bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Short-term results for cohorts C and D.
Authors: Matsuda Satoru , Yamamoto Shun , Kato Ken , Daiko Hiroyuki , Kojima Takashi , Hara Hiroki , Abe Tetsuya , Tsubosa Yasuhiro , Kawakubo Hirofumi , Nagashima Kengo , Aoki Kazunori , Yachida Shinichi , Kitagawa Yuko 
Published: January 2022

286 Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell carcinoma (ESCC) consists of CDDP + 5-FU (CF). Recently, neoadjuvant DTX plus CF (DCF) therapy has shown promising efficacy for locally advanced ESCC. In addition, immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit in ESCC and potential as an NAC in several cancers, including lung, breast, skin, and bladder. We previously reported that neoadjuvant CF plus nivolumab (Nivo) therapy was tolerable and showed promising efficacy for ESCC; however, the efficacy of ICI with DCF as an NAC and the safety of subsequent surgery for ESCC patients remain unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. The eligibility criteria were histologically proven ESCC with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), patient age of 20-75 years, PS ≤1, and no prior cancer therapies. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 5 experimental cohorts: cohort C received 3 courses of DTX (70 mg/m2), CDDP (70 mg/m2), and Nivo (360 mg/body) on day 1 and 5-FU (750 mg/m2) on days 1–5 every three weeks. Cohort D received one administration of Nivo (240 mg/body) 2 weeks before chemotherapy followed by the same regimen as cohort C. Results: Twelve patients were enrolled in cohort C (n = 6) and D (n = 6) (median age [range]: 60 [31-74] years, PS 0/1: 11/1, clinical stage I/II/III/IVA: 2/2/7/1). Only one patient in cohort D developed DLT (grade 3 dyspnea and rash); no other DLT were seen. Grade ≥3 adverse events were neutropenia (n = 1), leukopenia (n = 7), anorexia (n = 3), hyponatremia (n = 2), febrile neutropenia (n = 1), nausea (n = 1), and lymphopenia (n = 1) during NAC, and lung infection (n = 2), peritoneal infection (n = 1), anemia (n = 1), lymph leakage (n = 1), vagal reflex (n = 1), dyspnea (n = 1), rash (n = 1), septic shock (n = 1), pleural effusion (n = 1), and pneumatosis intestinalis (n = 1) during the postoperative period. No treatment-related deaths were observed. All patients received 3 courses of NAC, and 11 patients (91.7%) achieved an R0 resection without treatment interruption. One patient (16.7%) in cohort C and 3 patients (50.0%) in cohort D achieved pathological complete responses. Conclusions: Neoadjuvant DCF + Nivo with/without prior Nivo administration followed by surgery for locally advanced ESCC was well tolerated and showed an extremely promising efficacy. Clinical trial information: NCT03914443.
A multicenter, open-label phase II trial of second-line apatinib plus irinotecan in patients with advanced gastric cancer.
