bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti PD-1 monoclonal antibody in patients with MSI-high and/or high tumor mutational burden for solid malignancies.
Authors: Guerra Veronica , Alwash Yasmin , Ocampo Marisol Lilian , Cusnir Mike
Published: June 2022

e15539

Background: High microsatellite instability (MSI-H) tumors have been associated with good responses to check-point inhibitors (CPI). With overall response rates (ORR) ranging between 36-46% among colorectal cancer (CRC) and other solid malignancies. Data regarding predictors of response and responses in non-CRC malignancies remains limited. We sought to evaluate the response to PD-1/PDL-1 CPI in patients with MSI-H and/or high TMB solid malignancies. Methods: Retrospective analysis of 16 patients (pts) who received 18 CPI-based therapies between October 2017 and February 2022. MSI-H and TMB status was assessed by CARIS, Guardant360 or INVITAE genetic testing. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included progression-free survival(PFS); overall survival (OS), and duration of overall response (DOR). Results: A total of 16 pts were included. The median age of 72 years (range 53-83), 44% were male and 75% Hispanic. 44% of pts had RCR and 50% were previously treated, and 50% were stage IV at diagnosis. The most common mutations were BRCA2 31%, PIK3cA 31%, KRAS 25%, and GNAS 25%. The majority of pts received single-agent CPI therapy (72%). After a median follow-up of 52 months, 11 pts continued to receive therapy, 2 pts completed treatment. 3 pts died from progression of the disease. 1 pts switched from single-agent pembrolizumab to nivolumab-ipilimumab combination followed by nivolumab maintenance due to disease progression. 15 pts were evaluable for response with an ORR of 33%, including 33% among pts with CRC and 27% for non-CRC malignancies. (Table - Response rates) The OS was not reached (NR), with a PFS of 53 months (PFS of 64% at 1 year and 56% at 4 years). The median DOR was not reached (NR). The treatment was well tolerated and pts received a median of cycles was 19 (range 3-51) with no discontinuations due to toxicities. The molecular mutations, clinical characteristics, type of malignancy, MSI-H, or H-TMB status were not significantly associated with response to CPI after logistical regression analysis. Conclusions: CPIs are an effective treatment option for patients with MSI-H and/or High TMB, with an ORR of 33%. However, pts achieved durable responses, with a median DOR not reached. We identify a higher incidence of SD rates among CRC pts (67% vs. 18% non-CRC). We did not identify any predictors associated with response to CPI, likely due to the small number of pts. However, there was a tendency to highest response rates among pts with MSI-H and high TMB.[Table: see text]
A multiple centers real-world study of regorafenib treatment modalities in Chinese metastatic colorectal cancer patients.
Authors: Li Xia Fen , Luo Huiyan , Wang Zhiqiang , Xiao Jian , Peng Jianjun , Wang Zi-xian , Zhai Xiaohui , Xu Rui-hua
Published: June 2022

e15543

Background: To evaluate the efficacy and safety of different treatment modalities of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) in the real-world setting. Methods: Individual patient data were retrieved from three leading oncology centers in China from January 2016 to March 2021. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The characteristics of patients who received treatment are shown in the table. Twenty-one patients received regorafenib combined with capecitabine as the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. The median PFS and median OS were 8 (95% CI 4.36 - 11.00) months and 26.9 (95%CI 20.54 -NR) months. 101 patients received regorafenib and 69 patients received regorafenib plus immune checkpoint inhibitor (ICIs) as third or higher line treatment, the overall response was 4.1%(7/170), including one complete response. Patients combined with ICIs have longer PFS than those with regorafenib monotherapy (median PFS = 3.3 versus 2.1 months; p = 0.01). Starting dose was 80、120 and 160 mg in 64、40 and 39 patients, respectively. Dose reduction was observed in 43.3% (39/79) of patients receiving 120 and 160 mg as the initial dose. Conclusions: Different treatment modalities of regorafenib all showed promising efficacy and safety in the treatment of mCRC. Regorafenib combination is better than regorafenib monotherapy. Regorafenib combined with capecitabine provided a new treatment strategy during the epidemic but requires further investigation. Key words:Colorectal cancer; Regorafenib; Immune check point inhibitors; Real world[Table: see text]
The efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer.
Authors: Li Rongrong , Liu Zhenyang , Yin Xianli , Zeng Deyu , Jiang Shaofeng , Liu Wu
Published: June 2022

e15546

Background: To explore the efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer (mCRC). Methods: We retrospectively evaluated the outcomes of the patients with mCRC who received at least one cycle of sintilimab plus regorafenib in the Hunan Cancer Hospital between July 2019 and June 2021. These patients had previously received at least two lines of standard chemotherapy including fluorouracil, oxaliplatin, and irinotecan with or without targeted drugs such as bevacizumab and cetuximab.The primary end point was overall survival (OS). Results: With a median follow-up of 6.00 months (range 0.70-22.47), the median overall survival (mOS) and progression-free survival (mPFS) were 9.00 months (95%CI: 5.00-NA) and 3.30 months (95%CI: 2.50-4.70).There was no significant difference in OS and PFS between patients with and without liver metastases,the mOS was 9.00 months 95%CI:[8.00-NA] vs 8.00months 95%CI:[5.00-NA]; P= 0.38, the mPFS was 3.87 months 95%CI:[3.10-13.70] vs 2.79 months 95%CI:[2.37-5.03]; P= 0.12.Cox multivariate regression analysis demonstrated that cycles of regorafenib plus PD-1 was a significant independent risk factor for the OS ( P0.001),and it was a positive factor that there was just one metastatic site ( P= 0.0038).Patients who had previously undergone surgery were better than those who had not ( P= 0.0470).Seven patients got partial response and another 9 patients got stable disease in the 35 patients who were evaluated, but no complete response. Thus the objective response rate(ORR) was 20.0% and the disease control rate(DCR) was 45.7%.The incidence of grade 3/4 adverse evevts was 10.6%. Conclusions: The combination of sintilimab plus regorafenib had a manageable safety profile and promising efficacy in refractory mCRC patients. This combined therapy needs further prospective studies to verify the outcomes.[Table: see text]
Intratumor heterogeneity of positive lymph nodes provide a promising prognostic stratification factor for stage III colorectal cancer.
Authors: Gao Xin , Zhang Qi , Yu Tao , Zhang Shiyao , Liu Jian , Liu Tong , Liu Gang
Published: June 2022

