Background: Synergistic effects of immune checkpoint inhibitors (ICI) and chemotherapy (CTX) have been documented, demonstrating promising efficacy across diverse cancer types. This report presents a meta-analysis aimed at assessing the effectiveness and safety profile of ICI plus CTX in patients diagnosed with Human Epidermal Growth Factor Receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) cancers. Methods: PubMed, EMBASE, Cochrane Central, and ASCO Abstracts databases were systematically searched for randomized controlled trials comparing PD-1 or PD-L1 inhibitors plus CTX with CTX alone in patients diagnosed with HER2-negative gastric or GEJ cancers. The assessed outcomes included Progression-Free Survival (PFS) and Overall Survival (OS), stratified by PD-L1 Combinated Positive Score (CPS) in tumors, as well as any Adverse Events (AE) and Treatment-Related Adverse Events (TRAE) graded as ≥ 3. Statistical analysis employed a random effects model in R version 4.3.2, with heterogeneity assessed using the I 2 statistic. Results: We conducted a meta-analysis comprising 6 RCTs involving 5,520 patients, among whom 2,766 received PD-1 or PD-L1 inhibitors in combination with chemotherapy. This combined regimen demonstrated significant improvements in both general PFS (HR 0.73; 95% CI [0.68; 0.78]; p &lt; 0.01) and OS (HR 0.77; 95% CI [0.71; 0.84]; p &lt; 0.01). Specifically, the combination of ICI with CTX exhibited enhanced PFS across various subgroups, including CPS ≥ 5 (HR 0.66; 95% CI [0.59; 0.75]; p &lt; 0.01), CPS ≥ 10 (HR 0.75; 95% CI [0.65; 0.87]; p &lt; 0.01), and CPS ≤ 1 (HR 0.75; 95% CI [0.69; 0.82]; p &lt; 0.01). Median OS similarly reflected this improvement in CPS ≥ 5 (HR 0.71; 95% CI [0.63; 0.81]; p &lt; 0.01) and CPS ≥ 10 (HR 0.66; 95% CI [0.57; 0.75]; p &lt; 0.01) subgroups, albeit not in the CPS ≤ 1 subgroup (HR 0.91; 95% CI [0.77; 1.08]; p = 0.29). Furthermore, no significant differences were observed in the incidence of adverse events (AE) (RR 1.01; 95% CI [0.99; 1.04]; p = 0.221), while grade 3 or more treatment-related adverse events (TRAE) were slightly higher in the ICI plus CTX group (RR 1.15; 95% CI [1.01; 1.32]; p = 0.038). Conclusions: These findings indicate that the combination of ICI with CTX demonstrates superior efficacy compared to CTX alone in HER2-negative gastric or GEJ cancer. However, this efficacy trend is not maintained in patients with PD-L1 CPS ≤ 1 tumors. Moreover, the absence of differences in AE and the slight increase in TRAE in the ICI plus CTX group still further supports the safety profile of this combination therapy.
Effectiveness and safety analysis of serplulimab-based regimens in patients with HER2-negative advanced gastric cancer from a real-world retrospective study.
Authors: Qian Ding, Mengyao Wu, Danlei Yu, Di Sun, Na Li, Min Tao, Hong Zhu
Journal: Journal of Clinical Oncology (2024)

e16058 Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy are currently the preferred regimen for the treatment of HER-2 negative advanced gastric cancer. Serplulimab, an anti-PD-1 inhibitor, has been conditionally approved for the treatment of adult advanced gastric cancer. Because of the diverse nature of patients (pts), patient-centered, individualized treatment require accumulation of experience for real-world applications. Methods: We retrospectively studied 42 HER2-negative advanced gastric adenocarcinoma pts whose safety profiles of regimen containing serplulimab could be evaluated from April 2022 to October 2023 in the First Affiliated Hospital of Soochow University. Individualized treatment regimens mainly included serplulimab combined with one or two selected drug(s) from platinum, taxanes, and fluoropyrimidines. Results: Cut-off on January 30 th , 2024, 30 pts (71.4%) received serplulimab based regimens as the first line (1L), 12 pts (28.6%) received the second or more line (≥2L) therapy. The characteristics were as follows: the median age, 66 years (range 35-80 years); male/female 33 (78.6%)/9(21.4%); ECOG performance status 0-1/38, ≥2/4. The median follow-up was 5.7 months (range 0.2-22.3 mos). A total of 227 cycles of treatment was administrated with a median of 4 cycles (range 1-17). Among the pts evaluable for RECIST 1.1, ORR and DCR were 42.9% and 69.0% respectively. There were 3 pts with 3 or more metastatic lesions achieved PR. Nine 1L pts and one 2L pt receiving serplulimab combined with dual chemotherapy containing platinum achieved disease control more than a year. We also tracked 11 pts who experienced grade 1-2 immune-related adverse events (irAEs) reaped over 6 months PFS. Two of four pts who stopped immunotherapy but maintained 1 or 2 cycles of original combined chemotherapy obtained PFS for more than a year. Median PFS and DoR have not reached. The most common grade 3/4 AEs was myelosuppression (7.1%), increased aminotransferases (4.7%) and elevated creatinine (2.3%). 15 (35.7%) pts experienced immune-related adverse events (irAEs) of any grade including aminotransferase elevation, increased creatinine, but no grade 3 or higher irAEs observed. Conclusions: The real-world data analysis shows that serplulimab-based flexibly combination according to patient status, achieving tumor control in diverse pts while ensuring drug safety. We successfully validated the effectiveness and safety of chemo-immunotherapy strategy in real-world practice. [Table: see text]