Authors: Peng Jianjun , Li Yong , Xiao Jianjun , Liu Huaqiang 
Published: January 2022

287 Background: The best choice of second-line chemotherapy regimen for patients with advanced gastric cancer is still debated. Anti-VEGF target therapy is proven to be effective both in second and third line settings. Apatinib, a highly selective VEGFR2 inhibitor, has been demonstrated to be efficacious and well-tolerated for third line of treatment in gastric cancer. The aim of this study is to evaluate the safety and efficacy of apatinib in combination with irinotecan in the second line treatment of advanced gastric cancer. Methods: With the expectation of improving PFS to 4.4m, this investigator-initiated, single arm, multi-center, registered phase II prospective study was designed to enroll 62 eligible patients diagnosed with advanced gastric cancer. Each participant was expected to receive chemotherapy plus apatinib (irinotecan 1800mg/m2, d1, Q2W; apatinib 500mg po qd). The severity of side effects was established according to Common Terminology Criteria for Adverse Events (CTCAE),Version 4.0. Efficacy assessed every three cycles (6 weeks) during the study. The primary endpoint was PFS. The secondary endpoint was OS, ORR, and DCR. The tumor response was determined according to RECIST 1.1 criteria. Results: Baseline characteristics (FAS population): From March 2019 to April 2021, 31 patients from 4 centers in Guangdong province were enrolled. Among them, 28 are eligible for analysis. There are 16 females and 15 males, median age 55 years old. Safety: 82.4% patients reported adverse events (AEs). The incidence of grade 3-4 AEs was 52.9%. Main 3-4 AEs were neutropenia (32.4%), leucopenia (17.6%), anorexia (8.8%), hypoalbuminaemia (8.8%), thrombocytopenia (5.9%), nausea (5.9%). Efficacy: By Aug 31th, 2021, 28 patients were evaluable for response and survival, 1 of them achieved complete response (CR), 10 of them achieved partial response (PR), 8 achieved stable disease (SD), and 9 experienced progression disease (PD). The ORR is 35.48%, the DCR is 61.29%. Median PFS is 4.40m, median OS is 6.64m. Conclusions: Adding apatinib to irinotecan chemotherapy as the second line treatment would be well tolerant in patients with advanced gastric cancer. This indicated the combination could be a potential treatment option for patients with advanced gastric cancer. Clinical trial information: ChiCTR1900021377.
Efficacy and toxicity of neoadjuvant immune checkpoint inhibitors in resectable gastric cancer: A meta-analysis and systematic review.
Authors: Li Song , Xu Qian , Dai Xin , Zhang Xue , Huang Miao , Huang Kai , Wang Jian , Chu Jiahui , Liu Lian 
Published: January 2022

291 Background: Immune checkpoint inhibitors (ICI) have made significant breakthroughs in late-stage gastric cancer. It is an attractive issue whether ICIs also function in the neoadjuvant setting. Methods: A systematic review was performed using combined terms related to “stomach cancer”, “gastric cancer”, “gastroesophageal cancer”, “immune checkpoint inhibitor”, “PD-1”, “PD-L1” and “neoadjuvant” in PubMed and annual meeting of ASCO, ASCO GI, ESMO, and ESMO GI from 2019 to 2021. Complete pathological response (CPR) rates, major pathological response (MPR) rates, R0 resection rates, and side effects were pooled and analyzed. MPR was defined as ≤10% viable tumor cells and included CPR. Study outcomes were pooled using the function METAPHOR in the META package in R.3.6.1. The I2 and P statistics were used to evaluate heterogeneity among studies. Funnel plots were used for publication bias assessment. Results: A total of 13 phase I/II clinical trials, including 332 resectable gastric cancer (T2-4 or N+) patients with neoadjuvant ICI-containing treatments, were collected. The pooled rates of CPR, MPR, and R0 resection were 0.16 (95% credible intervals (CI), 0.12-0.22), 0.36 (95% CI, 0.24-0.51), and 0.97 (95% CI, 0.94-0.99), respectively. As a comparison, outcomes from 25 studies on neoadjuvant chemotherapy were also pooled, with rates of CPR 0.08 (95% CI, 0.06-0.11), MPR 0.22 (95% CI, 0.19-0.26), and R0 resection 0.84 (95% CI, 0.80-0.87). Besides, the overall grade 3 or higher toxicity rates were 0.24 (95% CI 0.03-0.54) vs. 0.28 (95% CI 0.13-0.47) in ICI-based treatment and chemotherapy groups. Stratified by treatment strategies, ICI alone showed the lowest efficacy (CPR 0.07, 95% CI 0.02-0.19 and MPR 0.16, 95% CI 0.03-0.29). Addition of chemotherapy to ICI promoted the CPR (0.15, 95% CI 0.10-0.22) and MPR (0.36, 95% CI 0.22-0.50). Further addition of radiotherapy displayed the highest CPR (0.35, 95% CI 0.21-0.52) and MPR (0.74, 95% CI 0.54-0.93). Only four trials reported the outcomes of dMMR/MSI-H patients, with superior CPR (0.39, 95% CI 0.20-0.62) and MPR (0.82, 95% CI 0.82-1.00), while those of pMMR/MSS patients were 0.05 (95% CI 0.00-0.13) and 0.20 (95% CI 0.20-0.31) respectively, among which 2 trials used ICI only. Conclusions: Neoadjuvant ICI plus chemotherapy/radiotherapy, instead of ICI alone, has better pathological responses and R0 resection rates than chemotherapy. dMMR/MSI-H is a superior biomarker for neoadjuvant ICI therapy for resectable gastric cancer. The value or biomarker of immunotherapy in pMMR/MSS patients remains exploring.[Table: see text]
Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: A phase II multicenter single-arm study and exploratory biomarker analysis.
