bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.