Insights into the structural and functional activities of forgotten Kinases: PCTAIREs CDKs
Authors: Javad Karimbayli, Ilenia Pellarin, Barbara Belletti, Gustavo Baldassarre
Journal: Molecular Cancer (2024)

Abstract In cells, signal transduction heavily relies on the intricate regulation of protein kinases, which provide the fundamental framework for modulating most signaling pathways. Dysregulation of kinase activity has been implicated in numerous pathological conditions, particularly in cancer. The druggable nature of most kinases positions them into a focal point during the process of drug development. However, a significant challenge persists, as the role and biological function of nearly one third of human kinases remains largely unknown. Within this diverse landscape, cyclin-dependent kinases (CDKs) emerge as an intriguing molecular subgroup. In human, this kinase family encompasses 21 members, involved in several key biological processes. Remarkably, 13 of these CDKs belong to the category of understudied kinases, and only 5 having undergone broad investigation to date. This knowledge gap underscores the pressing need to delve into the study of these kinases, starting with a comprehensive review of the less-explored ones. Here, we will focus on the PCTAIRE subfamily of CDKs, which includes CDK16, CDK17, and CDK18, arguably among the most understudied CDKs members. To contextualize PCTAIREs within the spectrum of human pathophysiology, we conducted an exhaustive review of the existing literature and examined available databases. This approach resulted in an articulate depiction of these PCTAIREs, encompassing their expression patterns, 3D configurations, mechanisms of activation, and potential functions in normal tissues and in cancer. We propose that this effort offers the possibility of identifying promising areas of future research that extend from basic research to potential clinical and therapeutic applications.
Phase 2 study of concurrent cisplatin, capecitabine and celecoxib with radiotherapy in patients with carcinoma of the oesophagus.
Authors: Kirti Srivastava, Bushra Khalid, Jasmeet Singh Tuteja, Mranalini Verma, Madan Lal Brahma Bhatt
Journal: Journal of Clinical Oncology (2024)

e16078 Background: Oesophageal cancer is the fourth common cause of cancer-related deaths in India. Definitive Chemoradiotherapy is standard for non-metastatic Squamous cell carcinoma of the oesophagus cancer. Chemoradiotherapy when given as definitive treatment is more effective than radiotherapy or chemotherapy alone. This treatment is usually offered to patients who are unsuitable for surgery. Unsuitability for surgery might be due to the extent of disease precluding the likelihood of a curative resection, or because the patient is physiologically not fit for surgery because of comorbidities or poor performance status. The aim of the present study was to analyse the effect of definitive concurrent chemo-radiotherapy in oesophageal cancer patients and assessment of toxicity profile and response. Methods: In the present Phase II study total 22 patients were recruited who had non-metastatic histologically confirmed carcinoma of the oesophagus selected for definitive chemoradiotherapy were enrolled. Chemotherapy consisted of three-weekly cycles of Inj. Cisplatin 60 mg/m2 given on D1, Tab. Capecitabine 625 mg/m2 given BD on D1-D21, and Tab. Celecoxib 200mg given BD on D1-D21. The planned protocol involved four cycles of concurrent chemotherapy. Radiotherapy in a dose of 50.4 Gy in 28 fractions was initiated on D1 of the second cycle of concurrent chemotherapy, or latest by D1 of the third cycle of concurrent chemotherapy. Results: In this Phase 2 study, 22 patients with a mean age of 55.68 ± 11.23 years, were treated. The tumor length averaged 6 ± 2.25 cm, with most common Stage III (52.17%), followed by Stage II (34.78%), Stage I (8.69%), and Stage IVA (4.34%). Grade 3 dysphagia was predominant (56.52%), followed by Grade 2 (34.78%), Grade 1 (4.35%), and Grade 4 (4.35%). During treatment, notable grade 1-2 toxicities included esophagitis(68%), fatigue(63%), nausea (54%), neutropenia (31%), anemia (22%), mucositis(18%), diarrhoea(13%), dermatitis(9%). There was gradual decline in the severity of dysphagia of all patients. Of the 8 patients evaluated for response with a median follow up of 12 months, the complete response rate was 25%, partial response rate was 25% and 37.5% showed stable disease whereas 12.5% developed progressive disease. The median overall survival is yet to be estimated. Conclusions: A notable clinical response, indicating a substantial treatment effect was observed. While some treatment-related toxicities were present, This approach shows potential in the treatment of oesophageal carcinoma. However, this study is still ongoing and it would be hasty to draw definitive conclusions.
