bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characterization correlates of different metastasis in advanced colorectal cancer.
Authors: Xi Yanfeng , Fang Yi , Chen Siqi , Lu Guanghua , Deng Wanglong , Ding Ran , Bu Fanfeng
Published: June 2022

e15565

Background: As we all know that patients with advanced colorectal cancer (CRC) are often diagnosed with liver-only metastases (LM), pulmonary-only metastases (PM) and widespread metastasis (WM). Various methods have also been applied to molecular mutation detection in CRC, However, the differences in molecular mutation profiles between the different metastatic lesions are unclear. Methods: In the period of September 2019 to January 2022, 376 LM, 111 PM and 116 WM were included in this retrospective analysis. The average age of patients with LM, PM and WM were respectively 61, 63 and 63 (range, 21-86, 39-95, 29-83). The proportion of male patients accounted for about 60% of LM (246/376), PM (69/111) and WM (74/116) . In this study, we retrospectively analyzed the single nucleotide variants (SNV), copy number variation (CNV) and fusion variants, detected in patients with different metastatic lesions by using next-generation sequencing (NGS). Pearson’s chi-square test was used to test differences in mutation frequency. P-values < 0.05 were considered significant. SPSS 26.0 was used for the statistical analyses. Results: In LM, PM and WM analyzed cohorts, SNV was detected in 370, 108 and 114 patients. CNV was detected in 225, 58 and 60 patients, and fusions were detected in 25,7 and 9 patients. In LM, PM and WM analyzed cohorts, the genes with the highest mutation frequency were APC (11.60%, 8.73%, 6.40%), TP53 (8.90%, 7.70%, 5.29%), KRAS (5.90%, 6.67%, 5.03%) . In addition, the SMAD4 mutation frequency was 2.13%, 0.82% and 1.04%, respectively. APC and SMAD4 mutation frequency was higher in LM than PM ( P= 0.012, P= 0.007) and WM ( P < 0.0001, P= 0.008). 1026, 221 and 281 CNV were detected in LM, PM and WM, respectively. The genes with the highest mutation frequency were MYC (43%, 7.24%, 4.63%), MET (5.95%, 7.69%, 5.34%), EGFR (5.36%, 7.24%, 4.63%) and FLT3 (4.39%, 4.98%, 6.05%) in LM, PM and WM. The SMAD4 mutation frequency were 0.58% and 1.07% in LM and WM, which was not detected in PM. No significant difference was found in those CNVs. No characteristic fusions were found in the total analyzed cohorts. Conclusions: The SNV and CNV molecular mutation profiles were similar in LM, PM and WM. However, the genes with higher mutation probability show higher mutation frequency in LM. Compared with PM, SNV of SMAD4 displays a higher mutation frequency in LM. It has been previously reported that LM may display poorer overall survival (OS) compared with PM. Considering the effect of SMAD4 on the prognosis of CRC, this study may provide a possible analysis of the poor prognosis of LM patients. However, there is still a need for more clinical research to support these results.
Biomarker testing patterns among patients with early and late-onset metastatic colon cancer.
Authors: Mohammed Hina , Sweetnam Connor , Law Jeanna Wallenta , Toland Liz , Berry Anna B. , Brown Thomas D. , Zhang Chenan
Published: June 2022

e15575

Background: Molecular testing is essential in considering targeted therapies, particularly for the increasing number of metastatic colon cancer (mCC) patients (pts) diagnosed at younger ages who may present with more aggressive disease. This analysis compares demographic and clinical characteristics, and biomarker testing and positivity rates of mCC pts diagnosed at younger versus older ages. Methods: We analyzed 1029 pts with mCC (stage IV at diagnosis) between 01/01/2016 - 12/31/2020 who received care in community health systems in the United States. Pts 18-49 years at mCC diagnosis were considered early onset (EO), and those 50 or older were considered late onset (LO). We compared the distributions of year at diagnosis, gender, race/ethnicity, smoking status, histology, stage at diagnosis, tumor sidedness, KRAS, NRAS, and BRAF testing, and positivity rates between EO and LO mCC pts. Differences in distributions were assessed using chi-square tests. Results: EO pts (n = 148) were more likely to have left-sided tumors than LO pts (n = 881, 55% vs. 36%; p-value < 0.001), and were less likely to be ever smokers (24% vs. 40%; p-value < 0.001); the remaining demographic and clinical characteristics were similar between the two groups. Testing was significantly more common among EO than LO pts for KRAS (71% vs 48%), NRAS (39% vs 29%), and BRAF (41% vs 31%) (Table). Annual NRAS and BRAF testing rates increased between 2016 - 2020 for both groups: NRAS rates increased from 13% to 41%, and 5% to 37%, for EO and LO pts, respectively; BRAF rates increased from 13% to 41%, and 5% to 40%, for EO and LO pts, respectively. KRAS testing rates held at a consistent rate over time for EO pts, and increased over time among LO mCC pts (35% - 52%). The positivity rates for KRAS, NRAS and BRAF mutations were similar among tested pts in both groups. Conclusions: In this real world analysis, pts with EO mCC were more likely to have left sided primary cancers, and less likely to have a smoking history. Of note, BRAF testing showed a marked increase over time among all mCC pts. EO pts were more likely to receive KRAS, NRAS and BRAF testing. Further understanding of the correlates of EO mCC, biomarker testing practices, and subsequent treatment decisions is critical to improving pt outcomes.[Table: see text]
Homologous recombination deficiency is linked to shorter survival expectancy in late-stage colorectal cancer.
Authors: Li Jianxia , Zhang Jianwei , Dai Dandan , Hu Huabin , Cai Yue , Ling Jiayu , Zhang Xuan , Deng Yanhong
Published: June 2022