Authors: Xu Ting , Wang Xicheng , Xin Ying , Wang Zhenghang , Wang Yakun , Qi Changsong , Liu Dan , Li Yanyan , Gong Jifang , Li Jian , Huang Depei , Shen Lin 
Published: January 2022

301 Background: HER2 overexpression has proven to be an effective treatment target in several malignancies. Trastuzumab plus chemotherapy showed favorable clinical efficacy and safety in HER2-positive gastric cancer and breast cancers. In this study, we aimed to evaluate the antitumor activity of trastuzumab plus irinotecan in pretreated patients with HER2-postive unresectable metastatic CRC and explore biomarkers for response and resistance to this treatment. Methods: mCRC patients with confirmed HER2 positivity (defined as IHC3+ or IHC2+/FISH+ on archival tissue) and wild-type RAS gene that progressed after ≥ 1 prior systemic treatment were enrolled in this phase II clinical trial. Patients received trastuzumab (6mg/kg q3w) plus irinotecan (120mg/m2, d1,8 q3w) for the first six cycles and trastuzumab (6mg/kg q3w) as maintenance treatment sequentially. Primary end point is objective response rate (ORR) and secondary endpoints are progression-free survival (PFS) and safety. Pretreatment tumor tissue, plasma at baseline and after disease progression were collected and analysed using a customized NGS panel covering 733 cancer-related genes in a CAP/CLIA-approved laboratory (3DMed). Results: Between June 2019 and December 2020, 21 HER2 positive patients were enrolled, with median age 55(30-67). At data cutoff (August 1, 2021), six (28.6%) of 21 patients achieved a partial response, and 12 (57.1%) patients had stable disease. The median progression-free survival was 4.3 months (95% CI, 2.65 to 5.95 months). Treatment-related adverse events of grade 3 or 4 occurred in 9.5% of patients, with the most common being neutropenia. No treatment-related death was reported. HER2 3+ expression and higher tumor tissue HER2 copy number were associated with durable response (p for PFS = 0.09 and 0.019, respectively). Two patients with KRAS amplification and one patient with BRAF amplification and fusion mutation at baseline all experienced primary resistance. In the after-progression plasma samples, heterogeneous and complicated genomic alterations potentially contribute to the acquired resistance were observed, with RAS/MAPK pathway (n = 4), cyclin/CDK-RB-E2F pathway (n = 4), PI3K/AKT/mTOR pathway (n = 3), and HER2 gene (n = 1) involved. Intriguingly, except for the SNV, copy number variation and gene fusion may represent an important resistance mechanism of HER2 targeted therapy. Conclusions: Trastuzumab plus irinotecan showed promising efficacy and well tolerated safety profile in HER2-positive mCRC. This combination therapy might present a feasible option for patients with HER2-positive unresectable metastatic colorectal adenocarcinoma. ctDNA sequencing provides novel insights into genomic alteration underlying HER2 targeted therapy in HER2-positive mCRC. Clinical trial information: NCT03185988.
Efficacy of prophylactic pegfilgrastim on day three of preoperative DCF chemotherapy in elderly patients with resectable esophageal cancer.