Evaluating the efficacy of chemoradiotherapy combined with immunotherapy for local-regional recurrent esophageal cancer patients after esophagectomy: A retrospective analysis.
Authors: Qicen Xu, Dongjie Feng, Youtao Xu, Zihao Zhu, Yu Chen, Lijun Zhao, Cheng Kong, Ming Jiang, Ming Li, Ning Jiang, Xiangzhi Zhu
Journal: Journal of Clinical Oncology (2024)

e16085 Background: Chemoradiotherapy has been the standard-of-care for esophageal cancer patients with local-regional recurrent disease after esophagectomy without prior chemoradiation. Recent studies have demonstrated that immune checkpoint inhibitors confer survival benefits to patients with esophageal cancer. However, the effectiveness of chemoradiotherapy combined with immunotherapy remains undetermined in patients experiencing local-regional recurrence. Methods: Esophageal cancer patients treated at our institution were screened retrospectively for the following inclusion criteria: histological confirmation of squamous cell carcinoma; loco-regional recurrence after surgery-based first-line treatment; received chemoradiotherapy combined with immunotherapy regimen after loco-regional recurrence. Patients with prior radiotherapy were excluded. The endpoints of the study were overall survival (OS) and progression-free survival (PFS). Loco-regional recurrence was defined as recurrences from below the hyoid to the lower margin of the first lumbar vertebra, including supraclavicular, mediastinal, abdominal lymph nodes, and the tumor bed. PFS was defined as the time from the date of postoperative recurrence until disease progression, recurrence, death, or the last follow-up day; OS was determined as the duration from postoperative recurrence to the date of death from any cause or the last follow-up date. Results: Between January 2020 and July 2023, 685 patients were screened and 61 patients were finally enrolled in this study. The median follow-up period was 14 months (2.9~45.5 months). Regarding the regions of recurrence, 31 patients experienced exclusive mediastinal recurrence, and 30 patients had recurrence beyond the mediastinum (supraclavicular lymph node [n = 21], abdominal lymph node [n = 8], both supraclavicular and abdominal lymph node [n = 1]). In these cases, 26 patients (43%) experienced recurrence after receiving chemoradiotherapy combined with immunotherapy (loco-regional failure [n = 15], distant metastasis [n = 3], and both loco-regional failure and distant metastasis [n = 8]). Fourteen (23%) patients died from disease progression. The median PFS was 18 months (95%CI, 9.6-26.4) and the median OS was not reached. The 2-year OS rate was 65%. In univariate analysis, patients with recurrence in supraclavicular/abdominal lymph nodes had a worse prognosis (P = 0.014, HR = 2.765). Conclusions: Chemoradiotherapy combined with immunotherapy showed a favorable efficacy in radiotherapy-free esophageal cancer patients experiencing loco-regional recurrence post-surgery. Additionally, the regions of recurrence may influence patient outcomes.
Effect of simvastatin on PD-L1 via ILF3 to enhance CD8<sup>+</sup> T cell-mediated ferroptosis in gastric cancer cells.