e15576

Background: Colorectal cancer patients with high-level microsatellite instability (MSI-H) benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers to predict their prognosis. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients’ overall survival. Methods: We used whole-exome sequencing (WES) to analyze 99 colorectal cancer samples. The patients were further classified into different groups based on their microsatellite status (MS), homologous recombination deficiency (HRD) score, as well as other clinical characteristics, which might associate with clinical outcomes. Afterward, survival analysis and stratification analysis were performed to explore the significant prognosis and predictive indicators in each group. Additionally, we assessed somatic genomic lesions, copy number aberrations, and mutational pathway, and analyzed the differential genetic patterns in distinct clinical benefit groups. Results: The multivariate Cox regression analysis proved that HRD score was associated with significant OS (HR 0.19, 95% CI 0.12-0.94, p = 0.002), suggesting HRD are prognostic factors for late stage CRC. Therefore, the patients were classified into two subgroups according to the value of the HRD scores (HRD-high vs HRD-low). For comparison, the prominent difference was observed in the somatic mutations and copy number alterations (SCNAs). Our results showed TP53 (78%) , APC (50%) and KRAS (41%) as the most frequently cancer-related mutations in CRC, consistent with previous studies. In patients with MSS group, the SMAD4 mutation was occurred frequently (p < 0.01), as well as a distinctive pattern of chromosomal amplification in HRD-high group patients. However, in patients with MSI group, none significant mutations were observed in HRD-high and HRD-low groups. Conclusions: We integrated HRD statue as prognosis and predictive factors for late stage CRC as determined using WES sequencing. Moreover, we also provide a comprehensive differential genetic pattern in stratification of CRC patients, as well as underscore an importance of combining strategy for molecular diagnosis of CRC.
Anti-PD-1 antibody plus regorafenib in refractory microsatellite stable metastatic colorectal cancer: A retrospective study.
Authors: Li Rongrong , Liu Zhenyang , Yin Xianli , Zeng Deyu , Jiang Shaofeng , Wu Liu
Published: June 2022

e15582

Background: To investigate the efficacy and safety of anti-PD-1 antibody plus regorafenib in refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Methods: We retrospectively analyzed the efficacy and safety of 103 MSS mCRC patients treated with anti -PD-1 antibodies(including nivolumab, pembrolizumab, camrelizumab, sintilimab, and toripalimab) combined with regorafenib(80 mg once daily for 21 days on/7 days off)between July 2019 and June 2021 in Hunan Cancer Hospital. Results: 103 patients had received at least one dose of regorafenib plus anti -PD-1 antibody. Due to COVID-19 pandemics, economic or other reasons, 48 patients (46.6%) did not return to hospital for second cycle of combination treatment .With a median follow-up of 5.30 months (range 0.50-22.50), the median overall survival (mOS) and progression-free survival (mPFS) were 8.40 months (95%CI:6.40-12.70) and 2.50 months (95%CI:2.27-3.47) in the entire cohort, respectively. The mOS and mPFS were significantly longer in patients who received more than 1 cycle (n = 55, 53.4%) compared to those who received just 1 cycle(n = 48, 46.6%). (16.07 vs. 4.37 months, HR 0.21; 95%CI:[0.12-0.38]； P﹤0.001; 3.10 vs. 1.11 months, HR 0.12; 95%CI: [0.05-0.31];P﹤0.001). Further analyses revealed that sintilimab (n = 66, 64.1%) significantly improved mPFS from 1.61 months to 3.30 months, compared to other anti-PD-1 antibodies (n = 37, 35.9%) (HR 0.55; 95%CI:[0.31-0.99];P = 0.044). Cox multivariate regression analysis demonstrated that cycles of regorafenib plus PD-1 was a significant independent risk factor for the OS and PFS( P0.001).Patients who had previously undergone surgery were better than those who had not ( P= 0.029).Sintilimab plus regorafenib had a better PFS benefit( P= 0.044.)Seven patients were diagnosed as partial response and another 16 cases were diagnosed as stable disease in the 55 patients who were evaluated, but no complete response. Thus the objective response rate was 12.7% and the disease control rate was 41.8%.Treatment-related adverse events of grade 3 or higher occurred in 13 (12.6%) patients. Conclusions: The combination of regorafenib plus anti-PD-1 antibody had a manageable safety profile and promising efficacy in MSS mCRC patients, especially in patients who received more than one cycle. Compared with the other anti-PD-1 antibodies, sintilimab may have more encouraging efficacy, which needs further prospective studies.[Table: see text]
Covid-death mean-imputation (CoDMI) algorithm and survival analysis: First clinical application in rectal cancer.
Authors: De Felice Francesca , Mazzoni Luca , Musio Daniela , Tombolini Vincenzo , Moriconi Franco
Published: June 2022

