bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of neoadjuvant sintilimab combined with chemotherapy TP for locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Li Zhao , Xu Peng-Fei , Mao Wei-Min , Kuang YuKang , Fan Hai-Yin , Zou Bin , Zhu Jian-Feng , Li Chao , Cheng Xiao-Liang , Liu Xing-Fei , Guo Changying
Published: June 2022

e16038

Background: Although preoperative chemoradiotherapy is the standard of care for patients with locally advanced esophageal cancer, ESCC still has a dismal prognosis. Sintilimab, a humanized IgG4 monoclonal antibody with high affinity and specificity for PD-1, has shown promising efficacy with overall survival in ESCC in a phase II study (ORIENT-02, NCT03116152)1. KEEP-G 03 given the encouraging MPR and favorable tolerability of preoperative sintilimab in combination with triplet chemotherapy in resectable ESCC (KEEP-G 03, NCT03946969)2. This trial evaluates the feasibility and safety of preoperative sintilimab in combination with chemotherapy of TP in ESCC. Methods: This is a single-arm, single center research, phase 2 trial to assessment the efficacy and safety of asintilimab and chemotherapy of TP(Q3W 2-4 cycle) as neoadjuvant treatment of locally advanced ESCC. The key eligibility criteria was locally advanced ESCC, ECOG PS 0 or 1, and at least one measurable lesion per RESIST v1.1. aSintilimab: 200mg for 60kg, 3mg/kg for body weight < 60kg; TP: pacilitaxel 175mg/m2 plus cisplatin 75mg/m2. Primary Objectives: pCR, MPR. Secondary Objectives: R0 rate, RFS, OS, Safety (CTCAE 5.0). Exploratory Objectives: The alteration of molecular biomarkers to neoadjuvant treatment including PD-L1, TMB, DDR, etc. Results: From 1/2020 to 12/2021, 20 eligible patients were recruited in the Jiangxi Tumor Hospital, NanChang, China. Conclusions: Given the encouraging MPR and favorable tolerability, the combination of sintilimab and chemotherapy of TP could be a potentially feasible and safe neoadjuvant option for locally advanced ESCC. The trial will be continued to evaluate the feasibility of this regimen.[Table: see text][Table: see text][Table: see text]
Definitive chemoradiotherapy +/- induction chemotherapy in esophageal cancer: A real-world experience.
Authors: Matoska Thomas , Jurkowski Lauren , Banerjee Anjishnu , Shreenivas Aditya V. , Shukla Monica , Martinez Enrique , Kodali Divya , Linsky Paul , Gasparri Mario , Chakrabarti Sakti , George Ben , Gore Elizabeth , Johnstone Candice Aitken , Johnstone David , Puckett Lindsay
Published: June 2022

e16072

Background: The SEER 5-year overall survival rate for all stages of esophageal cancer (EC) was 25% in 2019. Definitive chemoradiation (CRT) remains the primary treatment approach for locally advanced EC in the US, however, there are data to support use of induction chemotherapy (CT) in addition to CRT, particularly in adenocarcinoma (AC) histology. The purpose of our study was to assess outcomes in EC patients treated with definitive CRT (+/- induction) to determine which prognostic factors predicted for better survival in a recent, real-world cohort of patients, including those with limited stage IV disease. Methods: This retrospective study included Stages II-IVB (AJCC 8th ed.) EC patients treated with definitive CRT (radiation dose of ≥40 Gy and at least two cycles of concurrent CT [+/- induction CT, +/- esophagectomy]) at our institution between 2008 and 2020. To analyze prognostic factors and estimate OS, univariate models (UVA) and a multivariate (MVA) Cox proportional hazards regression model including age, Stage (II, III, IVA, IVB), AC vs. SCC, esophagectomy, ECOG performance status (PS), and induction CT were performed. Results: Of the 183 patients treated with definitive CRT, 18 were stage II, 119 stage III, 21 stage IVA, and 25 stage IVB. There were 45 SCC and 138 AC patients (Table). Prognostic factors associated with prolonged OS on MVA included lower PS (p<0.01) and esophagectomy (p = 0.05). Stage IVA was associated with shorter survival (p<0.01). Induction CT (delivered in 53% of AC, 31% SCC) was associated with improved survival on UVA (p=0.04), but not MVA (p = 0.08). By histology, 5-year survival rate was 42.7% and 18.2% for AC and SCC, respectively. Conclusions: At our institution, those who received an esophagectomy and those with lower ECOG scores had better survival. The 5-year survival rate was higher for AC patients compared to SCC, with more AC patients receiving esophagectomy and induction CT (significant on UVA, but not MVA). The 5-year survival rate for AC in our study was nearly identical to that seen in the CROSS trial (Shapiro et al. 2015) AC cohort but included >25% stage IV patients. This modern cohort also included poor PS (ECOG≥2) patients (9.2% AC and 13.6% SCC), suggesting induction CT, in addition to pre-operative CRT + surgery, may have added benefit in a real-world practice. Thus, further prospective study is needed.[Table: see text]
Camrelizumab in combination with fluorouracil or taxol plus platinum chemotherapy as first-line treatment of esophageal squamous cell carcinoma: A multicenter, open-label, prospective cohort study.
Authors: Zhao Jun , Hu Wenqing , Zhang Xiaoling , Du Yunyi , Yao Chunmei , Ma Ning , Yang Wei , Yang Bo , Xue Yudong , Gao Yangjun , Wang Yu , Liu Min , Wang Mei , Wang Hui , Feng Tingting , Cai Linlin , Zhang Cuihua , Ma Kai , Xu Ning , Lu Jing
Published: June 2022

