bluuebunny/crossref_metadata_2025_split huggingface dataset:
DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial.
Authors: Klempner Samuel J , Chao Joseph , Uronis Hope Elizabeth , Sirard Cynthia A. , Kagey Michael , Baum Jason , Song James , Wang Jin , Kim In-Ho , Lee Keun Wook , Oh Do-Youn , Sonbol Bassam Bassam , Wainberg Zev A. , Ajani Jaffer A. 
Published: January 2022

292 Background: Despite recent approval of anti-PD-1 antibodies as 1L therapy in HER2(-) advanced GEA, benefit remains modest and limited largely to PD-L1(+) patients (pts), primarily those with combined positive scores (CPS) ≥5. Thus novel therapeutic approaches are needed for this pt population. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated improved clinical outcomes in pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Methods: DisTinGuish (NCT04363801) is a Phase 2a single arm 2-part trial; Part A investigated DKN-01 (D) + tislelizumab (TS) + CAPOX as 1L therapy for pts with advanced HER2(-) GEA regardless of DKK1 status; Part B investigated two dosing cohorts of D (300 mg and 600 mg) + TS as 2L therapy for DKK1-high advanced GEA pts. Primary objective was to examine safety and tolerability and secondary objectives evaluated multiple efficacy endpoints including overall response rate (ORR) in a modified intent to treat (mITT) population (>1 dose D). Results: Forty-nine pts enrolled between 01 Sept 2020 and 15 Sept 2021; 25 pts in Part A and 24 pts in Part B (D-300 mg). Key clinicopathologic features and efficacy outcomes are shown in Table. The most common D-related AEs were low grade (G1/2) fatigue, nausea, and diarrhea. Nine pts had D-related ≥G3 toxicities, elevated AST/ALT, elevated alkaline phosphatase, hypophosphatemia, hyponatremia, lymphopenia, neutropenia, diarrhea, vomiting, fatigue all occurring in 1 pt and pulmonary embolism in 2 pts (one G5 event). No new safety signals were observed in Part A or B1. Duration of response (DoR), median PFS and median OS have not been reached for Part A. Last pt enrolled in Part B1 on 15 Sept 2021. Conclusions: The combination of D/TS + CAPOX represents a well-tolerated, active 1L combination, particularly for DKK1-high patients consistent with the proposed mechanism of action. Activity appears to be independent of PD-L1 status. Part B1 is aligned with biomarker enrichment and efficacy and biomarker data will be presented along with updated Part A efficacy data. Clinical trial information: NCT04363801. [Table: see text]
Nivolumab plus ipilimumab in second-line combination therapy for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial).
Authors: Ebert Matthias Philip , Meindl-Beinker Nadja M , Gutting Tobias , Maenz Martin , Betge Johannes , Schulte Nadine , Zhan Tianzuo , Weidner Philip , Hofheinz Ralf-Dieter , Vogel Arndt , Angermeier Stefan , de Wit Maike , Jakobs Ralf , Karthaus Meinolf , Stocker Gertraud , Thuss-Patience Peter C. , Leidig Tobias , Haertel Nicolai 
Published: January 2022