e15592

Background: We illustrate a clinical application of Covid-Death Mean-Imputation (CoDMI) algorithm in survival analysis. CoDMI algorithm is a new statistical tool that allows to adjust, through mean imputation based on the Kaplan-Meier model, Covid-19 death events in oncologic clinical trials, providing a complete sample of observations to which any statistical method in survival analysis can be applied. Methods: We analyzed a group of patients who received trimodal treatment – neoadjuvant chemoradiotherapy, followed by surgery and adjuvant chemotherapy – for primary locally advanced rectal cancer (LARC). Overall survival (OS) was calculated in months from the date of diagnosis to the first event, including date of last follow-up or death. Because Covid-19 death events potentially bias survival estimation, to eliminate skewed data due to Covid-19 death events the observed lifetime of Covid-19 cases was replaced by its corresponding expected lifetime in absence of the Covid-19 event using CoDMI algorithm. In a traditional Kaplan-Meier approach, patient died of Covid-19 (DoC) can be: i) excluded to the cohort; ii) counted as censored (Cen); iii) considered as died of disease (DoD). CoDMI algorithm offers an additional, more satisfactory option: iv) DoC events are mean-imputed as no-DoC cases at later follow-up times. With this approach, the observed lifetime of each DoC patient is considered as an “incomplete data” and is extended by an additional expected lifetime computed using the classical Kaplan-Meyer model. Results: In total 94 patient records were collected. At the time of the analysis, there were 16 DoD cases, 1 DoC patient and 77 Cen cases. The DoC patient died due to Covid-19 52 months after diagnosis. CoDMI algorithm computed the expected future lifetime (beyond the DoC time of occurrence) provided by the Kaplan-Meier estimator applied to the no-DoC observations as well as to the DoC data itself. Given the DoC event at 52 months, CoDMI algorithm (applied in its standard form: DoC as virtual DoD) estimated that this patient would be died after 79.5 months of follow-up. Table summarizes the 2-year OS and the 5-year OS rates for the different treatment of DoC event. Since our sample contains only one DoC case, the effects on the estimates of the options considered differ very little. In this situation, however, one can better understand how CoDMI algorithm works. Conclusions: CoDMI algorithm leads to the “unbiased” (appropriately adjusted) OS probability in LARC patients with Covid-19 infection, compared with that provided by a naïve application of the Kaplan-Meier approach. This allows a proper interpretation of Covid-19 events in survival analysis. A user-friendly version of CoDMI is available at https://github.com/alef-innovation/codmi.
Attitudes of physicians and patients toward the timing of adjuvant treatment in colon cancer.
Authors: Jafari Mehraneh D. , Brouwer Julianna , Mesiti Andrea , McKinney Chelsea , Wenzel Lari B. , Pigazzi Alessio , Zell Jason A.
Published: June 2022

e15596

Background: We have previously shown in a Phase I trial that administration of immediate adjuvant chemotherapy (IAC) at the time of surgical resection and immediately postoperatively is safe and feasible in colon cancer (CC) patients. IAC avoids delays in adjuvant treatment and has the potential to improve survival and quality of life. However, two fundamental questions must be answered: will patients be willing to accept the possibility of more severe side effects in exchange for earlier treatment (Tx) completion and theoretically better survival? And will physicians depart from established CC treatment practices?. Methods: A web-based survey was administered to newly diagnosed CC patients (within 1 year of surgery) and survivors (> 1 year post op). A similar web-based survey was administered to surgeons and medical oncologists in academic and community settings across the country. Surveys assessed patients’ and providers’ treatment preferences, attitudes towards care, and perceived barriers to IAC. Descriptive statistics were conducted including chi-square tests to compare differences between patients’ and providers’ responses. Results: Responses were collected from 35 patients and 40 providers. Patient respondents were 48% survivors and 52% newly diagnosed CC patients. Among the providers, 60% of the medical oncologists and 75% of the surgeons worked at academic medical centers. Compared to providers, patients were more willing to: 1) proceed with IAC to finish treatment earlier thereby improving quality of life (p = 0.002); 2) proceed with IAC to finish treatment earlier, despite potential side effects (p < 0.001); and 3) proceed with a single dose of intraoperative chemotherapy that, based on final pathologic stage, may not be needed (p = 0.002). Patients were also more likely than providers to indicate that there are no barriers to collaborative care (p = 0.001) while providers were more likely to cite that collaborative care is time consuming (p = 0.001), comes with scheduling challenges (p = 0.001), and that physicians are not readily available to participate in it (p = 0.003). Conclusions: We observed a disconnect between what providers and patients value in the perioperative and adjuvant colon cancer treatment course. Colon cancer patients are willing to accept intraoperative chemotherapy and early adjuvant chemotherapy via this novel multidisciplinary approach even if this treatment were associated with additional side effects, and without promise of a survival benefit.[Table: see text]
Interim analysis of neoadjuvant chemoradiotherapy with sequential ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.
Authors: Laengle Johannes , Kuehrer Irene , Pils Dietmar , Stift Anton , Teleky Bela , Herbst Friedrich , Dauser Bernhard , Monschein Matthias , Razek Peter , Haegele Stefanie , Hulla Wolfgang , Biebl Matthias , Geinitz Hans , Petzer Andreas L. , Bitterman Clemens , Laengle Friedrich , Tamandl Dietmar , Widder Joachim , Schmid Rainer , Bergmann Michael
Published: June 2022

e15604

Background: Immune checkpoint inhibitors (ICI) do not seem to be effective in solid cancers, which lack an immunogenic priming. Radiotherapy (RT) can induce an immunogenic cell death (ICD) and thereby restore the susceptibility to ICI, especially in microsatellite stable (MSS) cancers. This study evaluates safety, tolerability and feasibility of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in locally advanced rectal cancer (LARC). Here we present the first requisite interim analysis. Methods: This is a prospective, randomized, open-label, multicenter, phase II investigator- initiated trial (IIT). Key eligibility criteria are patients with LARC and the medical need for a neoadjuvant CRT, without metastatic disease that is considered incurable by local therapies. In total 80 patients will be randomized (ratio 30:50) to receive either neoadjuvant CRT alone (50 Gy in 2 Gy fractions over 25 working days + concurrent capecitabine 1650 mg/m2/d PO) or in combination with a single dose of IPI 1 mg/kg IV at day 7, following 3 cycles of NIVO 3 mg/kg IV Q2W, starting on day 14. Patients undergo surgery within 10-12 weeks post CRT. The primary endpoint is safety of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Surgical complications are graded by the “Clavien-Dindo Classification” v2.0 and treatment-related adverse events (TRAEs) by the Common Terminology Criteria of Adverse Events (CTCAE) v5.0. Interim analyses for the surgical complication “reoperation” will be assessed after every 10th patient in the IPI/NIVO treatment arm. Reoperation numbers are compared to historically known and published ratios. If the observed case numbers are above the calculated upper 95% confidence interval (95% CIup), the study will be terminated. Results: From 06/2020-02/2022, 36 patients have been accrued, of whom 23 were randomized to the CRT+IPI/NIVO arm. Of these, the first 10 patients who underwent successful surgery were used for the present interim analysis. No patient experienced a surgical complication with the need for a reoperation (3Grade IIIb). Any surgical complication occurred in 8 (80%) patients, with the most common being Grade I (70%) and Grade II (50%) events. Conclusions: The addition of sequentially applied IPI and NIVO to neoadjuvant CRT does not increase the number of surgical reoperation rates. The study meets it’s interim analysis criteria to be safe to continue accrual. Clinical trial information: NCT04124601.
Lenvatinib plus hepatic arterial infusion of modified FOLFOX regime(FOHAIC) in patients with BCLC stage C hepatocellular carcinoma.
Authors: Mai Qicong , Shi Feng , Chen Xiaoming
Published: June 2022