Authors: Ikeda Go , Ohara Akihiro , Itoyama Mai , Azuma Ikuko , Yamamoto Shun , Honma Yoshitaka , Oguma Junya , Ishiyama Koshiro , Daiko Hiroyuki , Kato Ken 
Published: January 2022

305 Background: Preoperative neoadjuvant chemotherapy with cisplatin plus 5-FU (CF) is the standard treatment for resectable esophageal cancer (EC). Docetaxel plus CF (DCF) is also a promising preoperative treatment; however, a high frequency (5%-30%) of febrile neutropenia (FN) has been reported in patients (pts) receiving DCF, and elderly pts reportedly have a high risk of FN. The use of primary prophylactic pegfilgrastim (PG) on day 3 of DCF in resectable EC pts might prevent FN. We conducted a retrospective review to assess the efficacy of primary prophylactic PG administration on day 3 of preoperative DCF in elderly pts with resectable EC. Methods: EC pts who had received preoperative DCF between 2009 and 2021, were ≥70 years old, and had adequate organ functions and an adequate PS were eligible for this retrospective study. Pts were assigned to receive either PG-containing DCF (day3 prophylactic PG: D3PG) or standard DCF (non-prophylactic PG: NPG). Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and antibiotic prophylaxis was mandatory on days 5-15 in each group. In the D3PG group, PG was administered subcutaneously on day 3. We retrospectively evaluated the relative dose intensity (RDI), histopathological efficacy, and adverse events (CTCAE ver5.0). Results: A total of 52 pts (D3PG, 17; NPG, 35) with a median age of 72 years were identified. The PS (0/1/2) and clinical stage (I/II/III/IVB [only supraclavicular lymph node]) were 10 (58.8%)/5 (29.1%)/2 (11.8%) and 0/1 (5.9%)/10 (58.8%)/6 (35.4%) in the D3PG group and 20 (57.1%)/15 (42.9%)/0 and 2 (5.7%)/5 (14.3%)/24 (68.6%)/4 (11.4%) in the NPG group, respectively. Three pts discontinued treatment because of toxicity (FN and nausea in D3PG and FN and diarrhea in NPG) and progression in each group, and all the pts underwent surgery. The RDIs (DTX/CDDP/5-FU) were 0.870/0.862/0.871 in the D3PG group and 0.833/0.829/0.830 in the NPG group. Five (29.4%) pts in the D3PG group and 10 (28.6%) in the NPG achieved a pCR. The common grade ≥3 adverse events (D3PG/NPG) were leukopenia (17.6%/51.4%), neutropenia (11.8%/71.4%) and FN (5.9%/20.0%). Conclusions: The use of primary prophylactic PG on day 3 of preoperative DCF improved the treatment safety treatment in elderly pts with resectable EC. No significant differences in treatment efficacy were seen between the D3PG and NPG groups despite the higher number of pts with a worse general condition or more advanced disease in the D3PG group than in the NPG group.
Safety and efficacy of intraperitoneal paclitaxel plus systemic FOLFOX for gastric cancer with peritoneal metastasis: Phase I results.
Authors: Kang So Hyun , Min Sa-Hong , Kim Jin Won , Lee Eunju , Lee Sangjun , Oh Hyeon Jeong , Park Young Suk , Lee Yoon Jin , Kim Ji-Won , Ahn Sang-Hoon , Suh Yun-Suhk , Lee Keun-Wook , Lee Hye Seung , Kim Hyung-Ho 
Published: January 2022

309 Background: Peritoneal metastasis (PM) still remains a major obstacle in the treatment of stage IV gastric cancer. This study was designed as a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients. Methods: Patients with gastric adenocarcinoma with PM were enrolled. Peritoneal cancer index (PCI) score was evaluated, and IP + IV chemoport insertion was done. The initial dose of IP paclitaxel was 40mg/m2, then stepped up to 60 then 80mg/m2. Target dose was 100mg/m2. IV FOLFOX was administered on the same day (oxaliplatin 100mg/m2, leucovorin 100mg/m2, fluorouracil 2400mg/m2). Dose limiting toxicity (DLT) was defined as leukopenia ≥ grade 4, thrombocytopenia ≥ grade 3, febrile neutropenia ≥ grade 3, and other nonhematologic toxicity ≥ grade 3. Results: Fifteen patients were enrolled, and two patients were dropped due to patient consent withdrawal. There was no DLT at 40 and 60mg/m2 doses. Two patients had grade 3 febrile neutropenia at dose 80mg/m2, and thus the final recommended phase II dose was 60mg/m2. Other patients underwent IP paclitaxel and FOLFOX without serious adverse events. Seven patients underwent second-look diagnostic laparoscopy, and the average change in PCI score was -5.6 ± 9.3. Four patients received gastrectomy, and the ascites conversion rate was 4/5 (80%). Median survival time was 16.6 months (95% CI, 7.2 – N/A). Conclusions: The biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose for a phase II trial is 60mg/m2. Clinical trial information: NCT03618758.