Authors: Danping Sun, Wenbin Yu, Xiaohan Cui
Journal: Journal of Clinical Oncology (2024)

e16056 Background: Immunotherapy is vital in the comprehensive treatment of gastric cancer (GC). However, the prognosis of GC patients remains unfavorable, necessitating to exploration of novel therapeutic approaches and medications. Methods: PD-L1 expression was observed using small interfering RNA and plasmid to knock down and overexpress ILF3, respectively. The expression of ILF3, PD-L1, and ferroptosis marker molecules (SLC7A11 and GPX4) was detected upon simvastatin stimulation of gastric cancer cells co-cultured with activated CD8 + T cells. To assess the impact of ILF3 and simvastatin stimulation on the induction of ferroptosis in gastric cancer cells by CD8 + T cells, various assays including CCK8, MTT, ROS, Fe2+, MDA, GSH, and LPO were conducted. Cleavage under targets and Tagmentation (CUT&amp;Tag) was employed to validate the mechanism of simvastatin by regulating ILF3 expression. Whole genome sequencing and KEGG analysis reveal that ILF3 regulates PD-L1 expression through the DEPTOR/mTOR signaling pathway. Results: Statin treatment decreased the serum levels of ILF3 and PD-L1. This study found that ILF3 was positively correlated with the expression of PD-L1, and the knockdown of ILF3 effectively inhibited the expression of PD-L1, thus enhancing the cytotoxicity of CD8 + T cells to gastric cancer cells. Meanwhile, simvastatin inhibited the expression of PD-L1 through ILF3, which enhanced the induction of ferroptosis in gastric cancer cells by CD8 + T cells. Further studies found that simvastatin inhibited ILF3 expression by decreasing the acetylation level at residue site H3K14 in ILF3, while ILF3 inhibited PD-L1 expression through the DEPTOR/mTOR pathway. Conclusions: Simvastatin further recruited CD8 + T cells to enhance anti-tumor immunity by inhibiting PD-L1 expression by ILF3 and induced GC cells to undergo ferroptosis to achieve synergistic immunotherapy. This study elucidated the new mechanism of statins to improve GC immunotherapeutic effect. It revealed a new theoretical basis for using statins in GC treatment to improve the prognosis of GC patients.
Analysis of factors affecting complete pathological remission after neoadjuvant immunocombination chemotherapy treatment for locally advanced esophageal squamous carcinoma.
Authors: Ziyi Liao, Daiyuan Ma
Journal: Journal of Clinical Oncology (2024)

e16061 Background: Chemotherapy combined with immunotherapy for locally advanced esophageal squamous carcinoma has achieved a high rate of complete pathological remission, which is conducive to a better prognosis for patients; however, not all ESCC patients benefit from ICI therapy, so finding validated prognostic markers of efficacy will help us to screen for populations that are superior to neoadjuvant immunotherapy. Methods: Patients with locally advanced esophageal squamous carcinoma treated with neoadjuvant immune-combination chemotherapy followed by radical surgery from January 2019 to June 2023 at our institution were collected. The grouping was based on whether pathologic complete remission (pCR) was achieved after neoadjuvant therapy. Clinical and treatment-related data as well as hematologic, inflammatory, and nutritional indices within 1 week before neoadjuvant therapy and within 1 week after 2 cycles of neoadjuvant immune-combination chemotherapy treatment were collected from all patients, and univariate and multivariate analyses were performed to assess independent predictors of pCR. Results: Patients in both pCR and Non-pCR groups were more likely to obtain pCR if they had pre-treatment BMI &gt; 21Kg/m 2 vs BMI ≤21Kg/m 2 , number of neoadjuvant therapy cycles ≥3 cycles vs number of neoadjuvant therapy cycles = 2 cycles, and CYFRA21-1ng/ml &lt; 3.28 vs ≥3.28 before neoadjuvant therapy (p &lt; 0.05). Patients with albumin ≥40.10g/L vs albumin &lt; 40.10g/L, NLR &lt; 2.50 vs NLR ≥2.50, and NRI ≥98.06 vs NRI &lt; 98.06 were more likely to achieve pCR before treatment in both groups (p &lt; 0.05). SII ≥521.75 VS SII &lt; 521.75 was more likely to achieve pCR after 2 cycles of treatment (p &lt; 0.05). Univariate analysis of the comparison of dynamic changes in nutritional inflammatory indexes during treatment between the two groups of patients showed that pCR was more likely to be achieved in patients with persistently elevated eosinophil counts and NLR after 2 cycles of neoadjuvant immune-combination chemotherapy treatment (p &lt; 0.05). The results of multifactorial analysis showed that pre-treatment BMI, SII after 2 cycles of treatment, and dynamic changes in eosinophils during neoadjuvant therapy were independent influences on complete pathological remission after neoadjuvant immune-combination chemotherapy treatment (p &lt; 0.05). Conclusions: Complete pathological remission after neoadjuvant immune-combination chemotherapy treatment for esophageal squamous carcinoma was significantly correlated with the patient's pre-treatment BMI, Post-treatment SII, and eosinophil dynamics during treatment.