e16000

Background: Lenvatinib is the first-line TKI treatment for BCLC stage C hepatocellular carcinoma (HCC) with better objective response rate (ORR) and longer progression free survival (PFS) than sorafenib, but the prognosis is still unsatisfactory. Hepatic arterial infusion chemotherapy of modified FOLFOX regime (FOHAIC) has shown promising results for patients with advanced HCC. This study aimed to update the result of efficacy and safety for lenvatinib plus FOHAIC in patients with BCLC stage C hepatocellular carcinoma. Methods: This was a retrospective study including 46 patients from Nov 2018 to April 2021 Patients with BCLC stage C hepatocellular carcinoma. Patients were treated with 8 mg(≤60kg) or 12mg(> 60kg) lenvatinib once daily initially and FOHAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). Best response according to the RECIST 1.1 and mRECIST criteria. PFS, overall survival (OS) and treatment-related adverse events(TRAE) were also evaluated. Results: 46 patients(median age: 54.9 years) underwent a total of 223 cycles of HAIC therapy (mean: 4.8 cycles). 43 (93.5%) patients with HBV infection.35(76.1%). Patients were diagnosed with vascular invasion. 45 (97.8%) patients were classified as Child-pugh A class and 1 (2.2%) patients were Child-pugh B class. The ORR were 58.7% (RECIST 1.1, 27 of 46) and 76.1% (mRECIST, 35 of 46), the disease control rate (DCR) was 93.5% (RECIST 1.1/mRECIST). With a median follow-up period of 14.9 months, the median PFS and median OS were 15.9 months and 27.9 months, respectively.TRAE occurred in 36 of 46 patients (78.3%), most common TRAE were hypertension (41.3%), diarrhea (34.8%), fatigue(34.8%), abdominal pain(32.6%), hand-foot skin reaction(23.9%),and weight loss(19.6%). The grade 3/4 TRAE were more frequent in abdominal pain(8.7%), hypertension (6.5%) and diarrhea(6.5%). Conclusions: This study demonstrated that lenvatinib plus FOHAIC had acceptable toxic effects and shown promising ORR, PFS and OS in BCLC stage C hepatocellular carcinoma. Warrants its further investigation in a large-scale trial.[Table: see text]
Deciphering genomic characteristics of ERBB family members potentially involved in the recovery of anti-cancer immunity for intrahepatic cholangiocarcinoma patients.
Authors: Zhang Wei , Xu Zanmei , Zhang Zewu , Song Tianqiang , Pang Fei
Published: June 2022

e16003

Background: Previous studies showed that the efficacy of immune checkpoint inhibitor (ICI) is enhanced in hepatobiliary cancers harboring activating gene alterations of ERBB family members. The purpose of this study was to explore genomic characteristics of ERBB family members as well as the relationship of them with the activity of anti-cancer immunity in Chinese intrahepatic cholangiocarcinoma (ICC) patients. Methods: Fifty-four ICC patients which carried at least one gene mutation of ERBB family members were pre-selected from 508 ICC patients included in the China Pan-cancer project of OrigiMed 2020 (https://www.cbioportal.org/study/summary?id=pan_origimed_2020). Targeted sequencing was implemented with cancer-related 450-gene panel. Tumor mutation burden (TMB) and microsatellite status were evaluated. To explore the molecular mechanisms, two human cholangiocarcinoma cell lines, RBE and HuCCT1, were transfected with a lentivirus to obtain the cells with stable S310F mutation and overexpression of ERBB2. Results: The variation frequencies of EGFR, ERBB2, ERBB3 and ERBB4 were 2.8% (14/508), 3.5% (18/508), 3.3% (17/508) and 2.4% (12/508) in Chinese ICC patients, respectively. All the patients harboring ERBB family gene mutations were classified as TMB-H (cutoff = 10 Muts/Mb), when co-mutated with ACVR2A or TGFBR2. Moreover, ACVR2A and TGFBR2 were identified as driver genes in the cohort with oncodriveCLUST. TMB and the proportion of MSI-H patients were significantly elevated when ERBB family members co-mutated with ACVR2A (mutation vs wild: TMB, 38.2 ± 19.1 vs 7.0 ± 8.6 Muts/Mb, p<0.0001; MSI-H, 77.8% vs 4.9%, p<0.0001), or with TGFBR2 (TMB, 33.1 ± 8.7 vs 9.0 ± 14.4 Muts/Mb, p<0.0001; MSI-H, 83.3% vs 9.1%, p<0.001). Besides, ACVR2A and TGFBR2 were enriched in TGF-β pathway. Flow cytometry analysis revealed that ERBB2 S310F mutation and amplification were increased by approximate 3-fold and 3.5-fold in PD-L1 expression of cell line RBE ( p < 0.0001, respectively); by approximate 2-fold and 3-fold upregulation of PD-L1 expression in cell line HUCCT1 ( p < 0.0001, respectively). Western-blot results suggested that ERBB2 mutation/overexpression mediated PD-L1 upregulation through the RAS/ERK/c-JUN pathway. T cell cytotoxicity-mediated killing assay demonstrated that ERBB2 S310F mutation and overexpression induced the recovery of anti-cancer immunity by about 30% ( p < 0.05) both in RBE and HuCCT1 cells. Conclusions: The present study revealed two distinct genomic characteristics potentially involved in the recovery of anti-cancer immunity of intrahepatic cholangiocarcinoma patients: on one hand, co-mutation of ERBB family genes with ACVR2A or TGFBR2 was enriched in TGF-β pathway, contributing to MSI-H/TMB-H; on the other hand, ERBB2 might impact expression of PD-L1 by regulating the RAS/ERK/c-Jun pathways.
Assessment of effectiveness of neoadjuvant chemotherapy in patients with resectable gastric cancer.
Authors: Patsko Veronika , Lukashenko Andrii , Ostapenko Yuriy
Published: June 2022