303 Background: Overall survival of patients with advanced and refractory esophageal squamous cell carcinoma (ESCC) is poor. Most patients are 65 years or older, present with advanced and metastatic disease and suffer from extensive co-morbidity and decreased functionality. While approved therapies beyond first-line therapy have not been available for decades, just recently treatment with PD-1 antibodies has shown to improve progression-free and overall survival in this patient cohort. Thus, we assessed the combination of nivolumab and ipilimumab in this vulnerable and older patient population. Methods: In this multi-center, open-label phase II trial older patients with ESCC with progression or recurrence of disease following first-line therapy were treated with nivolumab and ipilimumab. Patients had to pass a brief geriatric assessment using the G8 screening tool in combination with the Deficit Accumulation Frailty Index (DAFI). A safety run–in phase was initiated with nivolumab (240mg fixed dose Q2W). Following a safety assessment, patients then went on to receive the combination therapy of nivolumab/ipilimumab (nivolumab 240 mg fixed dose Q2W; ipilimumab 1 mg/kg Q6W), in case safety was critical patients were allowed to continue with nivolumab monotherapy. The primary outcome was overall survival. Progression-free survival, quality of life and adverse events were also assessed. Results: In total 66 evaluable patients (16 female, 50 male) with ESCC were enrolled in this trial after successful geriatric assessment, median age was 70.5 years (range 55-84 years). 44 patients were treated with the combination therapy of nivolumab and ipilimumab, 22 patients with nivolumab only. The primary endpoint was met with a median OS of 7.2 months (95% CI, 5.7 to 12.4 months) (p < 0.006; versus historical control treated with standard chemotherapy). Median PFS was 2.7 months (95% CI, 2.5 to 2.9 months). ORR was 18.2% (95% CI, 9.8 to 29.6), all cases were partial responses. Grade 3 or more treatment related adverse events were observed in ̃25% of patients. Conclusions: The combination therapy of nivolumab and ipilimumab demonstrates improved overall survival and sustained confirmed responses in the second line therapy of older European patients with ESCC. Geriatric assessment is feasible in the setting of a prospective immune therapy trial. Overall, the RAMONA trial confirmed efficacy and safety of combination checkpoint inhibitor therapy in G8 prescreened older patients with ESCC in Europe beyond first line therapy. Clinical trial information: NCT03416244.
Definitive chemoradiotherapy for locoregional recurrence of esophageal squamous cell carcinoma patients after radical surgery: Retrospective study.
Authors: Harada Kentaro , Yamamoto Shun , Ohara Akihiro , Itoyama Mai , Honma Yoshitaka , Kashihara Tairo , Inaba Koji , Ishiyama Koshiro , Oguma Junya , Igaki Hiroshi , Daiko Hiroyuki , Kato Ken 
Published: January 2022

314 Background: The prognosis of esophageal squamous cell carcinoma (ESCC) patients with recurrence after radical surgery remains poor, with a median overall survival (OS) of 5-10 months. Locoregional recurrence (LR) have a potential to cure by definitive chemoradiotherapy (dCRT) or surgery. However, there are a few data on clinical outcomes of the patients with LR. We evaluated the efficacy and safety of dCRT for LR after radical surgery retrospectively. Methods: The subjects who had LR after surgery were corrected from medical record between January 2015 and April 2020 in our hospital. LR was defined as recurrence within the regional and supraclavicular lymph nodes after curative surgery. CRT consist of fluoropyrimidine and platinum with radiation at a dose of 50.4-60Gy. Complete response (CR) rate, progression-free survival (PFS), OS, and safety was evaluated. Results: Twenty-five patients who had LR after surgery were analyzed with the median follow-up time of 21.5 (range: 0.47-60.2) months. Patients’ characteristics at the initiation of dCRT were as follows; median age (range): 70 (40-70) years old, male/female: 20 (80%)/5 (20%) patients, PS 0/1/2: 11 (44%)/12 (48%)/ 2 (8%) patients. Chemotherapy regimens were cisplatin and 5-fluorouracil in 23 (92%) patients, nedaplatin and 5-fluorouracil in 1 (4%) patient, and S-1 in 1 (4%) patient. Radiation doses were 60 Gy in 24 (96%) patients and 50.4 Gy in 1 (4%) patient. CR was achieved in 13 (53%) patients. The median PFS was 9.7 (95%CI: 5.6-NA) months, and the median OS was 28.8 (95%CI: 21.2-NA) months. The one-year survival rate was 78.7 (95%CI: 56.1-90.6) % and the three-years survival rate was 25.9 (95%CI: 5.1-54.1) %. Grade 3 or higher adverse events were observed in 3 (12%) patients of neutropenia, in 3 (12%) patients of leukopenia, and in 2 (8%) patients of febrile neutropenia. Treatment-related death due to febrile neutropenia was observed in 1 (4%) patient. No patient presented with severe late toxicity after dCRT. Conclusions: In this study, dCRT for LR after surgery was tolerable and promising efficacy with curative intent.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable PM from gastric cancer outstanding result from multicenter cohort study.
Authors: Alyami Mohammad , Khomiakov Vladimir , Lintis Alexandru , Piso Pompiliu , Eveno Clarisse , Glehen Olivier ,   ISSPP PIPAC cohort study
Published: January 2022