e16084

Background: The introduction of immune checkpoint inhibitors (ICIs) after chemotherapy and targeted therapy has altered the treatment pattern of esophageal squamous cell carcinoma (ESCC). However, using ICIs alone results in a poor response rate. Fortunately, fundamental research indicates that chemotherapy might trigger immunogenic death of tumor cells by releasing tumor antigens, hence eliminating immune system repression of tumor cells. On this basis, a number of clinical studies, including KEYNOTE-590, CheckmMate-648, ORIENT-15, and ESCORT-1st, on the first-line treatment of ESCC with ICIs coupled with chemotherapy, including fluorouracil or taxol and platinum (PF or TP), were conducted and yielded favorable results. However, the advantage of safety and effectiveness of ICIs combination with PF and TP in Chinese ESCC remains unknown. Furthermore, since the southeast part of Shanxi province has a high prevalence of esophageal cancer, the geographical features of ESCC patients will be examined. Methods: Camrelizumab was maintained after 6 cycles of camrelizumab in combination with PF or TP chemotherapy. From May 2020 to February 2022, our study has included 40 locally progressed and advanced ESCC patients. Camrelizumab was administered in combination with PF to 11 patients and TP to 29 patients. Every 6 weeks, efficacy was examined using RECIST 1.1, and 33 patients were evaluated. This research was registered with the Chinese Clinical Trials Registry (ChiCTR2000037942). Results: The median treatment time was 5.8m. 82.5% (33/40) patients were availably evaluated. The objective response rate (ORR) was 72.7% (24/33) and the disease control rate (DCR) was 97.0% (32/33). There is no statistically significant difference in ORR ( p=0.1779) and DCR ( p=0.1005) between PF and TP (55.6% vs 79.2%, 88.9% vs 100%) regimens. At this moment, mPFS has not been achieved. The most common adverse events (AEs) were anemia (22.5%, 9/40), lymphocytopenia (15%, 6/40), neutropenia(15%, 6/40), reactive cutaneous capillary endothelial proliferation (RCCEP) (12.5%, 5/40) and fatigue (7.5%, 3/40). Thrombocytopenia (2.5%, 1/40), neutropenia (2.5%, 1/40) and leukopenia (2.5%, 1/40) were the most common grade 3 or 4 toxicities The most frequently reported immune-related AEs were RCCEP (12.5%, 5/40) and hypothyroidism (7.5%, 3/40). There were no new significant adverse events. Conclusions: Camrelizumab in combination with chemotherapy is a promising regimen with good tolerability in the first-line treatment of ESCC. Compared with FP, TP had more therapeutic advantages, But the result is a stage summary, and further observation is needed. Clinical trial information: ChiCTR2000037942. [Table: see text]
Molecular profile of exosomal miRNA differential expression in ascites of untreated advanced gastric cancer patients with peritoneal metastases.
Authors: Wu Yi , QI Changsong , Gao Jing , Chong Xiaoyi , Shen Lin
Published: June 2022

e16086

Background: The incidence of gastric cancer is high, and the proportion of peritoneal metastases among patients with early-stage operable gastric cancer is about 10%-20%, while the proportion of peritoneal metastases among patients with stage 3 (stage III) gastric cancer is as high as 40%. The prognosis of gastric cancer patients with peritoneal metastases is poor, with a median survival of 7 months. Exosomes are considered to be carriers of intercellular communication and abundant miRNAs (miRNAs) are enriched in patients' ascitic fluid exosomes. Methods: Ascites exosomes were characterized according to ISEV2018. The pro-tumor proliferation and metastatic ability of ascites exosomes in gastric cancer patients with peritoneal metastases was observed by small animal in vivo imaging. Six untreated ascites exosomes from gastric cancer patients with peritoneal metastases were selected for miRNA sequencing with five ascites exosomes from patients with benign disease to determine differentially expressed molecular profiles. The target mRNAs of selected miRNAs were predicted by miRhybrid, TargetScan database, and enriched in KEGG database for the function of target mRNAs. Results: Compared to ascites exosomes from patients with benign disease, or ascites exosomes removed from gastric cancer patients with peritoneal metastases, ascites exosomes from gastric cancer patients with peritoneal metastases had a significant contribution to tumor proliferation and metastasis. Among them, molecules such as miR-196 were expressed up-regulated in all six samples of gastric cancer peritoneal metastasis group, and the difference was significant. The target mRNAs of differentially expressed miRNAs were associated with motility, adhesion, stromal degradation, hypoxia tolerance, apoptosis, and angiogenesis (biological behaviors involved in this process of gastric cancer peritoneal metastasis). Conclusions: Molecules such as miR-196 are important for the clinical problem of peritoneal metastasis of gastric cancer and can be used as biomarkers for disease assessment and potential therapeutic target.
Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach.
Authors: Zhu Mengxuan , Chen Erbao , Yu Shan , Xu Chen , Yu Yiyi , Cao Xin , Li Wei , Zhang Pengfei , Wang Yan , Cui Yuehong , Li Qian , Liu Tianshu
Published: June 2022