e16006

Background: Despite a sharp decrease in gastric cancer (GC) incidence, it remains one of the most common cancers in Ukraine as well as the whole world. According to big data from randomized trials that was analyzed, neoadjuvant chemotherapy (CT) was one of the most effective options. This study was performed to assess the effectiveness and safety of neoadjuvant chemotherapy among patients with resectable gastric cancer. Methods: 73 patients with resectable gastric cancers were randomized in two groups: group A (n = 38) who underwent neoadjuvant chemotherapy (with FLOT scheme) followed by planned surgery and group B (n = 35) for whom only surgery was performed. Data was collected in the clinic of National Cancer Institute from 2011 to 2017. Primary endpoints were overall survival (OS), progression free survival (PFS) and biological marker evaluation. Results: Molecular marked VEGFR-1 was found to correlate with cancer tumor cells sensitivity to chemotherapy. There was no significant difference in 5-year OS (55.2% in group A and 57.1% in group B respectively, p = 0.18). There was also no significant difference in PFS between two groups (32.6 month vs 33.1 month respectively). Conclusions: this study showed that there is no significant difference for OS and PFS in patients with resectable gastric cancer whether they received neoadjuvant CT or not. But it was found that there molecular markers such as VEGFR-1 could be used as a predictors for tumor response on systemic treatment. Determination of sensitivity to neoadjuvant CT helps to avoid useless toxicity and offers reducing the overall cost of treatment.
Neoadjuvant pembrolizumab plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): Interim results.
Authors: Wang Weiwei , He Jia , Wu Xi , Zhou Weixun , Zhao Luo , Li Li
Published: June 2022

e16011

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in China. Its prognosis remains poor and neoadjuvant treatment may improve the prognosis for resectable ESCC. The combination of immunotherapy with cytotoxic agents has shown encouraging antitumor activity in multiple tumors but data are lacking to support this approach as a neoadjuvant strategy for locally advanced ESCC. We conducted a prospective clinical trial of pre-operative pembrolizumab with chemotherapy in patients with locally advanced ESCC. Methods: Patients with clinical stage IIB-IVA ESCC eligible for resectable surgery were prospectively enrolled. Patients received neoadjuvant pembrolizumab (200mg) and chemotherapy (docetaxel 75mg/m2 plus cisplatin 75mg/m2 or carboplatin area under curve 4-5) every 3 weeks for four cycles before surgery. The primary endpoint was pathologic complete response (pCR) rate and radical (R0) resection rate. Secondary endpoints include Disease Free Survival (DFS), adverse events, and the correlation between biomarkers and immunotherapy efficacy. Results: From August 2020 to January 2022, 27 eligible patients participated the study. Twenty-four patients have completed four cycles of neoadjuvant therapy, among whom 22 patients were radiologically evaluable after neoadjuvant therapy. The objective response rate (ORR) was 68.2% and disease control rate was 100%. Among 22 patients with resectable tumors, 14 patients underwent McKeown MIE and 5 patients are still waiting for the surgery. Three other patients who achieved partial response (PR) refused surgery due to fear of complications. For 14 patients who underwent esophagectomy within 29-74 (median44) days after neoadjuvant treatment, all achieved radical resection. pCR (ypT0N0) was observed in 4 patients (4/14, 28.6%). Three patients (3/14,21.4%) had a College of American Pathologists (CAP) score of 1, one (1/14, 7.1%) had a CAP of 2, and 6 (6/14, 42.9%) had a CAP of 3. Most treatment-related AEs (TRAEs) were grade 1 or 2. Grade 3/4 TRAEs of leucopenia, decreased neutrophil count and dermatitis occurred in 9 (33.3%), 14 (51.9%), and 1 (3.7%) cases, respectively. No surgical complication was observed. Conclusions: Neoadjuvant pembrolizumab plus chemotherapy has achieved satisfactory initial efficacy and safety results in locally advanced ESCC. A phase III randomized controlled trial is required to confirm the clinical benefits of this neoadjuvant therapy.
Encouraging efficacy of sintilimab combined with nanoparticle albumin-bound paclitaxel and platinum as the first-line treatment for metastatic esophageal squamous cell carcinoma: A retrospective study.
Authors: Wang Chao-Jie , Feng Jiang-Shan , Zhao Wei-Feng
Published: June 2022