e15554

Background: Stage III colorectal cancer (CRC) is defined as patients with regional positive lymph nodes (pLN) but without distant metastasis, including stage IIIA, IIIB, IIIC. The prognosis of patients with stage III CRC varies dramatically, with 5-year survival rates ranging from 80 percent to 30 percent form stage IIIA to IIIC CRC, that does not exactly to be fully explained by the difference in the number of pLN. Therefore, other prognostic indicators need to be identified to improve and personalize prognosis prediction for patients with stage III CRC. Intratumor heterogeneity (ITH) widely exists between primary and metastatic lesions of CRC, however, there have been few studies focused on ITH of pLN. Therefore, this study aims to explore whether ITH of pLN could serve as a novel prognostic stratification factor for stage III CRC. Methods: We retrospectively analyzed the Poly-G genotype to reconstruct high-confidence phylogenetic trees for 20 CRC patients using 317 accurately scraped biopsy (134 primary tumors, 66 lymph node metastases and 37 normal samples). Root diversity score (RDS) index was used to reflect ITH of pLN. The association among Poly-G mutation rates, RDS index and clinical pathological data was analyzed. The area under the receiver operating characteristic (ROC) curves were calculated and the cut-off valve was confirmed. Results: Poly-G mutations accumulate in the occurrence and development of CRC. Poly-G mutation rate was correlated with tumor grade, N stage and microsatellite state (all P < 0.05), and had a certain correlation trend with age (P = 0.066). The results of multivariate Cox regression analysis showed that ITH of pLN was an independent risk factor for recurrence and metastasis which lead to a poor progression free survival (PFS). The area under the curve (AUC) was 76%, and the cut-off valve of RDS index was 0.25. We also found ITH of pLN was not associated with substages of stage III CRC, which indicated that ITH of pLN and the number of metastases are two different dimensions. Conclusions: ITH of pLN may provide a promising prognostic stratification factor for the patients with stage III CRC. A higher ITH of pLN indicates that subclones with distant metastasis potential might more likely to exist in the primary tumors, which lead to a poor PFS including recurrence and distant metastasis. In addition, ITH of pLN is not related to the number of lymph node metastases in stage III CRC, suggesting that ITH of pLN is promising to serve as a supplementary strategy of TNM staging for patients with Stage III CRC.
The effect of tumor purity on next generation sequencing of colorectal cancer.
Authors: Yu Tao , Zhao Xinyu , Guo Xianchao , Zhang Qi , Zhang Shiyao , Zhao Zhicheng , Liu Tong , Liu Gang
Published: June 2022

e15557

Background: Considerable advancements have been made in tumorigenesis, therapeutic target and diagnostic markers of colorectal cancer by next generation sequencing (NGS). However, almost tumor tissues contain the non-cancerous components, such as inflammatory cells and stromal cells. The DNA from these cells may cause the fraction of reads containing somatic mutations from tumor cell decreases. Therefore, it’s necessary to systematically clarify the relationship between tumor purity and NGS in colorectal cancer. Methods: Formalin fixed and paraffin embedded (FFPE) blocks were collected and cut into 20-40 8 um-thick sections used for genomic DNA extraction. Sections were evenly divided into two groups, purity group and non-purity group. In purity group, the sections were stained with Histogene (Life Technologies), a PCR-compatible tissue stain. And the tumor samples were accurately collected on the section under the microscope. No special treatment before sequencing in non-purity group. Next-generation sequencing (NGS) based on a 425-gene panel was performed in tumor samples and matched plasma samples. Results: 30 samples were included in this study. 687 non-synonymous mutations were found in purity group, 271 mutations were found in non-purity group, including 247 common mutations in both group, 440 purity-specific mutations (false negative mutations), and 24 non-purity-specific mutations (false positive mutations). The Variant allele fraction (VAF) of common mutations in purity group was significantly higher than that in non-purity group (Wilcoxon test: P< 0.05). The number of mutations in purity group was higher than that in non-purity group, but no significant difference between them (10.5[3, 154] vs 9[3-90], Wilcoxon test: P> 0.05). The false positive ratio (the number of false negative mutations/the number of common mutations) was negatively correlated with tumor purity (Spearman rank correlation test: r = 0.4280, P = 0.02596). When the tumor purity below 30%, 86% false negative mutations belong to high-frequency mutation (VAF > 10%) in purity group. Only 8% false negative mutations belong to high-frequency mutation when purity above 30%. The false positive ratio (the number of false positive mutations/the number of common mutations) wasn’t correlated with tumor purity (Spearman rank correlation test: r = 0.1387, P= 0.4648). Conclusions: Tumor purity is an importance role in precise NGS of colorectal cancer. Higher tumor purity can ensure the integrity of NGS.
Neutropenia as a predictor of efficacy in the treatment of metastatic colorectal cancer with TAS-102 (trifluridine - tipiracil).
Authors: Rodriguez Garcés Maria Yeray , Domínguez Senín Loreto , Amor Urbano María , Aviñó Tarazona Victoria
Published: June 2022