e16094

Background: Hepatoid adenocarcinoma (HAC) is a rare pathological subtype of extrahepatic tumor, featured by hepatoid differentiation and α-fetoprotein (AFP)-production. Hepatoid adenocarcinoma of the stomach (HAS), accounting for 0.17 to 15% of gastric cancers, is the most common subtype of HAC, and has attracted increasing attention duo to its high degree of malignancy. Compared with classic gastric cancer (GC), HAS showed a higher rate of vascular invasion, lymph node metastasis, and liver metastasis, with only 9% survival at 5 years. In this study, we aim to investigate the molecular features of HAS and identify the potential therapeutic targets for HAS. Methods: We conducted whole-exome sequencing (WES) of 40 paired tumor and normal samples, including 25 HAS, 6 HAC of other organ and 9 AFP-producing gastric cancer (AFPGC). All patients underwent radical surgery at Shanghai Zhongshan Hospital between July 2013 and September 2017. qRT-PCR, Western blot and immunohistochemistry were detected to explore MUC19 expression in HAS. CCK8 assay, Transwell assay, immunofluorescence assay and subcutaneous xenograft tumor model were used to detect functional effects and the mechanism of MUC19. Results: In HAS patients, the top 5 frequently mutated genes were TP53 (44%), TTN (44%), MUC19 (40%), CCNE1 (28%) and CDC27 (28%). Further compared with TCGA datasets, MUC19, CCNE1, CDC27 mutations were almost undetectable in STAD, CRC and HCC. In terms of CNV analysis, VSTM2B, PLEKHF1, POP4, URI1 and TERT were the most frequently amplificated genes in HAS tumor tissues. Interestingly, amplification of 4 genes (VSTM2B, CCNE1, LEKHF1, POP4), which located in chr19q12, was significantly associated with poor prognosis. The tumor mutational burden (TMB) levels and AFP expression of HAS and AFPGC patients were no significantly different, while patients with higher TMB had a remarkably longer overall survival ( p= 0.0065). Moreover, we found MUC19 expression was positively correlated with AFP levels in HAS and MUC19 promoted the transcription of AFP in GC cells. Mechanistically, MUC19 contributed to the aggressive malignancy phenotypes of GC cells through activating the Wnt/β-catenin signaling pathway. Conclusions: MUC19 may be a potential target for HAS diagnosis and treatment. Amplification of genes located in chr19q12 occurred frequently in HAS and were associate with poor prognosis. TMB was sensitive for the overall survival of HAS patients.
Does hyponatremia predict worse outcomes in gastric cancer?: A nationwide study.
Authors: Franco Jorge , Franco Diana , Farooq Umer , Ma Irene
Published: June 2022

e16098

Background: Hyponatremia has historically been reported to increase mortality and length of stay in hospitalized patients with solid tumors. There are sparse reports of hyponatremia linked to gastric cancer in the published literature. Therefore, we evaluated mortality, morbidity, and resource utilization in gastric cancer patients secondary to hyponatremia. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with gastric cancer. Effect of hyponatremia was studied on mortality, morbidity, and resource utilization. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses. These included: gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, cirrhosis, nephrotic syndrome, hypothyroidism, adrenal insufficiency, alcohol use disorder, and admission for hypovolemia or psychogenic polydipsia and various patient and hospital characteristics. Results: Out of 43,015 patients with gastric cancer in 2019, 13.59% (5,845) had hyponatremia on presentation (Table. 1). Patients with hyponatremia had 12.23% in-hospital mortality, while 6.69% for patients without hyponatremia. After adjusting for confounders, hyponatremia imparted higher odds of mortality (Adjusted odds ratio (aOR) for mortality 1.89, 95% confidence interval (CI): 1.54–2.32, P< 0.01). Hyponatremia also resulted in higher resource utilization marked by the length of stay, hospital charges, and ICU admission (higher mean LOS by 2.09 days, higher mean total hospital charges by $22,320, and higher odds of ICU admission). In addition, patients with hyponatremia had higher odds of acute renal failure (aOR 2.38, 95% CI: 2.05–2.77, P< 0.01). Rates of cerebral edema and altered mental status were equal between the two study groups ( P> 0.05). Conclusions: Hyponatremia in gastric cancer patients had a prevalence of 13.59% and resulted in increased in-hospital mortality. Whether time-efficient treatment of hyponatremia would help reduce mortality and improve outcomes remains to be determined in future studies.[Table: see text]
Serum cytokines could be predictors for PD-1 antibody response in advanced HBP cancer.
Authors: Mei Shengmin , He Zenglei , Wang Bin , Xue Liang , Xu Li , Ling Qi
Published: June 2022

e16114

Background: According to previous clinical trials and pilot studies, PD1 antibodies might provide favorable long-term survival in combination with chemotherapy for unresectable hepatobiliary and pancreatic (HBP) cancers. We conducted a real-world evaluation of PD1 antibodies in patients with unresectable HBP cancers. We also aimed to explore biomarkers for the early prediction of PD1 antibodies response. Methods: From Jan 2021 to Dec 2021, 48 unresectable HBP cancers were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine. The key eligibility criteria were:(1)histopathologically confirmed advances unresectable HBP cancers; (2)without systematic treatment; (3)¡Ý18 years old; (4)ECOG PS 0 or 1. Clinical decisions were made by multi-disciplinary team (MDT). The treatment efficacy was evaluated by mRECIST. Results: A total of 48 patients were finally included and analyzed, which their baseline characteristics were listed in Table. we assessed the treatment efficacy using the dynamic change of tumor makers. And we observed that tumor markers of progressive disease(PD) group were higher than those of stable disease(SD) and partial response(PR) group. A total of 37 patients with complete biomarker data, were finally included in cytokines and immune response analysis. During the immune checkpoint inhibitors treatment, we detect the trough concentration of serum cytokines(IL-2, IL-4, IL-6, IL-10, IL-16, TNF-¦Á and TIFN-¦Ã). We observed that serum cytokines indexes of PD group were higher than those of SD and PR group. Conclusions: We observed that tumor markers of PD group were higher than those of SD and PR group. The serum cytokines (IL-4, IL-16 and TIFN-¦Ã) may be potential biomarkers for the early prediction of PD1 antibodies response. [Table: see text]
Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of recurrence after surgery—A single-arm, multicenter, phase II clinical trial.
Authors: Wu Zheng , Wang Zheng , Zhang Lei , Song Xiaojing , Du Xilin , Tan Kai
Published: June 2022