e16013

Background: Esophageal squamous cell carcinoma (ESCC) is one of the common malignancies worldwide and associated with poor prognosis. More recently, immunotherapy, especially monoclonal antibodies of programmed death receptor 1 (PD-1) and its ligand (PD-L1), has provided new treatment options for patients with various tumors. But there was no study to investigate the efficacy and safety of sintilimab combined with nanoparticle albumin-bound paclitaxel (Nab-PTX) and platinum as the first line treatment of metastatic ESCC. Methods: This was a retrospective study, the eligible metastatic ESCC patients were given sintilimab in combination with Nab-PTX and cisplatin or nedaplatin for up to 4-6 cycles (every 3 weeks). After immunochemtherapy, patients without progressive disease (PD) continued to receive sintilimab every three weeks as maintenance treatment until unacceptable toxicity, PD, withdrawal of consent, or for up to 2 years. The primary end point was objective response rate (ORR), the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 22 patients diagnosed as metastatic ESCC were enrolled, one patient reached a complete response (CR), 15 patients reached a partial response (PR), 4 patients stable disease (SD) and 2 patients PD. The ORR was 72.7% (16/22), the DCR was 90.9% (20/22). The time to response (TTR) was 1.9 months (95% CI:1.7-2.2 months). The median PFS was 7.0 months (95% CI, 6.0-9.3 month), median OS was not reached (6.5 months to not reached). Treatment related adverse events (AEs) occurred in 21 patients (95.5%), and most of them were grade 1 and 2. AEs of grade 3 or 4 occurred in 10 (45.5%) patients, there was no treatment-related death in this study. Conclusions: The preliminary results of this study suggest that sintilimab combine with Nab-PTX and platinum for patients with metastatic ESCC had significant high ORR and encouraging median PFS, and the safety profile is manageable. Clinical trial information: ChiCTR2100051909.
APEC: Efficacy and toxicity of anlotinib plus PD-1 inhibitors as later-line therapy in advanced/metastatic esophageal squamous cell carcinoma (ESCC): A retrospective real-world study.
Authors: Liu Jun , Ma Xiumei , Wu Jianguo , Zhang Ming , Li Hongxuan , Cheng Yan , Fu Xiaolong
Published: June 2022

e16014

Background: Anlotinib has been approved in ESCC treatment because of its good tolerance and efficacy. Antiangiogenic target therapy plus immunotherapy has been initially recognized, whereas the data on the third & above line is still unknown. We aimed to retrospectively analyze the effect of anlotinib plus PD-1 inhibitor as later-line therapy on the survival of ESCC in the real world. (APEC, NCT 04984096). Methods: Retrospective data analysis was performed on ESCC patients (pts) treated with anlotinib plus PD-1 inhibitors as later-line therapy between Sep 2019 and Nov 2021 at Shanghai Chest Hospital, China. Demography, previous treatment, performance status, pathological classification, comorbidities, and distant metastatic organ status were collected. Progression free survival (PFS) was the primary end point of this study. The secondary end points were objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Tumor response was assessed per RECIST version 1.1 by the investigators. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results: There were 21 pts in the cohort. The average age was 61.5 (range 48-77) years old, and 95.2% patients were male. 7 cases (33.3%) had comorbidities. 2 cases (9.5%) had other tumor history. In addition, 19 pts (90.5%) had received radiotherapy, 21 pts (100.0%) had received chemotherapy and 19 pts (90.5%) had received immunotherapy. Among all pts, 1 patient achieved complete response (CR), 6 pts partial response (PR), 10 pts stable disease (SD), illustrating an ORR of 33.3 % and a DCR of 81.0%. Median PFS reached 8.1 months (95%CI 3.8-12.4) while median OS was not reached. All grades of TRAEs occurred in 95.2% pts and 90.5% were grade 1-2. Of note, grade 3-4 hematological toxicity (lymphocytopenia) was reported in only 2 patient (9.5%). All AEs were resolved after symptomatic treatment. Conclusions: Our data suggest that treatment with anlotinib plus PD-1 inhibitors as later-line therapy can result in curative effect of ESCC, which can achieve promising ORR, DCR and PFS with mild toxicity. To our knowledge, this is the first analysis to demonstrate the benefits of anlotinib plus PD-1 inhibitors as later-line therapy in ESCC. The data suggests that anlotinib plus PD-1 inhibitor is a new treatment in ESCC pts, and further validation in a larger cohort is needed. Clinical trial information: 04984096.
Serological markers associated with response and adverse events in patients of esophageal squamous carcinoma with toripalimab combined with nab-paclitaxel and S-1 as neoadjuvant therapy.
Authors: Zhang Guoqing , Yuan Jing , Xu Qing , Zhang Jing , Liu Minglu , Song Zhigang , Wu Liang Liang , Yang Bo , Hu Yi , Jiao Shunchang , Luo Haitao , Cui Xiaoli , Pan Chaohu
Published: June 2022

e16017

Background: Immune checkpoint inhibitor (ICI) combined with chemotherapy as a neoadjuvant therapy has been applied to the treatment of patients with esophageal squamous carcinoma (ESCC), however, there were a limited number of predictive biomarkers for response and adverse events. Methods: 60 patients diagnosed with ESCC and considered propable for surgical treatment were enrolled from October 2019 to September 2020 in the first medical center of Chinese PLA General Hospital and received Toripalimab combined with nab-Paclitaxel and S-1 as neoadjuvant therapy. Serum samples were collected at baseline and performed with 92 proteins using proximity extension assay technology. Results: In total, 50 patients were examined, and 3 patients did not pass quality control. Patients with IFN-Y-L, LAMP3-L and Gal.1-H at baseline were associated with longer overall survival. Furthermore, 21 proteins were found to be significantly lower in patients with severe side effects than in patients without serious adverse events. Conclusions: Our study found that serum levels of several proteins were associated with clinical benefit and severe side effects, and these proteins may be useful biomarkers for predicting response and severe side effects in ESCC treated with ICI and chemotherapy.
The advent of anti-PDL-1 antibodies in the treatment of advanced gastric carcinomas: A systematic review.
Authors: Vorla Mounica , Akbar Usman Ali , Ashraf Aqsa , Pusa Mounika , Barham Saman , Khan Adil , Sheikh Daniya , Dab Ammar Yaser , Qazi Shaheryar , Chaughtai Zeeshan , Anwer Faiz
Published: June 2022