e15564

Background: TAS-102 (trifluridine - tipiracil) increases the survival of patients with metastatic colorectal cancer (mCRC) in 3rd or successive lines based on the results in overall survival (OS) of the phase 2 trial by Yoshino T et al and of the subsequent phase 3 RESOURCE and TERRA. It has a good toxicity profile, mainly at the gastrointestinal and hematological levels. Different publications relate neutropenia secondary to this drug with greater clinical benefit. Methods: Retrospective and multicenter observational study with patients diagnosed with mCRC treated with TAS-102 in the Juan Ramón Jiménez and General de Río Tinto hospitals (Huelva) between January 2016 and September 2021. We describe demographic data and other variables; subsequent Cox regression and multivariate analysis between OS and the different variables. We represent the OS median using Kaplan-Meier curves. Results: 47 patients were included. Median age 66 years; 66% men. No patient with ECOG > 2. Primary colon tumor in 55.4%; 72.3% with various metastatic locations. KRAS mutation in 63.8%. 78.8% in third line and the rest in fourth or successive. 80.9% have died. 82.9% abandoned due to progression and 8.5% due to toxicity: anemia 76.6% (grade ≥3 4.3%), neutropenia 74.5% (grade ≥3 44.7%), thrombocytopenia 10, 6% (grade ≥3 2.1%) and gastrointestinal 44.7% (grade ≥3 6.4%). The Kapplan Meier shows significant differences between the neutropenia curves 0 and grade 3-4 (median: 8 (95% CI 5.91-10.08) vs. 19 (95% CI 16.55-21.44) months; p = 0.043) and between the curves for grade 1-2 and grade 3-4 neutropenia (median: 8 (95% CI 2.9-13.09) vs. 19 (95% CI 16.55-21.44) months; p = 0.019). Cox regression identified grade 3-4 neutropenia and grade 1-2 anemia as positive predictors of OS. Multivariate analysis describes similar results (Table). Conclusions: Japanese series (Yohei Nose, et al; Katsuya Makihara, et al and T. Yoshino, et al) suggest a benefit in OS directly proportional to the degree of neutropenia found. In our study we obtain similar results, with better OS results for patients with grade 3-4 neutropenia. Therefore, we consider severe neutropenia as a possible predictor of the efficacy of TAS-102. Although our series is one of the largest published to date, we need more studies with a larger sample to obtain robust and enlightening results.[Table: see text]
Plasma methylated DNA markers detect recurrence and response to therapy in colorectal cancer.
Authors: Zhu Mojun , Taylor William R. , Mahoney Douglas W. , Then Sara S. , Berger Calise K. , Burger Kelli , Gonser Anna M. , Doering Karen A. , Foote Patrick H. , Kaiser Michael W. , Allawi Hatim T. , Hubbard Joleen M. , Kisiel John B.
Published: June 2022

e15567

Background: Radiographic surveillance of colorectal cancer (CRC) after therapy is costly and insensitive. We have reported high cross-sectional performance of methylated DNA markers (MDMs) for detection of primary CRC and metastatic recurrence. This study evaluated MDMs to detect recurrence and measure response to anti-cancer therapy in a longitudinal cohort. Methods: This was a nested case-control study drawn from a prospective cohort of adult patients with CRC who completed definitive treatment and followed forward from the start of surveillance by cross-sectional imaging (CT or MRI) and carcinoembryonic antigen (CEA), collected every 3-6 months under routine care. Blood was collected in LBgard® tubes (Biomatrica, San Diego CA). Cases had recurrent CRC (defined by RECIST v1.1 or radiographic findings that justify re-initiation of anti-cancer therapy as determined by treating clinicians). Controls remained NED (no radiographic recurrence and off therapy for ≥4 surveillance visits). From 6mL of plasma, MDMs ( CNNM1, ANKRD13B, FER1L4, ZNF568, CHST2, ZNF671, VAV3, QKI, GRIN2D, DTX1, PDGFD, SFMBT2, JAM3) were measured by target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Previously published random forest models of MDMs +/- CEA, developed on independent patients with intact primary tumors, were used to develop a summary score. Results: With a median follow-up of 276 days (IQR 187-343) and 3 visits per patient (54 visits total), 18 patients had recurrence after start of surveillance. Another 18 patients remained NED after median 555 days (IRQ 469-662) and 4 surveillance visits per patient (76 visits total). Using a 90th %-ile cut-off summary score from 60 NED patients in a prior cross-sectional measurement, the MDM panel was positive in 15 of 18 patients who recurred and only 2 of the 18 NED patients (Table). Of the 76 patient visits for NED patients, 67 (88%) were below the threshold. The MDM panel score crossed the positivity threshold by a median of 127 days (IRQ 0-233) preceding clinical or radiographic documentation of recurrence. A random forest model with CEA was more sensitive but less specific (Table). In patients who resumed therapy, the MDM panel scores correlated closely with subsequent RECIST scores (not shown). Conclusions: Plasma MDMs rise in anticipation of recurrent CRC prior to radiographic detection and remain low in patients without radiographic disease over serial measurements, warranting further development of this tumor-agnostic liquid biopsy approach as a cost-effective tool to assist cancer surveillance.[Table: see text]
Prognostic values of immune landscape in Ras-mutant colorectal cancer peritoneal metastases.
Authors: Yan Dong , Sun Lixin , Yang Jiandong , Zhang Xuyang , You Xia , Sun Tingting , Qi Chuang
Published: June 2022