331 Background: PIPAC is a recent approach for intraperitoneal chemotherapy with promising results for patients with peritoneal metastasis (PM). It is a safe and well-tolerated treatment. Our aim was to report oncological outcomes after PIPAC for gastric PM. Methods: International retrospective cohort study of consecutive patients with gastric PM. Outcome measures were overall survival (OS), radiological response (RECIST), histological response by use of Peritoneal regression grading system (PRGS) and cytology, peritoneal cancer index (PCI) and symptoms. Results: 586 non-selected patients with a median age of 56 (47-64) years, 54% of them were female and underwent a total of 1566 PIPAC procedures. 37% of patients were treated with 2 or more lines of IV chemotherapy, median PCI at first PIPAC was 14 (7-24) and 63% of them were with signet ring adenocarcinoma. Grade III-IV morbidity was 5.1 % and 1.9% died within 30 days from PIPAC procedure. Median OS was 15.4 months from diagnosis and 20.1 months for patient with more than 3 PIPAC. 263/586 patients (44.9%) had ≥3 procedures ( pp: per protocol) with the following outcomes: RECIST: 4.3% complete response 11% partial remission, 44% stable; PRGS1 39% at PIPAC3 and negative cytology at PIPAC3 in 16% of patient. In multivariate analysis, 3 PIPAC or more HR 0.3 (95% CI 0.27-0.51), 2nd and 3rd line of chemotherapy HR 0.48 (95% CI 0.25-0.92) and CRS&HIPEC after PIPAC HR 0.3 (95% CI 0.18-0.51) were predictors for survival. Conclusions: Based on this large multicentre cohort study, PIPAC could be considered as an option for the treatment of PM from gastric cancer. More prospective study will validate this indication in the near future.
CSF-1R inhibitor, pexidartinib, sensitizes esophageal cancer to PD-1 immune checkpoint blockade in a rat model.
Authors: Paskewicz Michael , Omstead Ashten , Zheng Ping , Gorbunova Anastasia , Salvitti Madison , Alleyne Adam , Reed Payton , Ballengee Sydne , Islam Nabeela , Jobe Blair A. , Kelly Ronan Joseph , Zaidi Ali Hussainy 
Published: January 2022

333 Background: Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, is a multi-gene tyrosine kinase inhibitor, targeting FLT3, KIT and CSF1R. In particular, pexidartinib by targeting CSF-1R down modulates macrophage mediated pro-survival tumor signaling. Recently, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in multiple solid tumors. Methods: Seventy-two rats underwent an end-to-side esophagojejunostomy to induce gastroesophageal reflux, resulting in EAC carcinogenesis. At 32 weeks postoperatively, tumor bearing animals were randomized to a dose of 30mg/kg of pexidartinib or vehicle control, 5 days on and 2 days off (14 day cycle), for a total of 3 cycles. A PD-1 inhibitor, AUNP-12, at a dose of 3mg/kg or placebo, was administered on day 12 of each cycle. At 38 weeks postoperatively animals were euthanized. Safety and efficacy was evaluated by objective health assessments, pre and posttreatment MRI, RT-PCR, immunofluorescent labeling and a serum cytokine assay. Results: The pexidartinib +/- PD-1 inhibitor (Px+P and Px-P) groups demonstrated no significant difference in daily weight change (p = 0.98) or in mortality (p = 0.59) when compared to vehicle control (V+P and V-P) groups. On post-mortem serum analysis AST (p = 0.01) and ALT (p = 0.001) were elevated, while albumin (p = 0.57) and BUN/creatinine ratio (p = 0.09) were reported within normal ranges, when comparing treatment to placebo groups. Pre to posttreatment, mean MRI tumor volume decreased by 37% and 54% in the Px-P and Px+P animals and increased by 147% and 88% in the V+P and V-P animals, respectively (p = < 0.0001). Overall response rate was 69% and 87% in Px-P and Px+P animals compared to 21% and 13% in V-P and V+P animals, respectively (p = < 0.0001). Downstream gene expression demonstrated upregulation of TNF-α (p = 0.003), IFN-γ (p = 0.002) and IL-6 (p = 0.0001) and downregulation of IL-13 (p = 0.051), IL-10 (p = 0.051), TGF-β (p = 0.024) and Arg-1 (p = 0.0003), in treatment vs. placebo animals. Increased apoptosis (Cas-3 p = 0.0005) and reduced proliferation (Ki-67 p = < 0.0001) were reported in the treatment animals. Higher CD3+CD8+ T cell densities and CD86/CD206 macrophage ratio was reported in treatment groups compared to placebo (p = < 0.0001). Serum cytokine levels significantly displayed upregulation of TNF-α and IFN-γ and downregulation of IL-4 and IL-10 in the treatment animals compared to the placebo. Conclusions: Overall, this study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an esophageal cancer model, providing the rationale for future clinical strategies.
Applicability of advanced endoscopic balloon-type irreversible electroporation catheter on the esophagus: Preclinical animal study.
Authors: Jeon Han Jo , Choi Hyuk Soon , Park Jin Young , Yoon Ji Young , Park Geon , Sim Jeong Yoon , Bang Eun Joo , Kim Sang Hyun , Lee Kang Won , Lee Jae Min , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai 
Published: January 2022