e16020

Background: The poor prognosis of systemic chemotherapy in advanced gastric adenocarcinoma (GC) and gastroesophageal (GE) carcinoma prompted the development of novel agents such as anti-PDL-1 antibodies, which have the potential to overcome drug resistance due to signaling pathway overlap. We study here the safety and efficacy of standalone and combination chemo-immunotherapy in the treatment of advanced GC & GE Carcinomas. Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase & clinicaltrials.gov. A total of 300 articles were screened, and 7 studies were included. Results: With anti-PDL-1 inhibitors in phase III clinical trial, the overall survival (OS) was more remarkable in Chemotherapy (CTX) vs. Avelumab (AVE) (5 vs 4.6 mo). However, Nivolumab (NIVO 1mg and NIVO 3mg) significantly prolonged the OS when combined with Ipilimumab (IPI), but the grade > 3 adverse events were reported more in NIVO1 and NIVO3 regimen. Similarly, Pembrolizumab (P) increased both OS and progression-free survival (PFS) when used alone and as combination therapy compared to chemotherapy alone, as illustrated in the table. Conclusions: The anti-PDL-1 inhibitors show promising data to treat advanced or relapsed GC or GE Carcinomas with favorable side effect profiles. However, there is further need for high-quality large prospective randomized clinical trials.[Table: see text]
Intratumoral CD8+ t cell as a potential positive predictor for treatment of chemo-immunotherapy in PD-L1 negative advanced gastric cancer patients.
Authors: Tong Gangling , Zhu Meiqin , Chen Yaoxu , Wang Shubo , Cheng Boran , Wang Shubin , Liao Wangjun
Published: June 2022

e16029

Background: It was demonstrated that CPS PDL1 positive patients of advanced gastric cancer (GC) could benefit from specific immune checkpoint inhibitors (ICI) for first-line, and second-line or subsequent therapy. However, whether the application of ICI could lead to better clinical outcome in advanced GC patients who were negative for PDL1 remains further explore. Some studies showed that patients with specific tumor immune microenvironment (TME) are more sensitive to immunotherapy. Therefore, TME may be a potential positive predictor for PDL1 negative patients treated with immunotherapy. Methods: We retrospectively enrolled 26 advanced GC patients who were treated by chemoimmunotherapy in Shenzhen Hospital of Peking University and evaluated for clinical characteristics. Peritumoral and intratumoral Tumour-infiltrating lymphocytes (TIL) were detected by mIHC (multiplex immunofluorescence) among these patients. The correlation between PFS and clinical characteristics including TIL was analyzed by univariate survival analysis and multivariate Cox proportional hazards analysis. Results: In 26 patients, 5 patients (19.2%) experienced complete response (CR), 9 patients (34.6%) experienced partial response (PR), while 7 patients (26.9%) experienced stable disease (SD). Compared with non-responders, higher intratumoral infiltrating CD8+ T cells instead of other subtypes were detected in CPS PDL1 negative Patients who respond to chemoimmunotherapy. Further analysis revealed that CD8+ TIL was a predictive biomarker for PFS to chemo-immunotherapy in CPS PDL1 negative patients. Conclusions: For CPS PDL1 negative advanced GC patients, intratumoral CD8+ TIL may be a potential positive predictor for treatment of chemo-immunotherapy.
Cambrelizumab plus chemotherapy as conversion therapy for unresectable metastatic gastric cancer: A single-arm, multicenter, prospective clinical trial.
Authors: Li Shuang , He Liang , Li Meng , Wang Quan
Published: June 2022

e16032

Background: Although anti-PD-1 antibody in combination with chemotherapy has shown promising antitumor activity in advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), the evidence of conversion therapy for initially unresectable GC/GEJC is limited. Camrelizumab combined chemotherapy as conversion therapy for unresectable GC/GEJC was a prospective, single-arm, phase 2 study we conducted. Here, we updated the results of efficacy and safety of this study. Methods: Patients with HER-2 negative and PD-L1+ (CPS≥1) or MSI-H/dMMR, or EBV (+) unresectable gastric cancer were enrolled. Eligible patients must meet one of the following criteria: 1) peritoneal metastasis (CY1P0 or P1a, P1b or PCI < = 10); 2) liver metastasis (H1), < 3 metastatic sites; 3) para-aortic lymph node metastasis. For patients with lymph node metastasis or liver metastasis, they received 6 cycles of camrelizumab (200mg ivgtt on day1, q3w) plus SOX (Oxaliplatin, 130mg/m² ivgtt, d1, q3w, S-1 40/50/60 mg based on BSA, po, bid, d1-14, q3w) as conversion therapy. For patients with peritoneal metastasis, they received 6 cycles of camrelizumab (200mg ivgtt on day1, q3w) plus IP (Paclitaxel, 50mg/m², ivgtt, d1, d8, q3w. Paclitaxel, 20mg/m², intraperitoneal administration, d1, d8, q3w. S-1 40/50/60 mg based on BSA, po, bid, d1-14, q3w) as conversion therapy. Then patients without disease progression evaluated by imaging underwent gastrectomy of D2 lymph node dissection. The primary endpoint was R0 resection rate and 2 years survival rate, the secondary endpoints were objective response rate (ORR), pathological complete response (pCR) rate and overall survival. Results: Between December 30, 2020 and January 5, 2022, 31 patients were enrolled. 19 patients received SOX plus camrelizumab, 12 patients received IP plus camrelizumab. Unfortunately, 7 of them were confirmed PD by imaging. In addition, two patients refused gastrectomy and withdrew from the study. 12 patients underwent gastrectomy and 8 patients are in the process of conversion therapy. Among the 12 patients were evaluable, 9 of them gained R0 resection (75%), 1 patient (8.3%) achieved pCR and 2 patient (16.6%) reached TRG1. The most common grade 3 adverse events (AEs) were neutropenia (27.6%). No serious AEs resulted in termination of treatment or death. Conclusions: Camrelizumab combined with chemotherapy was an effective and safe conversion therapy strategy for patients with unresectable GC/GEJC. Furthermore, the analysis of biomarkers with clinical benefits is undergoing. Clinical trial information: NCT04694183.
Clinicopathological features, treatment outcome and survival of 115 cases of gastric adenocarcinoma with bone marrow metastasis and disseminated intravascular coagulation.
Authors: Xiao Jian , Cao Taiyuan , Du Ge , Zhai Xiaohui , Li Shanshan
Published: June 2022