e15583

Background: The peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor survival, especially in those with Ras mutations. However, knowledge on the mechanism of molecular biology in CRC peritoneal metastasis (CRCPM) is limited, and the impact of tumor immune microenvironment (TME) on PM pathogenesis and the prognosis of CRCPM remain unclear. Therefore, we characterized the TME of CRCPM and evaluated its potential diagnostic and prognostic values. Methods: This study involved 21 patients with metastatic CRC (mCRC), of whom 11 with CRCPM were classified into the experimental group and 10 with mCRC without PM (noCRCPM) were classified into the control group. Formalin-fixed and paraffin-embedded tissue of primary tumors from all patients was examined using the NanoString RNA sequencing system. The clinicopathological variables and TME biomarkers were compared using the chi-square test and Cox regression analysis. According to the results of multivariate analysis, a prognostic nomogram was generated, and its prediction ability was measured using the concordance index (C-index). Survival curves were generated using the Kaplan–Meier method, and survival comparison between groups was conducted using the log-rank test. Results: The TME in the CRCPM and noCRCPM groups was different, especially the expression of NOS2, TNSF9, KIR3DL2, MAGEA12, MRC1, KIR3DL1, and CD244 and the content of DC cells, macrophages, exhausted CD8+T cells, NK CD56dim cells, and M2 macrophages. Univariate analysis revealed that the expression of PTPN11, TIE1, MAGEA4, PDGFB, and PMS2 was significantly correlated with progression-free survival (PFS) time. These genes were subjected to the least absolute shrinkage and selection operator regression analysis and established a risk score model. Multiple Cox regression analysis showed that the risk score was a significant independent prognostic factor. However, considering the particularity of serum carcinoembryonic antigen (CEA), we built a combined model that included the CEA level and risk score. It could perform well in predicting the PFS time in patients with CRCPM (C-index 0.77). Conclusions: The TME of the primary lesion was significantly different between the CRCPM and noCRCPM groups. The model that combined the risk score and CEA level was a better outcome predictor among patients with CRCPM.
Analysis of demographic and staging characteristics in patients with colorectal cancer using the SEER registry.
Authors: Devanaboyina Monika , Bailey Morgan Marie , Kahlon Navkirat , Hamouda Danae M.
Published: June 2022

e15589

Background: Screening for colorectal cancer (CRC) has traditionally begun at age 50, with more recent guidelines suggesting beginning at age 45 to enhance earlier detection. Methods: Incidence data of CRC from the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 21 registry was utilized for this study. This study analyzed data from 2014-2018 with 95% confidence intervals for ages 50-64, 64-74, and 75+. Localized, regional and distant metastasis were coded according to the SEER database. Results: The incidence of CRC increased with age as individuals ages 75+ had the highest incidence at 211.8 per 100,000, compared to 70.7 for ages 50-64. In the age group of 75+, the incidence of localized CRC was 70.1 (95% CI: 69.2-71.0) and regional CRC was 69.2 (68.4-70.1) which was not statistically significant. Upon analyzing sex in CRC, female patients have a statistically lower chance of presenting with CRC at 59.5, 107.6, 192.1 for the age groups 50-64, 65-74, and 75+ respectively, whereas male counterparts have rates of 82.7, 152.9, and 240.2. Analysis of Asian females showed no difference in incidence of local and regional disease for ages 50-74. For ages 75+, the incidence of regional disease at 54.6 (51.3-58.1) was much higher than local disease at 45.3 (42.3- 48.5). Of note, Asian females aged 50-64, Hispanic females ages 65 and older, and Black and White females ages 75+ were equally likely to present with local or regional disease. White males had statistically significant higher odds of localized compared to regional cancer in all age groups. Further analysis shows that Asian males have an equal incidence of local and regional disease for ages 65 and above. Black males ages 75+ and Hispanic males ages 50+ had a similar incidence of local and regional CRC. Conclusions: Ensuring equitable access to screening and earlier screening may be beneficial and improve cancer-related mortality in certain demographics. A more modern data set should be analyzed to support these findings. This analysis was limited to incidence of CRC, and future studies assessing presentation at diagnosis could be insightful.[Table: see text]
COVID-19 infections among minority patients with gastrointestinal malignancies in urban safety net academic medical centers.
Authors: Gali Radhika , Viteri Malone Mariuxi Alexandra , Goel Sanjay
Published: June 2022