A prospective clinical trial of camrelizumab in combination with chemoradiotherapy in patients with metastatic esophageal squamous cell carcinoma.
Authors: Chen Yongshun , Zhao Wensi , Zuo Zhigang , Ke Shaobo , Shi Wei , Li Bin , Qiu Hu , Wang Jing , Gong Yi , CAI Xiaojun 
Published: January 2022

326 Background: Patients with metastatic esophageal squamous cell carcinoma (mESCC) have dismal prognosis, immune checkpoint inhibitors (ICIs) have been reported to offer objective response rate (ORR) of approximately 30% with a median progression-free survival (PFS) of 3.6 months for mESCC. Emerging evidence suggests that radiation might be a potent immunomodulator in multiple malignancies. In this trial, we aimed to assess the efficacy and safety of the combination of camrelizumab with radiotherapy and chemotherapy in mESCC. Methods: Patients with ECOG performance status of 0-1 and normal renal, liver and bone marrow function who initially diagnosed with mESCC or progressed after prior systemic treatments were received camrelizumab 200 mg of 21-day cycles plus radiotherapy (30-50Gy/10-25f) and platinum-based combination chemotherapy. The primary endpoint was disease control rate (DCR); secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) and safety. Chinese Clinical Trial Registry identifier: ChiCTR2000040533. Results: From September 2018 to March 2021, 34 patients (85.3% men; median age, 60 years; 85.3% ECOG PS=1; 61.8% ≥2 organ metastases) were recruited. At a median follow-up of 14.3 months, the DCR was 70.6% (24 of 34; 95%CI, 52.3 to 84.3); ORR was 38.2% (13 of 34; 95%CI, 22.7 to 56.4); 44.1% had decrease in measurable disease; ≥6 months clinical benefit rate (CBR) was 41.2% (14 of 34; 95%CI, 25.1 to 59.2). Median PFS and OS of 9.5 months (95% CI, 7.1 to NR) and 19.5 months (95% CI, 13.9 to NR), respectively. Of the 34 patients, 32 (94.1%) had treatment-related adverse events (TRAEs) of any grade and 13 (38.3%) had grade 3-4 TRAEs that including reactive cutaneous capillary endothelial proliferation (17.6%), myelotoxicity (23.5%) and interstitial pneumonia (2.9%). No treatment-related death occurred. To the cut-off date of observation, 15 (44.1%) patients died and 12 (35.3%) are still receiving the treatment without events. Conclusions: The combination of camrelizumab with radiotherapy and chemotherapy has notable efficacy compared with historical controls in mESCC with manageable safety. This combination therapy strategy should be validated in a larger trial in the future. Variable N=34 Clinical trial information: ChiCTR2000040533. [Table: see text]
Multiple combinational strategies of immunotherapy for esophageal squamous cell carcinoma: One institutional experience in Taiwan since 2016.
Authors: Chen Jo-Pai , Lu Wei-Chen , Wu Hsu , Kao Tsui-Mai , Chiang Keng-Man , Chen Hsing-wu , Kuo Sung-Hsin 
Published: January 2022

328 Background: ESCC is a health burden in Taiwan due to smoking and drinking habits. In R/M setting, the prognosis is worse. In 2021, KN590 study(pembrolizumab with chemotherapy in CPS≥10%), CM648 study(nivolumab with chemotherapy or nivolumab with ipilimumab in TPS≥1%), and ESCORt-1st study(camrelizumab with chemotherapy in TPS≥1%) have all been shown to get survival benefits compared with chemotherapy alone in front-line setting. Further immunotherapy combinations with targeted therapies and subsequent therapy options after anti-PD1 failure deserve more investigation. Methods: From early 2016 to late 2021, 26 advanced ESCC patients had ever received immunotherapy-containing regimens in Yun-lin Branch of National Taiwan University Hospital. We have reviewed basic characters, ICIs regimens, and treatment response of these patients. Results: 3 patients under progression during front-line KN590 got PR by subsequent afatinib(2) or lenvatinib(1) use. So, the overall response rate of advanced ESCC to immunotherapy-containing regimens was 59%(17/29) and disease control rate was 72%(21/29). Conclusions: Afatinib has multiple immuno-modulatory effects. AP or NA is an effective regimen in Taiwan, where double cancers, like HNSCC and ESCC, are popular due to smoking, drinking, and bêtel-nuts chewing. Following KN590 good efficacy was also seen in our institution and afatinib with anti-PD1 could be introduced in CT-unfit patients. In unresectable and/or oligometastatic ESCC, induction triple therapy may lead to conversion chemoradiation, even to final surgery. EGFR or VEGFR TKI with immunotherapy might also be a subsequent recue regimen after front-line anti-PD1 failure.[Table: see text]
Evaluation of near-Infrared fluorescence-conjugated peptides for visualization of human epidermal receptor 2-overexpressed gastric cancer.
Authors: Jeong Kyoungyun , Kong Seong-Ho , Bae Seong-Woo , Park Cho Rong , Berlth Felix , Shin Jae Hwan , Lee Yoon-Sang , Yun Hye Won , Koo Eunhee , Suh Yun-Suhk , Park Do Joong , Lee Hyuk-Joon , Yang Han-Kwang 
Published: January 2022

338 Background: HER2 is highly overexpressed in many kinds of cancers with a poor prognosis. Recently, near-infrared (NIR) fluorescence-based imaging is a growing field for both pre-clinical and clinical application. In this study, we aimed to synthesize Human Epidermal Receptor2 (HER2)-specific near-infrared (NIR) fluorescence probes and evaluate their applicability in cancer-specific image-guided surgeries using an animal model. Methods: An NIR dye emitting light of 800 nm (IRDye800CW, Li-COR, USA) was conjugated to trastuzumab and HER2-specific affibody using click mechanism. HER2 affinity was assessed by the surface plasmon resonance technique. HER2 positive/negative gastric cancer cell lines (NCI-N87 and SNU-601) were subcutaneously implanted into female BALB/c-nu (6 to 8 weeks old) mice. The biodistribution and fluorescence signal intensity were measured by Lumina II (Perkin Elmer, MA, USA) and a laparoscopic NIR camera (InTheSmart, Seoul, Korea) after injecting the probes intravenously. Results: Trastuzumab-IRDye800CW showed higher affinity to HER2 (K(D) = 2.093(3)pM) than unconjugated trastuzumab(K(D) = 25.75pM). The significant signal of fluorescence was targeted to the HER2-positive tumors at 24hr after injection, while no or low signal retention was observed in negative group. The peak appears at 24hr after injection. On the other hand, small difference of affinity was shown between HER2-target affibody-IRDye800CW (K(D) = 4.71nM) and unlabeled pure affibody(K(D) = 1.42nM). The renal clearance of HER2-target affibody conjugated with IRDye800CW was so fast that we could not detect the signal. Conclusions: Our results suggest that trastuzumab conjugated with IRDye800CW can be a feasible tool to monitor HER2 status in pre-clinical cancer imaging. Moreover, this probe can provide complementary means for assessment of HER2 expression in gastric cancer patients and/or be used to further detection of HER2-positive lesions during image-guided surgery.