e16035

Background: Bone marrow (BM) infiltration is a special subtype of bone metastasis in gastric cancer (GC) and frequently complicated with disseminated intravascular coagulation (DIC) and other hematological disorders, which constitute a critical but poorly defined clinical syndrome (GBD syndrome). At present, only case reports are available about this peculiar disease. This pooled analysis was to describe its detailed clinicopathological features and treatment outcome. Methods: Cases reported in medical literatures or treated in our hospital from 2000 to 2021 were systemically scrutinized. The inclusion criteria were: adenocarcinoma in gastroesophageal junction or stomach, carcinomatosis in BM, and overt DIC. Detailed clinical and pathological data were reviewed. Based on the chronological order of the diagnosis of GC, BM infiltration and DIC, GBD syndromes could be classified as synchronous and metachronous type. Descriptive statistics, chi-square test, Fisher's exact tests, and survival analysis were performed as appropriate. Results: 115 cases of GBD syndrome were identified. 91 (79.1%) were synchronous and 24 (20.9%) were metachronous. Female patients were more than half in the study (61, 53.1%). The median age of 51 (9-87) was relatively younger than that of normal GC. ECOG PS 3-4 were present in 67 (58.3%) cases. 109 (94.8%) had poorly differentiated adenocarcinoma. Her-2 overexpression were only seen in 8 (6.9%) cases and none were d-MMR. 88.3% (53 out of 60) cases treated in our hospital showed remarkable CKMB elevation which was not mentioned in previous reports. Abnormal level of LDH and ALP were seen in 91.2% and 64.3% cases. Totally, 82 patients received anticancer therapy. 70 (85.3%) went through the first DIC strike. 5-FU and docetaxel were the most applied agents. Patients treated with BSC only survived 14 days (2-61). After the remission of DIC, patients with synchronous and metachronous BD syndrome achieved 168 and 182 days of overall survival, respectively (p = 0.932). Conclusions: CKMB might be a distinctive marker for GBD syndrome. Active chemotherapy achieved numerous remissions of DIC and a considerable survival. Further translational research and prospective trial are urgently needed.
The mortality of venous thromboembolism in hospitalized patients with different gastrointestinal malignancies.
Authors: Fatima Zainab , Darweesh Mohammad , Alhabhbeh Ammar , Abdel-Razeq Nayef Hikmat , Manthri Sukesh , Young Mark
Published: June 2022

e16036

Background: Venous thromboembolism (VTE) is associated with significant morbidity and mortality in cancer patients. Our study compares the mortality in hospitalized VTE patients among the five most common Gastrointestinal (GI) malignancies which includes esophageal, gastric, pancreatic, colorectal, and hepatobiliary cancers. Methods: A retrospective study was conducted utilizing the Nationwide Inpatient Sample database (NIS) from 2016 to 2018. Patients with Venous thromboembolism (VTE) were identified using ICD 10 codes from all primary discharge diagnoses. Only deep venous thrombosis (DVT) and pulmonary embolism (PE) were considered. Patients with VTE were further divided into groups: esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, hepatobiliary cancer, and compared with patients who did not have these malignancies. Patients younger than 18 years of age or patients with missing age, gender or race were excluded. Among the hospitalized patients with VTE, we investigated the difference in mortality with different gastrointestinal malignancies. Adjusted odds ratio (OR) was calculated using multivariate regression analysis. Results: Among 751,834 patients discharged with a VTE diagnosis, 0.24% had esophageal cancer, 0.25% had gastric cancer, 0.93% had pancreatic cancer, 1.10% had colorectal cancer, 0.35% had hepatobiliary cancer, and the other 97.14% did not have these malignancies. The study shows that adults admitted to the hospitals for VTE have higher mortality when compared to patients who did not have GI malignancies, with esophageal cancer having the highest inpatient mortality with an OR of 2.66 (95% CI 1.78-3.94, P of 0.00). For the remaining GI cancers, gastric cancer had an OR of 1.74 (95% CI 1.141-2.661, P of 0.010), pancreatic cancer had an OR of 1.74 (95% CI 1.402-2.178 P of 0.000), hepatobiliary cancer had an OR of 1.67 (95% CI 1.144-2.439 P-value of 0.002) and colorectal cancer had OR of 1.18 (95% CI 0.930-1.517 P of 0.169), which was not statistically significant. Conclusions: Pancreatic and gastric cancers have a higher risk of VTE and frequently score high in validated VTE risk assessment tools such as the Khorana score. This study shows that VTE in hospitalized patients with esophageal cancer is associated with greater mortality. More research is needed to analyze the outcomes of VTE in cancer patients and to identify those who would benefit from thromboprophylaxis. Due to the nature of the NIS database, one of the study's limitations was the difficulty in identifying patients receiving DVT prophylaxis.