e15610

Background: COVID 19 infection has worse outcomes and is more severe among frail patients and with co-morbidities. Additionally, it was suggested by Mehta et al that gastrointestinal malignancies may have worse outcomes. Based off these findings, we have evaluated outcomes and potential predictors of these outcomes in patients with gastrointestinal malignancies and COVID 19 infection. Methods: We conducted a retrospective evaluation of 69 cases of patients between February 2020 to February 2021, that had both COVID 19 infection and a gastrointestinal malignancy, including: gastric, colon, pancreatic, biliary, and hepatic. We studied population general characteristics, most common tumors, oxygen requirements, management and death frequencies, at two urban safety net hospitals. Results: The median age of patients with gastrointestinal malignancies and COVID-19 infection was 68 (33 to 87), it was more frequently seen among males (N = 46, 67%); patients had on average 1-7 other comorbidities (N = 55, 80%), hypertension being the most common (N = 43, 62%). All patients in this study were minorities, the majority being Hispanics (N = 32, 46%), followed by African Americans (N = 21, 30%), the rest of patients were minorities such as Asians, Native Americans, and others (N = 16, 23%). We noted that more than half of patients were obese (N = 24, 35%), or overweight (N = 19, 28%), with a mean BMI of 26.24. Most patients were non-smokers (N = 39, 57%). The performance status among these patients was excellent in the large majority (ECOG 0-2; N = 62, 90%). The majority of malignant tumors were adenocarcinomas (N = 63, 91%); others included neuroendocrine tumors (N = 4, 6%) and gastrointestinal tumors (N = 2, 3%), the majority were advanced stage disease between stage III to stage IV disease (N = 38, 55%). The most common malignancy was colon cancer (N = 44, 64%), and also was the most reported deaths were among patients those patients with colon cancer (N = 13, 57%). Among patients that needed to be hospitalized (N = 43, 62%), needed some sort of oxygen supplementation (N = 36, 84%), a small number of patients required ICU admission (N = 8, 19%). When hospitalized, patients were mostly treated with hydroxychloroquine (N = 30, 70%) and steroids (N = 7, 16%). Inflammatory markers such as D-dimer, ferritin, C-RP were not reported in the majority of cases. Overall, the case fatality rate across all gastrointestinal malignancies was noted to be substantial (N = 22, 32%), 35% in males and 26% among females (p = 0.46). Conclusions: During the first year of the COVID-19 pandemic, patients with gastrointestinal malignancies who were infected, seemed to have a high chance to be admitted to the hospital (62%), once hospitalized the majority required some sort of oxygen supplementation (84%) and had a high case fatality rate from the COVID-19 infection (32%).
A real-world assessment of genomic testing and treatment in stage 4 gastric cancer patients.
Authors: Conner Therese , Arguello Roy , Loaiza-Bonilla Arturo , Hauser Robert S , Harris Barbara , Cruz Jackeline
Published: June 2022

e16007

Background: In gastric cancer, genomic testing plays an important role in treatment decisions that could improve response and extend life. While advanced therapies are recommended for certain patients, little is known about the frequency of real-world testing and treatment in metastatic disease. This study sought to assess the incidence and results of genomic testing among metastatic gastric cancer patients in the United States. Methods: This retrospective study used de-identified electronic health record data from adult Stage 4 gastric and gastroesophageal junction (GEJ) adenocarcinoma patients who received treatment at Cancer Treatment Centers of America (CTCA) from 2016-2021. Results: Among 238 patients, 172 had gastric and 67 had GEJ cancer. Mean age at diagnosis was 56 years (SD = 10.5), 64% were male, and 68% were Caucasian. Of 238, 101 (42%) received genomic testing at CTCA, 113 days (median) post-diagnosis. 49 (21%) were HER2+; 89 (37%) had PD-L1 testing, of which 67 (75%) were > 1%. Four (2%) had tumor mutation burden (TMB) >10 (high). Among 48 (20%) patients who received trastuzumab, 85% started in 1st line, and 97% of cycles were combination therapy. Of the 33 patients who received pembrolizumab, 97% started in 2nd line; 79% started prior to 2020 and 94% of cycles were monotherapy. Conclusions: In stage 4 gastric cancers, this study found that almost half of patients received genomic testing within the first year of diagnosis. Percentages of patients with gene amplification were within ranges of similar studies. Timing of trastuzumab and pembrolizumab was in accordance with guidelines. Most patients initiated pembrolizumab prior to 2020, suggesting early adoption of use. Cost-utility analyses of treatment options may be warranted in future research.[Table: see text]
Effect of deep neuromuscular block on surgical pleth index-guided remifentanil administration in the elderly undergoing laparoscopic gastrectomy for gastric cancer.
Authors: Kim Ji Eun
Published: June 2022

e16048

Background: Deep neuromuscular block (NMB) has been increasingly utilized in laparoscopic oncologic surgery, but its role in reducing intraoperative opioid requirement has yet to be investigated. Opioid in cancer patients is related with immunosuppression. Surgical pleth index (SPI) quantifies nociception. We investigated the effects of deep NMB on remifentanil requirements in the elderly patients undergoing laparoscopic gastrectomy under SPI-guided anesthesia. Methods: In this randomized controlled trial, the elderly patients aged 60–85 years who underwent laparoscopic gastrectomy for gastric cancer were included. Arrythmia, peripheral vascular disease and chronic opioid user were excluded. The patients (n = 60) were randomly allocated into deep (n = 30) or moderate (n = 30) NMB groups between December 2019 and December 2020. The moderate NMB group was maintained as Train-of-four count 1-2 during surgery and revered using neostigmine 50 ug/kg after the end of surgery. The deep NMB group was maintained as post-tetanic count 1-2 and reversed with using sugammadex 4 mg/k. The remifentanil dose was assessed during intubation, from skin incision until CO2 insertion, and pneumoperitoneum. Results: Demographic, hemodynamic and operational data were similar between two groups, except rocuronium dose. The remifentanil doses administered for tracheal intubation and during time from skin incision until CO2 insertion were similar (P = 0.412 and P = 0.649). In addition, total dose of remifentanil administered during pneumoperitoneum was not significantly different between two groups (P = 0.315), which remains non-significant when adjusted by weight, duration or both (P = 0.603, P = 0.146, and P = 0.389). Consequently, total dose of remifentanil administered during anesthesia was not different (P = 0.247). In post-anesthesia care unit, the pain score and the number of patients receiving analgesics were not different (P = 0.064 and P = 0.773). However, the duration of post-anesthesia care unit stay was significantly lower in the deep NMB group compared with in the moderate NMB group (P = 0.011). Conclusions: Deep NMB did not reduce the remifentanil requirement compared with moderate NMB in the elderly patients undergoing laparoscopic gastrectomy under SPI-guided anesthesia. Clinical trial information: NCT04205097.
A systematic review and meta-analysis to evaluate the efficacy and safety of nivolumab for advanced esophageal, gastroesophageal, and gastric cancer.
Authors: Oyenuga Mosunmoluwa , Mohamed Mohamed G , Sartaj Sara , Patel Rushin , Lacasse Alexandre , Mehta Mudresh , Sen Sandeep
Published: June 2022