339 Background: Irreversible electroporation (IRE) is a new destructive technique that removes undesirable tissues using an electric field. Main mechanism of IRE is through the creation of permanent, nano-sized pores on the cell membranes, resulting in cell death. It poses, however, one technical challenge as contractions of smooth muscle of the gastrointestinal tract may prevent IRE from effectively electroporate the cell. The present study aims to demonstrate the applicability of this newly designed endoscopic balloon-type IRE catheter in destroying undesired tissues. Methods: The electrical field generated at 1500V with 40 pulses during ablation with the balloon-type catheter in esophagus were simulated using COMSOL Multiphysics. After a pig was anesthetized, a 0.035-inch Jagwire was inserted through the duodenum using a gastroscope. An IRE catheter was then manually advanced into the esophagus along with a guidewire. The fluoroscopy with contrast medium was employed to determine target lesions with clips. Following the sequential ablation along the esophagus, electrical parameters as well as the number of interruptions encountered were recorded. The pigs used in the experiments were sacrificed after 24 hours and tissue specimens obtained were evaluated using H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results: Based on the COMSOL simulation, the heated portion, approximately 57 degrees of Celsius, was observed only at the edge of the electrodes. Fluoroscopy demonstrated the balloon-type catheter was not adjacent to the heart and tightly blocked the lumen of esophagus as it adheres to the mucosal layer during inflation. The IRE catheter was able to overcome muscle contractions during ablative process and deliver all electrical energy of the scheduled sequences. A total of 12 ablations were performed in three pigs, and the success rate of balloon catheter was 91.7% (11/12). Histological slides from H&E staining and TUNEL assay showed nuclei, stained brown, which indicates apoptosis at the ablation site. Conclusions: The IRE balloon-type catheter demonstrated its applicability and effectiveness as an electroporation-based treatment in esophagus as validated in the experimental results. Further studies regarding electrodes improvement to heat-free condition and its safety related assessment would be needed.
CD44v6 high membranous expression as a predictive marker of therapy response in patients with gastric cancer.
Authors: Park Ji-Hyeon , Almeida Gabriela M. , Pereira Carla , Lemos Carolina , Campelos Sofia , Gullo Irene , Martins Diana , Gonçalves Gilza , Leitão Dina , Neto João Luís , André Ana , Borges Clara , Almeida Daniela , Lee Hyuk-Joon , Kong Seong-Ho , Kim Woo Ho , Carneiro Fatima , Almeida Raquel , Yang Han-Kwang , Oliveira Carla 
Published: January 2022

342 Background: In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Methods: Two GC surgical cohorts, from Portugal and South Korea (n = 964), were characterized for the extension of CD44v6 membranous immunoexpression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. Results: High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002–2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery (p < 0.05), particularly those with heterogeneous CD44v6- positive and -negative populations (CD44v6_3+) (p < 0.007 and p < 0.009). Conclusions: Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.
Association of leptin with migration, invasion, and cancer stem-like properties in gastric cancer cells.
Authors: Park Ki Bum , Chung Kyong-Hwa 
Published: January 2022