e16120

Background: Hepatectomy is considered to be an effective curative treatment for hepatocellular carcinoma (HCC), however, high recurrence rate after curative resection severely reduces the long-term survival of HCC patients (pts). Transarterial chemoembolization (TACE) as adjuvant therapy has been proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy, but the effect is still unsatisfactory. ALTER-H004 trial was designed to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Here we updated the results at the data cutoff of January 20, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H004 was planned to enroll 30 pts which with histologically confirmed HCC and undertook hepatectomy within 1-2 months. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5 cm and < 10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II). Eligible pts received conventional TACE treatment within 1-2 months after hepatectomy. On the 3-5th day after TACE treatment, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 20, 2022, 26 pts were enrolled and 25 pts received at least once tumor assessment. According to RECIST 1.1, 14 of 25 did not progress were still on treatment and 7 relapsed. One withdrew the consent and 3 discontinued because of intolerable adverse events. The longest duration of treatment is 16.53 months. The DFS were not mature and the 6-month DFS rates were 77.45% (95% CI: 53.83̃89.99). 12 of 25 pts (48.0%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (20.0%) included hypertension (8.0%), leukocytopenia (8.0%) and ascites (4.0%). No grade 4 or 5 TRAEs occurred. Conclusions: The update results suggested that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited promising clinical benefit and favorable safety profile, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04213118.
Feasibility of disease recurrence monitoring in liver post-transplantation for patients with hepatocellular carcinoma via personalized and tumor-informed ctDNA test.
Authors: Abdelrahim Maen , Esmail Abdullah , Saharia Ashish , McMillan Robert , He Aiwu Ruth , Starr Jason S. , Dhani Harmeet , Aushev Vasily N. , Koyen Malashevich Allyson , Rattigan Nicole Hook , Gauthier Phil , Jarudi Adham , Ghobrial Rafik Mark
Published: June 2022

e16123

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy for which liver transplantation can be curative. Unfortunately, ̃8-20% of HCC patients will go on to relapse post-transplantation. Personalized and tumor-informed circulating tumor DNA (ctDNA) testing (Signatera, bespoke mPCR NGS assay) has been validated to accurately predict relapse across solid tumors, ahead of radiological imaging. Here, we demonstrate the feasibility of ctDNA testing for monitoring relapse in HCC patients who underwent liver transplantation with curative intent. Methods: A total of 10 HCC patients, stage I-IV, who underwent curative liver transplantation with longitudinal ctDNA monitoring were included in the analysis. Alpha-fetoprotein (AFP) levels and images were measured during surveillance in a subset of patients. Results: In this cohort of 10 patients, 2 (20%) tested ctDNA positive during surveillance, both of whom relapsed. Of these, one tested ctDNA positive two months prior to imaging. Of the 8 patients who did not test ctDNA positive during surveillance, all remained disease-free by imaging. Two patients had elevated AFP, neither of whom relapsed. Of the 2 patients who relapsed, AFP levels were available for one patient and fell within the normal range. Conclusions: Our study illustrated the feasibility of performing longitudinal ctDNA assessment in patients with HCC (post-transplantation) during surveillance. ctDNA status but not AFP was associated with recurrence and was able to inform disease status ahead of imaging. To facilitate clinical decision-making, specifically with adjuvant therapy and immunosuppression management, additional studies with larger patient cohorts will be needed to validate the clinical utility of ctDNA testing in HCC.
B-catenin mutations and the response of advanced hepatocellular carcinoma to immune checkpoint inhibitors.
Authors: Mahadevia Himil , Imperial Robin John Lester , Toskich Beau , Mody Kabir
Published: June 2022

e16124

Background: Immune checkpoint inhibitors (ICI) have emerged as a standard treatment option for advanced hepatocellular carcinoma (HCC). Unfortunately, many patients with advanced HCC develop progressive disease on ICI therapy. Furthermore, clinical predictors of response to ICI therapy in HCC are poorly understood. B-catenin mutations are among the most frequent genetic abnormalities in HCC and may provide a mechanism for immune evasion and poor response to ICI (Ruiz de Galarreta, Marina et al. “β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.” Cancer discovery 9,8 (2019): 1124-1141. doi:10.1158/2159-8290.CD-19-0074). Methods: We conducted a retrospective cohort study of patients with advanced HCC who were treated with ICI therapy. All patients had ctDNA tumor profiling and were assessed for B-catenin mutation status. Disease status was determined by RECISTv1.1. Median progression-free survival (PFS), 3-month PFS, 6-month PFS, and the disease control rate (DCR) on ICI therapy were compared between B-catenin mutation (BCM) and B-catenin wild-type (BCWT) groups. Results: 15 stage III/IV HCC patients were included in the study. 9 patients harbored BCMs and 6 patients were BCWT. The median PFS in patients with BCM HCC was 4.0 months versus 4.9 months in patients with BCWT HCC. At 3 months, PFS was 56% for BCM HCC compared to 67% for BCWT HCC. Furthermore, the 6-month PFS was 11% for BCM HCC and 50% for BCWT HCC. For best response, 33% of patients with BCM HCC achieved stable disease compared to 67% of patients with BCWT HCC. No patients in our cohort achieved partial or complete response. The DCR for BCM HCC was 33% and the DCR for BCWT HCC was 67%. Conclusions: In patients with advanced HCC, B-catenin mutation status may serve as a potential biomarker of response to ICI therapy. Our data suggests that patients who do not harbor these mutations, have a more durable response to ICI therapy. Further studies are needed to validate these findings.
The value of pretreatment 18F-FDG PET/CT to predict the pathological treatment response of hepatocellular carcinoma patients treated with PD-1 inhibitors and lenvatinib as a conversion therapy in BCLC stage C.
Authors: Wang Guanyun , Ma Guangyu , Zhang Wenwen , Xu Baixuan , Lu Shichun , Chen Jiaxin , Luan Xiaohui , Wang Zhanbo , Xu Xiaodan , Guan Zhiwei , Tong Shuang
Published: June 2022

e16130

Background: Current systemic therapy for patients with hepatocellular carcinoma (HCC) in BCLC stage C consists of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aimed to assess the parameters of pretreatment 18F-FDG PET/CT as a predictor of the pathological treatment response (PTR) of HCC patients treated with PD-1 inhibitors and lenvatinib as a conversion therapy in BCLC stage C. Methods: We retrospective analyzed 20 consecutive patients with HCC in BCLC stage C. All patients underwent pretreatment 18F-FDG PET/CT and treated with PD-1 inhibitors and lenvatinib as a conversion therapy and surgery. Patients were categorized into responders (n=9) and non-responders (n=11) according to PTR. The PTR was classified based on the primary tumor cellularity (responder, defined as <10% cellularity). The parameters of PET/CT including lesion size, SUVmax (max standardized uptake value), SUVmean (mean standard uptake value), MTV2.5 (metabolic tumor volume2.5), TLG2.5 (total lesion glycolysis2.5), SUVpeak (peak standard uptake value), and TLR (tumor-to-normal liver standardized uptake value ratio, SUVmax of the tumor/SUVmean of the normal liver parenchyma) were calculated and compared between two groups. The diagnostic efficacy was evaluated by ROC. PTR was compared with pretreatment 18F-FDG PET/CT parameters by using Spearman correlation analysis. The prognosis was followed up. Results: TLR (5.59±1.90 vs. 2.84±1.70, respectively; P=0.003) showed significant difference in responders and non-responders and the largest area under the curve (sensitivity: 1.000, specificity: 0.727, positive predictive value: 0.750, negative predictive value: 1.000, AUC=0.899, 95%CI: 0.759-1.000), and optimal diagnostic threshold of 3.09. The relationship between 18F-FDG PET/CT parameters and PTR showed TLR had moderate positive correlation with pathological treatment response, with correlation coefficients (rs) of 0.69 ( P＜0.05). During the follow-up, no patients died, and 1 patient (11.1%) showed tumor recurrence in responders. In all 11 non-responders, 5 patients (45.5%) had tumor recurrence and 4 patients (36.4%) died. Conclusions: The TLR may be a powerful marker to predict the PTR of HCC patients with BCLC stage C who treated with PD-1 inhibitors and lenvatinib as a conversion therapy.[Table: see text]
Role of metformin in the treatment of cholangiocarcinoma: A systematic review.
Authors: Adigun Aisha Olanike , Naeem Aleena , Poladi Keerthi , Moorthy Vivek Soorya Sathya , Fatima Farwah , Ahmad Muhammad , Zamani Zarlakhta , Haider Mobeen Zaka , Zamani Nilofar , Mushtaq Muhammad Umair
Published: June 2022

e16132

Background: Non-cancer medications and their potential anti-cancer activity have attracted significant interest in recent years. The aim of this research is to conduct a systematic assessment of the existing evidence on the usefulness of metformin in the treatment of cholangiocarcinoma. Methods: We conducted literature search using PubMed, Clinicaltrials.gov, Embase, and Cochrane to retrieve studies evaluating the role of Metformin in the treatment of Cholangiocarcinoma. Three studies were finalized after careful screening. Results: We analyzed 3 studies. The total population was 638. The types of Cholangiocarcinoma varied from intrahepatic cholangiocarcinoma found in 293, to extrahepatic Cholangiocarcinoma in 365 and gallbladder carcinoma in 149 patients. Patients were in different stages of treatment such as undergoing chemotherapy, surgery or post- resection and/or post chemotherapy. The mean survival rate was significantly increased to 30.4 months and 13.2 months in patients using Metformin vs. 23.48 months and 10.3 months among patients not using Metformin (p < 0.0005) after resection of the tumor. An increase in the mean survival rate was reported among patients using Metformin vs. non-users after the administration of chemotherapy, i.e., 25.9 months vs. 10.6 months (p = 0.0016), respectively. Metformin in combination with Chloroquine showed favorable results regarding adverse events, however, no clinical activity was reported against IDH-1 mutated intrahepatic cholangiocarcinoma. Conclusions: Our analysis concludes while the use of Metformin is associated with significantly improved post-operative survival, it does not show any significant clinical activity against IDH-1 mutated intrahepatic cholangiocarcinoma. Metformin also showed significant improvement in patients taking chemotherapy. Studies, including trials to evaluate the effectiveness of Metformin alone or used in combination with non-cancer medications or chemotherapeutic agents could provide more definitive recommendations for the treatment of Cholangiocarcinoma.[Table: see text]
Frequency of loco-regional complications and their IMPACT on hospitalization outcomes in patients with cholangiocarcinoma.
Authors: Shah Mihir , Kumi Dennis Danso , Deenadayalan Vaishali , Ferreira de Araujo Litvin Rafaella , Dasgupta Mona , Turk Ekrem , Gupta Shweta
Published: June 2022

e16135

Background: Cholangiocarcinomas, based on their anatomic location are prone to a myriad of local and regional complications. This study aims to explore if the outlook of patients differs based on what type of loco-regional complications they are admitted with. Methods: The National Inpatient Sample (NIS) was queried to identify adult patients with underlying cholangiocarcinoma between 2016-2018. Relative frequency and diagnosis of locoregional complications as principal diagnosis in these patients were identified and top 5 loco-regional complications were studied and compared for all-cause mortality, mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using t-test, univariate and multinomial logistic regression. Results: There were 26,410 hospitalizations in patients with cholangiocarcinoma. Upper gastrointestinal bleed (UGIB) represented the most frequent loco-regional complication (9.2%), followed by acute liver failure and cancer pain admission (6.7% each). Mortality rate of all admissions was 5.84%; all complications except failure to thrive were associated with significantly increased odds of mortality, the highest in acute liver failure (AOR- 3.72). Except admissions for cancer associated pain, all complications were associated with statistically significant increased LOS, highest in UGIB (Adjusted mean difference of 5 days). Similarly, admission with UGIB was associated with the highest THC while cancer pain admission had a much lower cost. Conclusions: Among the loco-regional complications of cholangiocarcinoma that were studied, UGIB was the most frequent, associated with longest hospital LOS (5 extra days) and highest THC. Admission with acute hepatic failure was associated with the highest odds of mortality while cancer associated pain and failure to thrive were associated with the shortest length of stay and lowest mean charges. Further efforts are needed to improve outpatient pain management to prevent these admissions and identify ways to improve outcomes in patients with UGIB. [Table: see text]
Regorafenib (REGO) ± PD-1 inhibitor in second-line setting for unresectable hepatocellular carcinoma (uHCC) in real-world practice.
Authors: Bi Huaqiang , Pei Jun , Ma Kuansheng , Zhang Yanling , Xia Feng
Published: June 2022

e16148

Background: No response and resistance occurred for the most uHCC patients with the treatment of molecular targeted agents and\or anti-PD-1 inhibitors. And the second-line therapies are still unmet the ideal clinical outcome. A pilot study that assessed the effectiveness of the combination therapy of REGO + PD-1 inhibitor in second-line setting for pts with advance uHCC showed promising result. Methods: This single-center, retrospective, real-world study was conducted between Jan 2019 to Jul 2021. All patients with uHCC, who were treated with second-line REGO + PD-1 inhibitor or REGO monotherapy were evaluated. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS) were observed. Results: Forty-six patients with uHCC were included in the study, and most had received previous systemic treatment including targeted therapy and immunotherapy. In all pts, median treatment duration of regorafenib was 152.5 days. Median follow-up was 9.0 months. Tumor response was evaluated in 25 and 21 pts in REGO + PD-1 inhibitor and REGO monotherapy group respectively, ORR was 40% and 19.0% respectively; DCR was 88% and 71.4% respectively. Median OS was not reached in either group; the median PFS of the REGO + PD-1 inhibitor group was 11.5 months, which was significantly higher than that of the REGO monotherapy group (5.1 months) (C2=3.867; P=0.049). The most common AE grade ≥3 was diarrhea (4.3%), and was solely observed in REGO monotherapy group. Conclusions: Our preliminary findings suggested that the striking improvement in PFS and ORR were compelling in the REGO + PD-1 inhibitor group, and regardless of previous treatment, regorafenib was clinically effective for uHCC pts in second-line treatment whether in combination with PD-1 inhibitor or not in Chinese patients. And there was a trend to increased efficacy with no increased toxicity in combination therapy. Further analysis in a real-world study with a large sample size is crucial to substantiate our results.
Comparison of immune checkpoint inhibitor monotherapy versus Sorafenib in unresectable hepatocellular carcinoma.
Authors: Chan Abigail Sy , Rout Amit , Kumar Rohit
Published: June 2022

e16160

Background: Combination immune checkpoint inhibitors (ICI) or with a vascular endothelial growth factor receptor (VEGFR) agent is now the standard 1st line (1L) therapy in patients with advanced/unresectable hepatocellular carcinoma (uHCC). Currently, there is a paucity of data on the use of ICI monotherapy when combination ICI/VEGFR is contraindicated. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety outcomes of ICI monotherapy versus sorafenib in patients with uHCC in the 1L setting. Methods: A systematic search of electronic databases was conducted for randomized controlled trials comparing ICI versus sorafenib in the treatment of uHCC. Efficacy endpoints were overall survival (OS), objective response rates (ORR), and progression free survival (PFS). Safety endpoints of interests were any adverse events (AE) and > grade 3 AEs. We performed random effects meta-analysis to estimate odds ratio (OR) with 95% confidence intervals for individual endpoints. Results: A total of 2 studies with 1521 patients were included in the final analysis. Compared to sorafenib, ICIs were associated with improved OS [OR 0.75; 95% confidence interval (CI) 0.6-0.94]. Similarly, ICI had increased odds of ORR [OR 2.99; 95% CI 1.93-4.62] and PFS [OR 1.41; 95% CI 1.07-1.85] compared to the sorafenib arm. In the safety analyses, ICIs were associated with reduced risk of > grade 3 AE [OR 0.40; 95% CI 0.22-0.72] and any AEs [OR 0.25; 95% CI 0.12-0.55] when compared to sorafenib. Conclusions: Our meta-analysis suggests that ICI monotherapy has improved OS, PFS, ORR, and better safety profile in 1L uHCC compared to sorafenib.
Development of hand-food skin reaction correlates with prognosis of patients with HCC who were treated with sorafenib.
Authors: Lee Young-Sun , Lee Yoonseok , Oh Sang Cheul , Kim Ji Hoon
Published: June 2022

e16171

Background: Sorafenib is one of the effective systemic therapy in patient with advanced hepatocellular carcinoma (HCC). However, there are few prospective studies that have examined prognostic factors of sorafenib response. In this study, we analyzed prognostic factors of HCC patients who were treated with sorafenib. Methods: Between May 2016 and May 2018, 288 advanced HCC patients treated with sorafenib were enrolled at 13 hospitals. We analyzed possible prognostic factors of sorafenib response (overall survival and progression free survival) using Univariate and Multivariate analyses with Cox proportional hazards regression model. Results: Among the 288 patients, chronic hepatitis B (68.4%) was main cause in development of HCC. 85.4% of patients were in the advanced stage of Barcelona Clinic Liver Cancer. Hand-foot skin reactions (HFSR) were observed in 142 patients (49.2%). The univariate analysis identified presence of ascites, serum albumin level and creatinine level, presence of HFSR as potential prognostic factors for overall survival (OS). In multivariate analysis for OS, presence of HFSR (HR 0.144; 95% CI: 0.063-0.330, p 0.002), albumin level (HR ratio 0.283; 95% CI: 0.148-0.544, p < 0.001), creatinine level (HR 1.395; 95% CI 1.133-1.717, p 0.002) were significant factors of OS. In univariate and multivariate analysis, presence of HFSR (HR 0.212; 95% CI: 0.091-0.495, p < 0.001), and serum albumin level (HR 0.30, 95% CI: 0.158-0.568, p < 0.001) were show significant correlation with progression free survival. Conclusions: Developing HFSR from sorafenib therapy and high serum albumin level were associated with improved OS and PFS. Developing HFSR have been suggested as possible predictor of good sorafenib response. Clinical trial information: NCT03212625.
Clinical impact of the changes of muscle volume during various systemic therapies in patients with unresectable hepatocellular carcinoma.
Authors: Matsumoto Hiroaki , Tsuchiya Kaoru , Hayakawa Yuka , Tanaka Yuki , Ishido Shun , Inada Kento , Kirino Sakura , Yamashita Koji , Nobusawa Tsubasa , Kakegawa Tatsuya , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Kaneko Shun , Tamaki Nobuharu , Yasui Yutaka , Nakanishi Hiroyuki , Kurosaki Masayuki , Izumi Namiki
Published: June 2022

e16177

Background: Sarcopenia is associated with clinical outcomes in cirrhosis and hepatocellular carcinoma (HCC). However, the clinical impact of muscle volume during systemic therapy is unknown. We investigated the changes in muscle volume during various systemic therapies for HCC. Methods: The patients with unresectable HCC (u-HCC) treated with a molecular targeted agent as initial systemic therapy were included. The skeletal muscle mass index (SMI) was calculated from the skeletal muscle area at the L3 level of the lumbar vertebrae using computed tomography. Sarcopenia was defined as an L3 SMI value≦42 cm2/m2 for men and 38 cm2/m2 for women. ΔSMI was defined as the difference between baseline and 6-14 weeks after the administration of the agent. Results: A total of 174 patients was analyzed. The 1st-line agent was sorafenib (SOR) (n = 89), lenvatinib (LEN)(n = 58), and atezolizumab plus bevacizumab (ATE+BEV) (n = 27). In three groups, ATE+BEV group had significantly fewer discontinuation due to adverse events. (ATE+BEV 6 cases, LEN 31 cases, SOR 32 cases, p = 0.014). The median PFS was 4.1, 3.0, and 6.1 months in SOR, LEN, and ATE+BEV. The median Δ In patients treated with ATE+BEV, pretreatment sarcopenia was not associated with OS and PFS, while the patients with a SMI decrease (at 6-14W, n = 12) had significantly shorter PFS than the patients without a SMI decrease (n = 15) (p = 0.026). The best radiological response based on RECIST ver1.1 in ATE+BEV was CR (n = 2), PR(n = 6), SD(n = 15), and PD (n = 3). The patients without a SMI decrease tended to have better disease control rate than patients with a SMI decrease (100% vs. 75%, p = 0.08). There were no significant differences in age, etiology, ALBI score, BCLC stage, and pretreatment AFP between the patients with and without a SMI decrease. The significant factor associated with PFS after the administration of ATE+BEV as 1st-line was a decrease of SMI (HR9.44, 95% CI 1.04-85.6, p = 0.046). In patients treated with SOR and LEN, pretreatment sarcopenia and SMI decrease were not significantly associated with OS and PFS. Conclusions: The decrease of muscle volume at 6-14W was significantly associated with PFS in patients treated with ATE+BEV, while pretreatment sarcopenia was not a significant factor. Monitoring muscle volume during immunotherapy would be useful in clinical practice.
Genomic determinants and clinical relevance of cancer-associated thrombosis in biliary tract cancers.
Authors: Nichetti Federico , Provenzano Leonardo , Miliziano Daniela , Sposetti Caterina , Pircher Chiara , Bini Marta , Franza Andrea , Massa Giacomo , Niger Monica , Di Bartolomeo Maria , De Braud Filippo G.
Published: June 2022

e16179

Background: Biliary tract cancers (BTCs) are a group of rare tumors with a dismal prognosis and a complex molecular landscape. In this setting, the incidence and clinical relevance of cancer-associated thrombosis (CAT) is unknown, thus BTCs are not included in common thrombotic risk scores (e.g. Khorana Score). Moreover, retrospective studies highlighted associations between thromboembolic events and some genetic alterations, such as KRAS in lung and colorectal cancer, ALK/ROS1 in lung cancer and IDH1 mutations in glioma. Nevertheless, the impact of different genomic alterations on CAT risk in BTCs patients has never been investigated. The aim of this study was to investigate for the first time the incidence and the clinical relevance of CAT in a cohort of BTC patients. In addition, we investigated the association between tumor genomics and CAT in this patients’ population. Methods: Clinical and genomic data of consecutive BTC patients who underwent extensive molecular profiling with the FoundationOneCDx panel at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, were collected. The association between genomic alterations and CAT incidence was investigated with the Fisher exact test, considering alterations occurring in at least 5% of patients. Cox regression was used to analyze the impact of CAT, considered as a time-dependent covariate, on overall survival (OS). Results: 140 patients were included in the analysis, mostly represented by cases of intrahepatic cholangiocarcinoma (77%). CAT occurred in 18 (13%) patients, the majority being pulmonary embolism (28%) and visceral thrombosis (44%). Pathogenic KRAS and BRCA1 mutations were found in 33% and 11% of patients with CAT, resulting significantly associated with an increased risk of thrombosis ( p = 0.041 for both). Patients who experienced CAT showed a significantly poorer OS (HR 3.29, p = < 0.001). Conclusions: This is the first report describing a non-negligible incidence and significant prognostic impact of CAT in BTC patients. Future studies investigating the clinical and molecular risk factors for CAT in this population are needed to tailor thromboprophylaxis in this rare population.
Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma including FGFR2 fusion or rearrangement: Updated data from an open-label, single-arm, multicenter phase II study (CIBI375A201 study).
Authors: Shi Guoming , Huang Xiaoyong , Wen Tianfu , Song Tianqiang , Kuang Ming , Mou Haibo , Bao Lequn , Zhao Hai-Tao , Zhao Hong , Feng Xielin , Zhang Bixiang , Peng Tao , Zhang Yubao , Li Xiangcheng , Yu Hongsheng , Cao Yu , Luo Yang , Chen Mingxia , Fan Jia , Zhou Jian
Published: June 2022

e16183

Background: Pemigatinib is a selective FGFR inhibitor that showed effectiveness and tolerability in patients with cholangiocarcinoma with FGFR2 fusion or rearrangement. However, pemigatinib has not been investigated in Chinese population with cholangiocarcinoma (CCA). Initial efficacy and safety data were previously presented (G-M. Shi et al. ESMO 2021; NCT04256980). Here, we report updated follow-up results from the phase II study. Methods: Patients aged 18 years or older with recurrent or metastatic CCA that failed at least one prior systemic therapy were enrolled. In Part 1, 3 subjects were enrolled regardless of the FGFR2 status and were treated at 9 mg pemigatinib. The other 31 subjects with documented FGFR2 fusion or rearrangement were enrolled in Part 2 and received 13.5 mg pemigatinib. From 2/26/2020 to 12/20/2021, all the subjects in both parts were orally given pemigatinib QD on a 2 weeks on/1 week off schedule until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary efficacy end point was ORR assessed by independent radiological review committee (IRRC) per RECIST V1.1 in 31 patients enrolled in Part 2. Results: As of the data cutoff date (Dec 20th, 2021), with a median follow up of 12.6 (11.8, 14.2) months, among 30 efficacy evaluable subjects with 1 participant excluded due to inadequate FGFR2 aberrant frequency, the updated confirmed objective response rate (ORR) was 60% (95% CI: 42.5%, 77.5%) per RECIST 1.1. The median DOR was 8.3 months (95% CI: 6.5, 11.2), and with 8 pts still maintaining tumor control of partial response. The updated median PFS was 9.1 months (95% CI: 7.8, 11.0). The DCR was also 100% (95% CI: 100%, 100%). All 34 subjects were included for safety analysis. As of data cutoff the safety profile was consistent with the primary analysis, with no new safety signals or concerns identified. With the longer follow up time, the frequency of grade 3 or higher TRAEs was increased to 26.5%. One patient experienced TRAE leading to treatment discontinuation, while no TRAE leading to death was observed or reported. TEAEs leading to dose interruption or dose reduction occurred in 23.5% and 14.7% of patients, respectively. Conclusions: Pemigatinib was high response rate and manageable tolerability in Chinese patients with recurrent or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement. Editorial acknowledgement: Guoming Shi and Xiaoyong Huang contributed equally to this work. Clinical trial information: NCT04256980.