e16060

Background: Esophageal, gastroesophageal, and gastric cancers make up about 1% of the cancer cases in the United States and most patients are diagnosed at advanced stages. Despite treatment options available, these patients have a median survival of about one year. Due to the advancement in treatment using immune checkpoint inhibitors in cancer therapy, this class of medications were recently approved for their use in patients with esophageal, gastroesophageal, and gastric cancer. A literature review and meta-analysis was conducted to evaluate the efficacy and safety of use of nivolumab in these group of patients. Methods: We systematically searched multiple databases using pre-specified search terms. We included only RCTs comparing Nivolumab with/without chemotherapy versus chemotherapy, in patients with advanced esophageal, gastroesophageal, or gastric cancer. Co-primary outcomes were overall survival (OS) and progression free survival (PFS). We also reported response rates, sensitivity analysis and adverse effects (AE), using fixed effects model via RevMan 5.4 software. Results: Three RCTs were included with a total of 2,645 patient and a median follow-up of 13 months. The patients’ mean age was 62±22 years, 75% were males, 79% were stage IV metastatic disease, and 29% had ≥1% PD-L1 expression. Compared to the chemotherapy group, Nivolumab group had a significantly favorable OS and PFS [HR 0.78;95% CI (0.69, 0.87), P < 0.001], [HR 0.83;95% CI (0.75, 0.92), P < 0.001] respectively. Sensitivity analysis showed significant effect of Nivolumab only in patients with ≥1 % PD L1 expression [HR 0.71; 95% CI (0.64, 0.80), P < 0.001]. Chemotherapy group had a significantly favorable outcome regarding serious AE [OR 1.57;95% CI (1.28, 1.93), P < 0.001], and diarrhea [OR 1.29;95% CI (1.07, 1.56), P = 0.007], with no difference regarding AE leading to death [OR 1.75;95% CI (0.88, 3.47), P = 0.11]. Conclusions: The use of nivolumab in patients with advanced esophageal, gastroesophageal, and gastric cancers is associated with improved disease-free survival and overall survival compared to treatment with chemotherapy, albeit at an increased risk of serious adverse effects. The improvement in survival was significant in patients with ≥1% PD L1 expression.
Linkage of time interval from neoadjuvant chemoradiotherapy to surgery with pathological response and survival profile in resectable esophageal cancer patients.
Authors: Liu Jiaqi , Zeng Xiaoxiao , Zhou Xiaojuan , Xu Yong , Ding Zhenyu , Hu Yang , Yuan Yong , Chen Longqi , Wang Jin , Lu You , Liu Yongmei
Published: June 2022

e16071

Background: The optimal time interval from neoadjuvant chemoradiotherapy (nCRT) to surgery remains controversial in esophageal cancer (ESC) patients. Hence, this study aimed to evaluate the relationship of the time interval from nCRT to surgery with the prognosis in ESC patients. Methods: Totally, 166 ESC patients treated with nCRT followed by surgical resection were reviewed. Their pathological complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS) were analyzed. Based on the median duration from nCRT to surgery, patients were classified into duration from nCRT to surgery ≥66 days group or <66 days group. Results: The pCR rate was elevated in duration from nCRT to surgery ≥66 days group compared to <66 days group (48.3% vs. 25.3%, P = 0.002), while DFS ( P = 0.316) and OS ( P = 0.883) were of no difference between these two groups. The duration from nCRT to surgery (≥66 days vs. <66 days) (odds ratio (OR): 2.149, P = 0.039) was independently related to improved pCR rate as validated by multivariate logistic regression, while it did not correlate with DFS or OS (both P > 0.05) by univariate and multivariate Cox’s regression analyses. Moreover, female gender ( P=0.001) and radiation dose ≥40 Gy. ( P = 0.039) could independently predict better pCR rate; and pCR rate was independently related to longer DFS ( P = 0.003) and OS ( P = 0.008). Conclusions: The prolonged time interval from nCRT to surgery relates to a higher pCR rate but does not correlate with DFS or OS in ESC patients.
The analysis of CCND1 amplification in Chinese patients with esophageal carcinoma.
Authors: Liu Lianke , Xu Fang ye , Xu Jiali , Sun Wei jie , He Yuange , Shao Qianwen , Wang Ting
Published: June 2022

e16073

Background: The CCND1 gene is considered an oncogene located on human chromosome 11q13.3, Cyclin D1 protein encoded by the CCND1 gene is the critical gatekeeping protein in charge of regulating the transition. Previous studies have reported that CCND1 amplification associated with a negative response to immune checkpoint inhibitors (ICIs) in pancancers, but the association with clinical and molecular characteristics in esophageal carcinoma (ESCA) have not been researched. Herein, we explore CCND1 amplification profiles in Chinese patients with ESCA. Methods: A total of 59 patients of ESCA with paired tumor-normal samples were collected into the study. All samples were detected by DNA based sequencing with a 1021 gene panel. Results: Firstly, the frequency of CCND1 amplification in Chinese ESCA patients was 32.20% (19/59). Then, all the samples were divided into two groups according to whether CCND1 was amplified or not. In the CCND1 amplification group, the top8 co-mutated genes were TP53, FGF4, FGF3, FGF19, MYC, NOTCH1, CDKN2A, CDKN2B. We calculated the clinical and molecular characteristics between the two groups, the results showed there were no difference in gender, age and TNM stage. Meanwhile, the CCND1 amplification group had more somatic mutations (median 19 vs. 11, P = 0.0003), higher TMB value (median 8.64 vs. 5.76, P = 0.0199) and more TMB-H patients (47.37% vs. 17.50%, P = 0.018). Indicating the CCND1 amplification is associated with TMB-H in ESCA. However, previous studies have reported the negative impact of CCND1 amplification on the efficacy of ICIs in pancancer (including ESCA), these results suggesting the efficacy of ICIs in ESCA may be affected by multiple biomarkers, especially for TMB-H patients should be concerned about the high frequency CCND1 amplification, the patients may have a poorer benefit from immunotherapy. Conclusions: The efficacy of ICIs in ESCA may be affected by multiple biomarkers, especially for TMB-H patients should be concerned about the higher frequency of CCND1 amplification, these patients may have a poorer benefit from immunotherapy.[Table: see text]
Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first line sorafenib: Pooled efficacy and safety in Chinese patients across two global randomized phase 3 studies (REACH-2 and REACH).
Authors: Shao Guoliang , Bai Yuxian , Chen Xiaoming , Gu Shanzhi , Gu Kangsheng , Yuan Xianglin , Widau Ryan C , Zhang Wanli , Zhang Qiang , Qin Shukui
Published: June 2022

e16081

Background: REACH-2 and REACH were two global, randomized, double-blind, placebo (PL)-controlled phase 3 studies of Ramucirumab (RAM) versus PL in patients with HCC after prior sorafenib. REACH-2 confirmed the RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. A pooled analysis was performed to evaluate the efficacy and safety of RAM in Chinese patients (including patients from mainland China, Hong Kong, and Taiwan) from REACH-2 and REACH with baseline AFP ≥400 ng/mL. Methods: Except for AFP level requirement, REACH-2 and REACH were similar in study design and included patients who had advanced HCC (BCLC stage C or B disease refractory or not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior sorafenib. Patients were randomized to RAM (8 mg/kg) I.V. or PL Q2W, plus best supportive care, until disease progression or unacceptable toxicity. Individual patient data were pooled from REACH-2 and REACH (AFP ≥400 mg/mL). Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR), and safety were reported. Efficacy analyses were stratified by study to account for any potential difference in the two studies. Results: Data from 155 Chinese patients were pooled from REACH (51) and REACH-2 (104) (N = 98 RAM vs N = 57 PL). Baseline characteristics were generally balanced between arms in pooled data set; however, lower median level of AFP was noted in the RAM arm. In the pooled population, RAM treatment numerically improved OS over PL (median OS 7.1 months vs 4.7 months; HR = 0.735 [95% CI: 0.512, 1.055]). Improvements in PFS (median PFS 2.6 months vs 1.5 months; HR = 0.666 [95% CI: 0.459, 0.967]), ORR (3.1% vs 0%), and DCR (44.9% vs 29.8%) were also observed. Hypertension (6.1% vs 1.8%), pneumonia (5.1% vs 1.8%), and hyponatremia (5.1% vs 1.8%) were the Grade ≥3 treatment-emergent adverse events (TEAEs) among ≥ 5% patients that was more frequently observed in the RAM arm compared with the PL arm. Conclusions: Pooled analysis of two phase 3 trials of RAM as second-line treatment in patients with HCC following sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Chinese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the pooled Chinese population were consistent with the entire population from REACH/REACH-2 (AFP ≥ 400 ng/mL). Clinical trial information: NCT01140347, NCT02435433.
Mutational landscape of DNA damage response deficiency-related genes and its association with immune biomarkers in esophageal squamous cell carcinoma.
Authors: Xu Fei , Chen Zhiming , Chen Gang , Zhu Yongjun , Chen Ji , Miao Feng , Wu Ning , Yang Song , Mao Beibei , Wang Shengzhou
Published: June 2022

e16100

Background: Esophageal squamous cell carcinoma (ESCC) has limited effective treatment strategies. DNA damage response (DDR) genes are of therapeutic interest in multiple cancer types. This study aimed to depict the landscape of DDR mutations in ESCC and evaluate the association between DDR mutations and known immunotherapy biomarkers. Methods: We recruited 250 Chinese patients with ESCC and performed next-generation sequencing. The DDR status definition was based on the mutational status of any of the 25 DDR core genes. A total of 107 patients underwent a PD-L1 examination. PDL1-H was defined as CPS ≥10. Results: Among the 250 patients, 73 (29.2%) harbored at least one DDR gene mutation and were defined as DDR-mut. Among the six functional DDR pathways, homologous recombination (HR) (12.4%, 31/250) and others (11.6%, 29/250) were the most frequently mutated. DDR-mut patients were significantly associated with higher tumor mutational burden than those in the DDR-wt group ( P = 7.4e-07). Patients with PDL1-H accounted for 21.2% (36/107) of the patients. PDL1-H was more prevalent in DDR-mut than DDR-wt, although the P value did not reach a significant level (40.5% vs. 30%, P = 0.29). Further analysis revealed that BRCA1, one of the most frequently mutated genes in the HR pathway, was significantly associated with PDL1-H ( P = 0.01). Conclusions: Our data revealed a subset of patients with ESCC harbored DDR gene mutations. Patients with these DDR gene mutations are significantly associated with immune biomarkers, implying the potential feasibility of combining DDR agents with immunotherapy in patients with DDR deficiency.
Efficacy and safety of second-line regorafenib after sorafenib or lenvatinib first line in patients with unresectable hepatocellular carcinoma: A real-world study.
Authors: Xue Feng , Zhai Jian , Liu Jianwei , Fu Zhigang , Sun Yanfu , Ge Ruiliang , Bai Shilei , Li Xiaowei , Wang Kui , Qu Zengqiang
Published: June 2022

e16125

Background: To explore the safety, efficacy and long-term prognosis of patients with unresectable hepatocellular carcinoma (HCC) treated with regorafenib after failure of first-line treatment. Methods: This retrospective single center study included 50 unresectable HCC patients who received regorafenib as a second line treatment in our hospital. Based on the difference of first-line targeted drugs, the 50 patients were divided into sorafenib group (n = 22) and lenvatinib group (n = 28). The adverse events, efficacy and long-term prognosis of sorafenib or lenvatinib followed by regorafenib were analyzed. Results: The median age of the 50 patients was 54.5 years. The patients had the following clinical characteristics: ECOG score 0-1, HbsAg positive, cirrhosis, BCLC stage B/C in 95.5%, 95.5%, 90.9% and 90.9% of all patients respectively. The baseline clinical characteristics between the sorafenib and lenvatinib groups were not statistically different (all p > 0.05), except for age and total bilirubin which were in favour of lenvatinib group. Regorafenib was administered oral 160 mg once daily during weeks 1–3 of each 4-week cycle. For 50 HCC patients, the incidence rate of adverse events after accepting regorafenib was 68%. The incidence rate of grade I/II and III/IV adverse events was 60% and 24%, respectively. According to the standards of RECIST 1.1 and mRSCIST, objective response rate (ORR) and disease control rate (DCR) after receiving regorafenib were 14.0%, 62.0% and 22.0%, 60.0%, respectively. There was no significant difference in incidence of all adverse events and grade III/IV adverse events, ORR and DCR between the two groups ( p > 0.05). In terms of long-term prognosis, total overall survival (TOS) and regorafenib overall survival (ROS) in sorafenib group and lenvatinib group were 23.0 months (95% confidence interval [CI]: 15.1-30.9) vs. 29.7 months (95CI: 21.4-38.1), and 11.7 months (95CI: 7.1-16.3) vs. 15.9 months (95CI: 8.3-23.5). The difference was statistically significant ( p= 0.041 and P = 0.045). The regorafenib progression-free survival (RPFS) was 5.6 months (95CI: 1.9-9.2) vs. 8.0 months (95CI: 5.1-10.9) in sorafenib group and lenvatinib group, respectively. The difference was not statistically significant ( P = 0.380). Conclusions: The data suggest that regorafenib is an effective drug for second-line treatment of HCC, with an acceptable toxicity level, an ORR of 14%-22% and a DCR of 62%-60%. Both TOS and ROS in lenvatinib group are better than those in sorafenib group. The possible mechanisms was that EGFR activation limits the response of HCC cells to lenvatinib. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after the disease progresses.
Identification of a prognostic signature model for predicting disease-free survival of hepatocellular carcinoma.
Authors: Li Guangming , Liu Huanhuan , Zeng Daobing , Wang Menglong , Guo Qingliang , Wu Jushan , Fu Zhi , Zhang Haitao , Wang Huina
Published: June 2022

e16128

Background: Hepatocellular carcinoma (HCC) is a type of aggressive disease with poor prognosis. Although surgery is the most effective therapy for early liver cancer, recurrence rate is up to 50%. Therefore, it is crucial to predict the recurrence for improvement of prognosis of liver cancer. This study aim is to establish a prognostic model using for the prediction of recurrence in HCC. Methods: We collected the genomic and clinical data of 372 patients from the cancer genome atlas (TCGA) database. Mutational signature were established based on univariate Cox analysis and least absolute shrinkage and selection operation (LASSO) Cox regression analysis. A prognostic signature model were developed. Results: The patients with higher pathological T stage (p < 0.001) and old age (p = 0.05) were associated with a worse DFS. In addtion, patients with a HRD score over 24 had a worse DFS compared to those in patients with HRD score less than 24 (p < 0.001). Based on the 1 year DFS, 112 differential mutation gene (DMEs) and 326 differential expressed genes (DEGs) were identified. The univariate Cox and LASSO Cox regression models were employed to select 47 DMEs and 9 gene expression construct an prognosis model. The AUC is 0.612. A nomogram of DFS was established based on the prognosis model, HRD, and tumor stage. The AUC is 0.812 in training set and 0.842 in validation set. Conclusions: We established and validated a novel nomogram model based the genomic and clinical factors for predict DFS in Hepatocellular Carcinoma patients. This model has good predictive value for prognosis, which could improve the risk stratification and individual treatment of Hepatocellular Carcinoma patients.