352 Background: Obesity is a risk factor for various types of cancer, including gastric cancer. Leptin, an adipocyte-derived hormone, may function in stimulating the proliferation of gastric cancer cell. The purpose of this study was to evaluate the role of leptin in gastric cancer. Methods: Leptin level was assessed by ELISA and was compared in obese patients with gastric cancer (n=23) and non-obese patients with gastric cancer (n=23) as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the Janus kinase/signal transducer and activator of transcription (JAK-STAT) and MEK signaling pathways using wound healing assay, inhibition study, and ELISA. Cancer-initiating cells derived from gastric cancer cell lines were studied to investigate the effects of leptin to the maintenance of stemness and epithelial-mesenchymal transition using invasion assay, RT- PCR, and immunoblotting. Results: Obesity was associated with elevated leptin level and BMI has positive correlation with the leptin level ( p=0.001 for both). Overall survival was not significantly different between the two groups ( p=0.098). Leptin induces the migration and invasion of gastric cancer cells by activating AKT and ERK and up-regulating the expression of vascular endothelial growth factor (VEGF). Pharmacological inhibitors of JAK and MEK signaling pathways decreased both leptin-induced migration and invasion and the leptin-induced expression of VEGF. Leptin increased the mRNA and protein levels of the markers for stemness (CD44) and epithelial-mesenchymal-transition (Snail and N-cadherin). Conclusions: Leptin plays a role in gastric cancer by stimulating the migration and invasion of gastric cancer cells via activating the JAK-STAT and MEK pathways and contributes to the maintenance of cancer stemness and metastatic potential. Leptin presents evidence supporting the adverse effect of obesity in gastric cancer. Treatment targeting leptin-associated signaling pathways could be a potential strategy for managing gastric cancer.
Locally advanced esophageal cancer: Evaluation of prognosis by assessment of the “yp” stage based on the neoadjuvant regimen received.
Authors: Gunadasa Indika , Haydon Andrew , Zalcberg John Raymond , Khu Yin Li , Burton Paul , Brown Wendy 
Published: January 2022

356 Background: Neoadjuvant treatment in the form of chemoradiotherapy (nCRT) or chemotherapy (nCT) for resectable oesophageal cancer is the standard of care and improves R0 resection rates and overall survival (OS). The recently reported Neo-AEGIS study demonstrated ongoing equipoise between neoadjuvant chemoradiotherapy and peri-operative chemotherapy for oesophageal adenocarcinoma. There is limited data evaluating the prognostic outcomes by evaluation of the pathological stage after resection (yp stage) based on the neoadjuvant regimen received. The aim of this study was to look at the survival outcomes of patients with oesophageal cancer who received neoadjuvant therapy and to analyze the prognostic significance of pathological stage at surgery (“yp” stage) compared to the clinical stage based on the neoadjuvant therapy received. Methods: This was a single- centre, retrospective study over a fifteen-year period between 2005 and 2019. Consecutive patients with oesophageal and GOJ cancers that underwent resection post neoadjuvant treatment were included. The unit policy was to treat adenocarcinoma of the oesophagus and GOJ with perioperative chemotherapy until 2015 after which it was switched to neoadjuvant chemoradiotherapy in the form of the CROSS protocol. Results: Neoadjuvant treatment with either neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT) prior to surgical resection was undertaken in 137 patients with resectable oesophageal and GOJ cancers between the years 2005 and 2019. The median age was 65 and 79% of the cohort was male. The majority of tumours were located in the lower oesophagus or GOJ and 96 patients in the cohort were clinical stage 3. 126 patients had adenocarcinoma and 11 patients had squamous cell carcinoma. 72 patients received nCT, and 65 patients received the nCRT. The “yp” stage showed 26 patients achieved a complete pathological response (CPR) and 47 patients were down-staged. The clinical stage was not a predictor of overall survival (p = 0.65). On the other hand, the “yp” stage was a significant predictor of survival (p < 1×10-8). In patients who received nCRT, 18 achieved a complete pathological response compared to 8 patients who had received nCT. Patients who received nCRT showed improved survival compared to patients who received nCT (p = 0.043). Patients who achieved a CPR with neoadjuvant chemotherapy had an OS of 100% compared to OS of 80% in patients who received nCRT (p = NS). Neoadjuvant chemoradiotherapy was associated with less loco-regional recurrences and distant recurrences compared to neoadjuvant chemotherapy. Conclusions: The “yp” stages, as well as down-staging with neoadjuvant therapy are strong predictors of survival. A greater proportion of patients achieved down-staging and CPR following neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy.