bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular features differences between patients with BRAF mutant melanoma and thyroid cancer.
Authors: Huang Yingying , Zhao Yun-Bo , Ye Ke , Xiao Liang , Long Guo , Fang Tongdi , Yuan Mingming , Xia Xuefeng , Zhou Ledu
Published: June 2022

e15128

Background: The efficacy of BRAF inhibitors varies extremely among patients with different cancers, such as malignant melanoma (MM) and differentiated thyroid carcinoma (TC) (constituting > 95% of thyroid cancer). This study aims to investigate molecular biomarkers that may explain the efficacy difference of BRAF inhibitors in patients with MM and TC. Methods: Tumor tissue and paired peripheral blood samples from patients with MM and TC were sent for matched tumor-normal next-generation sequencing of 1021 cancer-related genes. MM and TC patients harboring known BRAF activating mutations were retrospectively recruited in this study. Concomitant mutations, tumor mutation burden (TMB) and other mutational features were compared between these two populations. Results: A total of 69 patients with MM and 315 patients with TC were included. The total and median number of mutations in these two groups were 503/6 and 605/1, respectively. Correspondingly, TMB was higher in MM compared with TC (median: 2.88 muts/Mb vs. 0.69 muts/Mb, p = 0.0002). Compared with TC, more copy number variants (CNV) (total number: 142 vs 5, p < 0.001) and less single nucleotide variants (total number: 353 vs 569, p < 0.001) were identified in MM. Most BRAF mutations in MM were located on V600, and other mutations including D594A/G/N, K483E/Q and K601E were identified. In TC, nearly all mutations were BRAF V600E. Excluding CNV and structural variants, the mutation frequency of 28 genes in MM was higher than TC. Pathway enrichment analysis suggested that 9 out of 28 genes (APC, ARID1B, ARID2, CDKN2A, CTNNB1, EGFR, PTEN, TERT, TP53) were significantly enriched on the hepatocellular carcinoma signaling. TERT, CDKN2A and PTEN were frequently mutated in MM, which may contribute to the efficacy difference of BRAF inhibitors in patients with MM and TC. Conclusions: This study found specific molecular features may explaining the efficacy difference of BRAF inhibitors in MM and TC, which requires further validation in patients treated with BRAF inhibitors.
Molecular phenotypes of colorectal cancer.
Authors: Krashikhina Tatiana
Published: June 2022

e15506

Background: Despite the positive results of colorectal cancer treatment, there is a group of patients that progresses despite successful treatment for I–II stage of the disease. it may be that modern predictors in do not fully cover the entire spectrum of molecular genetic traits, especially the tumor microenvironment. Perhaps expression analysis is not only tumor tissue, but resection margin could also reach a consensus on the molecular gene phenotypes of colorectal cancer with the achievement of the goal of prognostic efficiency and therapeutic and prophylactic diagnostic tactics. Methods: The expression level of 64 genes in tumor tissue in samples obtained from 172 patients with stage I–III CRC was analyzed by real-time Polymerase chain reaction (PCR). The mean follow-up time was 28.15±14.7 months. Data analysis and predictive modeling arrays using the R 3.6.3 Computation Evaluation Framework (R Foundation for statistical computing, Vienna, Austria) using additional packages rms 5.1-4, survival 3.2-7 and pROC 1.16.2. Results: As a result of statistical analysis, data were obtained on the presence of predictors of the studied unfavorable source code among the selected sets of genes carcinogenesis in colorectal cancer. The next step revealed progression status with BIRC5, IL2, SCUBE2, MYC and P16INK4A gene expression as in tissues tumors, and in resection margin. 2 regression models were built to predict survival without progression in patients with the inclusion of the level of expression in the tumor tissue- nor, the inclusion of the level of gene expression in tumor and resection margin. Model with inclusion only tumor transcripts statistics did not differ from models without predictors. Conclusions: In this study, it was possible to identify a group of genes associated with certain favorable prognosis and responsible in one way or another for proliferation, angiogenesis, immune status of the tumor. It can be concluded that the study of the level of expression of numerical genes in tumor tissue can become a promising direction for the selection of patients in the group of poor prognosis in colorectal cancer.
Update of a phase II, multicenter clinical trial: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Yan Jin , Han Yunwei , Zhang Li , Jin Yongdong , Sun Hao
Published: June 2022

e15566

Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients. Methods: In this open label, single-arm, multi-center, phase II clinical trial, 29 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (January 18, 2022), the total 29 patients were enrolled, of which 23 patients were available for efficacy assessment. In best overall response assessment, there were 56.5% PR (13/23), 34.8% SD (8/23) and 8.7% PD (2/23). The ORR was 56.5% (95% CI, 34.5-76.8%) and DCR was 91.3% (95% CI, 72.0-98.9%). The longest duration of treatment was 17.5 months. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥30%) were hypertension, leukopenia, nausea/vomiting, hypertriglyceridemia, neutropenia, hypohemoglobinemia, hypoalbuminemia. Grade 3/4 TRAEs (≥10%) were neutropenia (13.8%), hypertension (13.8%) and hypertriglyceridemia (10.3%). One grade 5 TRAE was pancytopenia that occurred at 2.7 months. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed favorable anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in randomized study continued subsequently. Clinical trial information: ChiCTR1900028417.
PD-1 inhibitors combined with apatinib for advanced diffuse gastric cancer: A retrospective study.
Authors: Chen Beibei , Zhao Huichen , Wang Saiqi , Lv Huifang , Xu Weifeng , Nie Caiyun , Wang Jianzheng , Zhao Jing , He Yunduan , Chen Xiaobing
Published: June 2022

e16009

Background: Numerous studies have shown that immunotherapy has a synergistic effect when combined with targeted drug therapy. Apatinib has been proven effective in advanced gastric cancer. Based on these facts and to assess the efficacy and safety of programmed death 1 (PD-1) inhibitors and apatinib as combination therapy in patients (pts) with unresectable locally advanced or metastatic diffuse gastric cancer(DGC), a retrospective clinical research study was carried out. Methods: Retrospective analysis of a cohort of pts with advanced diffuse gastric cancer received treatment of apatinib combined with PD-1 inhibitors enrolled in our institution between January 2019 and January 2021.Pts (n = 34) received PD-1 inhibitors and apatinib (250mg once daily) in this retrospective study. Overall survival (OS) and progression free survival (PFS) were estimated by Kaplan Meier curves, and other endpoints included objective response rate(ORR), disease control rate(DCR), prognostic factors. Results: A total of 34 pts were enrolled in a real-world dataset from Henan Cancer Hospital. 2 pts achieved partial response(PR),17 pts had stable disease(SD),and 15 pts had progressive disease (PD). The ORR and DCR were 5.88% (2/34) and 55.88% (19/34), respectively. The median PFS(mPFS) was 2.47 months (95%CI:1.9-3.0), and the median OS (mOS) was 6.80 months (95%CI 3.7-9.9). Pts with less than 3 metastatic sites had longer mOS than those with more metastatic sites(2.70 vs. 7.73 P < 0.05). And in this study, the levels of platelet, albumin, CEA, CA199, CA125 and LDH affect patients’ prognosis. Kaplan-Meier analyses revealed that patients with normal platelet had better mOS than those with higher platelet(mOS 7.10 vs 0.3; P < 0.05).And similar results were found in the pts with normal albumin. The mOS of those was longer than the pts with lower or higher albumin(7.73 vs 2.20 vs 2.53, P < 005). And we demonstrated that positive groups of CEA(> 4.7ng/ml), CA125(> 35U/ml), CA199(> 27U/ml) and LDH(> 245U/L) were significantly associated with worse outcomes than that of negative groups(all P < 0.05). The incidence of grade 3 or 4 treatment-related adverse events (TRAEs) was 26.5%(9/34). These adverse events (AEs) included pruritus, rash, hand-foot syndrome, hypertension and increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). No treatment-related deaths occurred. Conclusions: Combination therapy of PD-1 inhibitors and apatinib showed encouraging clinical activity and demonstrated tolerable toxicity in pts with advanced DGC. The level of platelet, albumin, CEA, CA199, CA125 and LDH could predict the prognosis of DGC patients.
Study on the efficacy and safety of sintilimab combined with nab-paclitaxel as second-line treatment for advanced or metastatic gastric cancer (GC)/ gastroesophageal junction (GEJ) cancer.
Authors: Wang Jianzheng , He Yunduan , Zhang Baiwen , Cheng Xiaojiao , Li Qingli , Lv Huifang , Nie Caiyun , Chen Beibei , Xu Weifeng , Zhao Jing , Tu Shuiping , Chen Xiaobing
Published: June 2022

e16016

Background: Advanced gastric cancer has poor prognosis and short survival period. Anti-PD-1 antibodies have shown some efficacy in second-line treatment of advanced or metastatic GC/GEJ cancer, but were not superior to monotherapy. The combination of chemotherapy and anti-PD-1 antibody has been proved to have synergistic effect. Nab-paclitaxel is one of the most commonly used second-line regimens in China. Therefore,we aimed to evaluate the efficacy and safety of sintilimab combined with Nab-paclitaxel in the treatment of advanced GC/GEJ cancer patients. Methods: We retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first line systemic therapies and treated with sintilimab combined with Nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progression disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). We further analyzed PFS between different subgroups of chemoimmunotherapy regimens in order to find which patients could benefit more. Firstly, The PFS of HER2 positive and HER2 negative patients was 7.1months (95%CI:3.367-10.833) and 5.3 months (95%CI:4.018-6.582), respectively (p = 0.947). The median PFS of PD-L1 positive, PD-L1 negative and PD-L1 unknown patients was 5.3months (95%CI:3.744-6.856), 8.1months(95%CI:3.371-12.829) and 6.1 months(95%CI:2.649-9.551)(p = 0.918). Finally, we analyzed the effect of chemoimmunotherapy cycles on PFS. The results showed that PFS of > 4 cycles was numerically longer than that of ≤ 4 cycles, and PFS were 7.1 months (95%CI:4.378-9.822) and 5.2months (95%CI:3.091-7.309)(p = 0.424), respectively. Most of the adverse events (AEs) were grade 1-2.The most common treatment-related adverse events (TRAEs) of grade 3-4 were anemia 5(12.8%), neutropenia 5(12.8%), leukopenia 4(10.3%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia 1(2.6%). Only one patient developed grade 4 hepatitis (2.6%). Conclusions: These results indicated that sintilimab combined with Nab-paclitaxel exhibited good anti-tumor activity and acceptable safety profile as second-line treatment for advanced or metastatic gastric cancer. These results warrant further accrual and evaluation and explore which patients can benefit more from the combined treatment strategy.
The microbial characteristics of patients with esophageal squamous cell carcinoma after chemotherapy and after immunotherapy.
Authors: Liu Yanjun , Zuo Jing , Fan Zhisong , Liu Liang , Wang Yudong , Feng Li , Han Jing , Wang Long , Zhang Xue
Published: June 2022

e16049

Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Previous studies have shown that chemotherapy and immunotherapy is affected by esophageal microbiome. The effect of esophageal microbiota on the efficacy of chemotherapy and immunotherapy for ESCC remain poorly understood. Methods: DNA was extracted from blood, oral mucosal, saliva, urine, fecal samples from 14 ESCC patients after chemotherapy and 18 ESCC patients after immunotherapy. Total microbial genomic DNA samples were extracted using an OMEGA Soil DNA Kit (D5625-01). The V3–V4 regions of bacterial 16S rRNA genes were amplified by PCR using the forward primer and the reverse primer and were sequenced with Illumina MiSeq platform. In order to comprehensively evaluate the α diversity of microbial communities, we used Chao1 and Observed Species indices to characterize the richness, Shannon and Simpson indices to characterize the diversity. PCoA were used to analyze differences in β diversity. Functions of 16S rRNA sequences were predicted using the PICRUSt2 and KEGG databases. Results: The α diversity in patients with ESCC after immunotherapy were higher than those in patients with ESCC after chemotherapy. There was a statistically significant difference in β diversities between ESCC patients after chemotherapy and ESCC patients after immunotherapy. In terms of the microbial functions in ESCC patients after chemotherapy and immunotherapy, the metabolic pathways accounted for the most. Conclusions: This study is conducive to exploring new mechanisms for tumor cells to evade host immune surveillance, providing new ideas and new strategies for the microecology-based therapy of ESCC.
FLOT neoadjuvant therapy turns the expression patterns of cancer cells similar to those of non-cancer cells in gastric cancer patients.
Authors: Barra Williams Fernandes , Silva Jessica Costa , Mourao Ronald Matheus da Silva , Anaissi Ana Karyssa , Demachki Samia , Ishak Geraldo , Calcagno Danielle Queiroz , Moreira Fabiano Cordeiro , Assumpção Paulo Pimentel
Published: June 2022

e16056

Background: FLOT perioperative have emerged as a new standard for locally advanced gastric cancer (LAGC). Nevertheless, the molecular consequences of such therapy remain obscure. Aiming to investigate changes in the tumor transcriptional landscape in LAGC patients treated with FLOT, a comprehensive analysis of messenger RNA (mRNAs) and long noncoding RNA (lncRNAs) expression was developed using next-generation sequencing (NGS). Methods: Paired tumor and non-tumor fresh samples, including 17 patients with intestinal-type LAGC submitted to neoadjuvant FLOT treatment (treated group) and 13 who did not receive neoadjuvant therapy (untreated group), were sequenced and compared. Differential expression analyses were performed using the DESeq2 package. Criteria for differentially expressed (DE) lncRNAs and mRNAs were|Log2(Fold-Change)| > 2; and adjusted p-value < 0.05. In silico analyses were adopted to identify DE lncRNAs with transcription factors (TFs) and RNA-binding proteins (RPBs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene ontology (GO) was also performed to elucidate these target proteins’ and mRNAs biological’s roles. Results: In tumor samples from the untreated group, 4443 mRNAs and 961 lncRNAs DE were found, in which 293 mRNAs and 148 lncRNAs accurately discriminated (the area under the curve ROC > 0.9) tumor and non-tumor tissues. Only 265 mRNAs and 29 lncRNAs DE were detected in treated patients, indicating that neoadjuvant therapy led to changes in expression patterns, making tumor tissues similar to non-tumor tissues. Subsequent analyzes identified that non-tumor tissues (treated vs. untreated) showed similar expression profiles. Among tumor samples, 34 mRNAs and 54 lncRNAs DE were found, in which 7 mRNAs and 16 lncRNAs can discriminate between treated and untreated tumors, indicating the effect of neoadjuvant treatment is predominant in the tumor. GO evaluation of genes was significant for 83 terms for biological process. The most annotated terms were the regulation of catalytic activity. We also observed that DE lncRNAs interact with TFs and RBPs were enriched in related cancer development and progression pathways, including transcriptional dysregulation and cellular senescence. Conclusions: Despite the need for further validation to better understand the transcriptional landscape related to neoadjuvant treatment, the present study highlights the functional relevance of lncRNAs in tumor biology and, mainly, shed light on the molecular effects of FLOT neoadjuvant treatment, that might help to guide future investigations aiming to establish personalized management of GC.
Real-world genomic testing, treatment, and outcomes in patients with cholangiocarcinoma with FGFR2 fusions/rearrangements.
Authors: Borad Mitesh J. , Conner Therese , He LiHong , Kazerooni Reza , Salimi Tehseen , Epstein Robert S.
Published: June 2022

e16168

Background: Several fibroblast growth factor receptor (FGFR) inhibitors have been recently approved or are in development for the treatment of cholangiocarcinoma (CCA) with FGFR2 fusions/rearrangements (f/r), such as the ATP-competitive inhibitors pemigatinib and infigratinib (FDA-approved in 2020/2021) and the covalent inhibitor futibatinib, which has shown efficacy in a pivotal phase 2 trial. To inform future evaluations of the impact of these agents in clinical practice, and understand other existing gaps in care, we investigated the characteristics and clinical management of patients with CCA and FGFR2 f/r prior to 2021. Methods: This real-world, retrospective cohort study used de-identified, patient-level electronic health records data from Cancer Treatment Centers of America (CTCA) to identify adults with a diagnosis of advanced intrahepatic CCA (iCCA) who received genomic testing between 2013-2021. Clinical/demographic characteristics, time to genomic testing, treatment patterns, and outcomes of patients with and without FGFR2 f/r were described. Results: 23 patients with FGFR2 f/r and 88 with FGFR wild-type (wt) iCCA were identified. Compared to FGFR wt, FGFR2 f/r had a higher proportion of female (65.2 vs 45.5%) and Black (39.1 vs 18.2%) patients (Table). Mean age at diagnosis was ̃60 y and >60% were diagnosed with stage 4 disease in both cohorts; 91.3% of f/r and 78.4% of wt patients had an ECOG PS 0/1. Median time from diagnosis to genomic testing was ̃5 mo; upon entry to CTCA, median time to testing was <2 mo. 17/23 patients in the f/r cohort had FGFR2 fusions (4 BICC1, 13 other). Three FGFR2 f/r patients received an FGFR inhibitor (pemigatinib) as next treatment after testing in 2020. A trend towards longer median overall survival in the f/r vs wt group (24.5 vs 17.8 mo), and a correlation of survival with ECOG PS were observed. Conclusions: This analysis provides insight into the real-world characteristics, clinical management and outcomes among patients with iCCA and FGFR2 f/r, predominantly prior to the introduction of FGFR inhibitors, providing a baseline for further study as the treatment landscape evolves. Of note, the time lag between diagnosis and genomic testing before entry to CTCA underlines the need for earlier testing to guide optimal therapy in clinical practice. [Table: see text]
Circulating tumor DNA is a potential prognostic risk factor of recurrence in patients with hepatocellular carcinoma treated by liver transplantation.
Authors: Jiang Nan , Zeng Xinchen , Tang Jianxin , Liang Ziming , Qi Xiaofang , Huang Lujia , Pang Fei
Published: June 2022

e16196

Background: Liver transplantation (LT) is one of the most effective therapeutic strategies for hepatocellular carcinoma (HCC), however, tumour recurrence after LT often leads to poor outcomes. At present, clinical characteristic profile, imaging diagnosis as well as level of serum biomarkers prior to LT could predict the prognosis in HCC patients treated by LT. However, the sensitivity and specificity of these biomarkers are limited, highlighting the crucial need to identify novel biomarkers. Previous clinical studies have shown that postoperative circulating tumor DNA (ctDNA) can be used as a predictive biomarker for the risk of recurrence in stage I-III solid tumor. This study aimed at investigating the relationship between the level of ctDNA and the probability of recurrence in HCC patients treated by LT. Methods: HCC patients receiving LT treatment were enrolled. Peripheral blood samples before LT and available matched tissue samples were collected. Targeted sequencing of 328 cancer-related genes were conducted. The clinicopathologic data of the patients was retrospectively analyzed. The predictive efficiency for recurrence after LT of different clinicopathologic parameters and ctDNA were accessed. Results: A total of 45 patients were enrolled, including 42 males (93%) and 3 females (7%), with a median age of 51 (range 31-76 years). Thirty-five patients (78%) had detectable ctDNA before LT while gene alterations were identified in tumor tissue of all the patients. Larger tumor size (> 5cm), cirrhosis, portal vein tumor thrombus (PVTT) and elevated AFP level (≥400ng/ml) prior to LT were associated with higher percentage of positive ctDNA (94% vs 73%, 84% vs 75%, 88% vs 79%, 88% vs 76%, respectively). Patients with micro-vessel invasion (MVI) had higher ctDNA abundance (maxVAF, P < 0.05). Interestingly, after over 3 years’ follow-up, clinical factors including MVI, PVTT, BCLC stage, maximum tumor diameter and serum AFP failed to predict disease free survival (DFS) and overall survival (OS). In contrast, the recurrence rate was remarkably augmented (48.6% vs 0%) and the median DFS was significantly decreased (390 days vs not reached, p< 0.05) in patients with detectable ctDNA. Conclusions: In conclusion, ctDNA could be a potential biomarker to sensitively predict the recurrence in patients with HCC treated by LT, which may help to improve the post-transplant management of these patients.
Racial disparities in the burden of depression and anxiety in patients with pancreatic cancer.
Authors: Franco Diana , Farooq Umer , Anwer Faiz
Published: June 2022

e16283

Background: The prevalence of depression ranges from 33% to 45% in pancreatic cancer, the highest among gastrointestinal malignancies. Psychiatric illnesses impact the quality of life and compliance with treatment and regular physician visits. Therefore, we sought to examine ethnic differences in the prevalence of depression and anxiety in pancreatic cancer. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with pancreatic cancer. Multivariate linear or logistic regression was used (for continuous and categorical variables, respectively). The confounders adjusted for in the regression models were: history of MI and stroke, coronary artery disease, sleep disorders, chronic pain disorders, smoking, alcohol, obesity, PTSD, sexual abuse, arthritis, and physical disability, in addition to patient and hospital-level variables. We used Stata, version 14.2, to perform analyses considering 2 sided P < 0.05 as statistically significant. Results: A total of 116,055 patients with pancreatic cancer were included. 13,825 (11.91%) had depression and 16,845 (14.51%) had anxiety. The prevalence of depression in various ethnic categories was: 13.63% in Whites, 7.59% in Blacks, 8.47% in Hispanics, and 5.63% in Asians ( P< 0.001). Anxiety prevalence was: 16.25% in Whites, 9.92% in Blacks, 11.65% in Hispanics, and 7.29% in Asians ( P< 0.001). On multivariate analysis, compared to Whites, all ethnic groups had lower odds of depression (Blacks; adjusted odds ratio (aOR): 0.45, 95% confidence interval (CI): 0.38–0.52, P< 0.001, Hispanics; aOR: 0.60, 95% CI: 0.49–0.73, P< 0.001, Asians; aOR: 0.43, 95% CI: 0.31–0.59, P< 0.001). Similar results were seen for anxiety when ethnic groups were compared to Whites (Blacks; aOR: 0.49, 95% CI: 0.43–0.56, P< 0.001, Hispanics; aOR: 0.67, 95% CI: 0.55–0.82, P< 0.001, Asians; aOR: 0.44, 95% CI: 0.33–0.59, P< 0.001). Conclusions: Whites had the highest burden of depression and anxiety in pancreatic cancer. However, Hispanics represented the ethnic minority with a greater prevalence of psychiatric disorders. Further research needs to establish the factors responsible for these ethnic differences.[Table: see text]
Complementary role for circulating tumor DNA and tumor tissue to detect clinical relevant alterations in patients with castrate-sensitive prostate cancer.
Authors: Yang Bin , Dong Baijun , Chen Wei , Zhao Tingting , Yang Guanjie , Xie Jun , Wang Ruiliang , Wang Hong , Huang Longfei , Liu Tongtong , Zhang Menghuan , Huang Hang , Peng Bo , Xue Wei , Yao Xudong
Published: June 2022

e17050

Background: Targeted sequencing of circulating tumor cell DNA (ctDNA) has been well studied in patients with metastatic castration-resistant prostate cancer (mCRPC), while its application in patients with castrate-sensitive prostate cancer (CSPC) is relatively limited. This study aimed to analyze the concordance of somatic alterations in ctDNA and matched tumor tissue samples oand investgate the clinical significance of genomic alterations in CSPC patients. Methods: 184 CSPC patients from three Chinese Hospitals were included (24 with localized PCa (LP), 46 with lymph node metastases (LNM), 42 with distant metastases of low tumor burden (LTB), and 72 with distant metastases of high tumor burden (HTB)). All patients had ctDNA samples and matched tumor tissues collected at time of primary biopsy (n = 78) or radical surgery (n = 106) for high-throughput targeted sequencing of multiple-gene. 36 prostate cancer clinical relevant genes were selected for analysis. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of genomic alterations and the time to CRPC. Results: Overall, 70.6% of CSPC patients had somatic alterations in tumor tissues, which was much higher than that in ctDNA (31.5%). The concordance for alterations detected in ctDNA and matched tumor tissue was 29.2%. In subgroup analysis, the concordance for LP, LNM, LTB and HTB group were 0%, 5.3%, 3.3%, and 49.1%, respectively. Most of alterations identified were unique in tumor tissues or ctDNA. Number of alterations in tumor tissue alone was 23, 54, 58 and 56 in LP, LN, LTB and HTB group, respectively. Number of alterations alone in ctDNA was 16, 27, 9 and 37 in LP, LN, LTB and HTB group, respectively. Combined analysis of the genomic alterations identified in ctDNA and tumor tissue demonstrated that the most frequent altered gene was FOXA1 (35%), TP53 (16%), SPOP (12%), CDK12 (12%) and NCOR2 (9%). For patients with distant metastases harboring any pathogenic somatic or germline alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1, the median time to CRPC was significantly shorter than wide-type patients (median, 17.3 mo vs Not reached；p＜0.005). In the multivariate COX analysis, alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was still found to be significant (P = 0.00737). Conclusions: The concordance of gene alterations in ctDNA and mathced tumor tissue in CSPC patients increased with disease progression. ctDNA or tumor tissue alone was insufficient to capture all clinically relevant alterations, and therefore combined use of them may provide more comprehensive information about prognosis and clinical treatment guidance for CSPC patients. Alteration of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was an independent prognostic factor for the time to CRPC.
Prevention of radiation-induced rectal injuries with perirectal blocks in radiation therapy.
Authors: Rodionova Olga G. , Sakun Pavel G. , Sheiko Elena A. , Karnaukhova Elena A. , Pustovalova Alla V. , Chalabova Tatiana G. , Savchenko Dmitriy A. , Kabanov Sergey N. , Adamyan Meri L. , Kruze Polina A. , Poryvaev Yuriy A. , Chernikova Natalia V. , Voshedskiy Vitaliy I. , Tolmacheva Ekaterina A. , Vasilieva Ekaterina O. , Solntseva Anna A. , Zhenilo Oksana E. , Cherkasova Anna A. , Krokhmal Yulia N.
Published: June 2022

e17507

Background: The purpose of this study was to evaluate perirectal blocks in prevention of radiation-induced rectal injuries in patients with cervical cancer. Methods: The study included 18 patients diagnosed with stage III cervical cancer (T3bNxM0) receiving chemoradiotherapy. All patients showed pronounced inflammatory and dystrophic changes in tissue planes and organs of the small pelvis due to comorbidities (diabetes mellitus, hypertension, pelvic varicose veins, proctitis, inflammatory and adhesive processes in the small pelvis reducing chemoradiotherapy effectiveness due to impaired microcirculation and increasing the risk of post-radiation complications). All patients received brachytherapy with additional perirectal administration of drugs relieving pain and inflammation and improving neurotrophic processes and microcirculation in tissues (novocaine 0.25% -20.0; milgamma 2.0; ceftriaxone 1 g; dexamethasone 8 mg). The combined administration causes drug potentiation, positively affects the nervous and neuromuscular systems, restores microcirculation and venous outflow, decreases swelling, improves tissue trophism, reduces blood vessel permeability, and improves reflexes from interoceptors. Radiation therapy was completed on schedule with the introduction of radical doses in all patients, which is challenging in patients with comorbidities leading to impaired trophism and tissue hypoxia. Results: Complete tumor regression confirmed by MRI and ultrasound was observed by the end of the treatment in 90% of patients, apparently due to the radiosensitizing effect on cervical cancer and the radioprotective effect on surrounding tissues. Conclusions: Parametrial blocks during brachytherapy improve the status of tissues of the small pelvis which, in turn, prevents radiation damage, contributes to the timely radiotherapy completion, and improves the treatment effectiveness and the quality of life of patients. This technique is especially relevant in view of the increasing number of diseases that disrupt microcirculation, and hence the oxygenation of tissues, causing tumor radio- and chemoresistance.
Multi-omics characterization of productive HPV integration in cervical cancer.
Authors: Sun Chaoyang , Fan Junpeng , Fu Yu , Peng Wenju , Li Xiong , Shen Yuanming , Zou Dongling , Xia Bairong , Song Kun , Chen Gang , Ma Ding
Published: June 2022

e17508

Background: Cervical cancer (CC), which is caused by high-risk human papillomavirus (HPV), remains a significant public health problem worldwide. HPV integration into the host genome is a critical aetiological event in cervical carcinogenesis and progression and it can be silent or actively transcribed that leads to production of viral-host fusion transcripts. We aim to study the characterization of silent and productive HPV integration in cervical cancer. Methods: Cervical cancer (CC), which is caused by high-risk human papillomavirus (HPV), remains a significant public health problem worldwide. HPV integration into the host genome is a critical aetiological event in cervical carcinogenesis and progression and it can be silent or actively transcribed that leads to production of viral-host fusion transcripts. We aim to study the characterization of silent and productive HPV integration in cervical cancer. Results: Virus capture sequencing revealed 762 virus-host DNA fusion breakpoints and only 142 (18.6%) were actively transcribed into fusion transcripts. The productive HPV integrations were nonrandom, with an increase in breakpoints in the HPV E1 region、 human introns and common fragile sites. They were associated with significant changes in host focal genome structure and gene transcription, but not in protein production in 40 kb region, and produced higher levels of E6 and E7 proteins detected by Western Blot. Clinical, transcriptional, proteomic, phosphoproteomic and single-cell data demonstrated that EMT, proliferation and extracellular matrix associated pathway were enriched in productive HPV integrated tumors and contributed to advanced clinical stage. Conclusions: We demonstrated that productive HPV integration is associated with higher E6/E7 proteins and enhanced tumor aggressiveness and immunoevasion in situ to advanced disease. This study improves our understanding of the effects of HPV fusion transcripts on the biology and pathophysiology of HPV-driven cervical cancer that has the potential to direct new prevention and therapeutic strategies
Analysis of the relationship between social determinants of health and survival outcomes in gestational trophoblastic neoplasia in the United States.
Authors: Liu Chrissy , James Alecia , Wolf Jennifer , Schmidt Marcia , Mitchell Edith P. , Calixte Rose , Clare Camille A.
Published: June 2022

e17537

Background: Gestational trophoblastic neoplasia (GTN) is a rare disease with a reported incidence of 1 in 40,000 pregnancies. There have been no studies evaluating the impact of social determinants of health (SDH) on outcomes in GTN. This study seeks to examine the influence of social and biologic prognostic factors related to survival among women with GTN. We hypothesized that older age at diagnosis, lower household income, and marginalized, racial/ethnic groups are associated with worse prognosis. Methods: In this retrospective study, the Surveillance, Epidemiology, and End Results (SEER) database was used to identify women with GTN diagnosed from 2010-2018. Clinical-pathologic characteristics were described including initial stage of disease, presence of brain metastases at diagnosis, treatment with chemotherapy or surgery, and treatment at a Commission on Cancer (CoC) accredited center. Demographic factors were collected, including race/ethnicity, age at diagnosis, marital status, median household income, and rural or urban location. Log-logistic regression models were used to estimate the association between various prognostic factors and the odds of survival. We compared overall survival distributions across race/ethnicity using the log-rank test. Results: Of the 1,149 eligible patients (pts), 36% were non-Hispanic White (NHW), 21% non-Hispanic Black (NHB), 28% Hispanic, and 14% Other (Native American, Alaska Native, Asian, Pacific Islander). Mean age was 33.8 years (range 14-87 years). The majority was in the 21-35 age group (51%). Compared to NHW pts, Hispanic pts had over two times the odds of increased survival (OR 2.11; 95% CI 1.08-3.27; p = 0.032). NHB pts had similar survival compared to NHW pts (OR 1.06; 95% CI 0.50-1.76; p = 0.860). Poor prognostic factors demonstrating decreased odds of survival included age ≥40 years (OR 0.139; 95% CI 0.025-0.478; p < 0.001) and widowed status (OR 0.09; 95% CI 0.018-0.375; p < 0.001). Localized stage (OR 2.94; 95% CI 1.13-5.53; p = 0.03), the absence of brain metastases (OR 4.58; 95% CI 1.96-7.91; p = 0.002), and rural location (OR 5.62; 95% CI 1.25-15.2; p = 0.028) were significantly associated with increased odds of survival. Household income and race/ethnicity were not independent predictors of survival. Conclusions: Compared to NHW pts, Hispanic pts have an increased cause-specific survival for GTN. NHB pts and NHW pts have similar survival. Additionally, rural location was significantly associated with greater odds of survival. Further research is needed to investigate the underlying mechanisms linking race/ethnicity and survival outcomes, considering structural racism, bias, and discrimination. Our findings highlight the importance of recognizing the role of racism and SDH on health disparities and call to attention the need for addressing social inequities in GTN.
Perioperative opioid-sparing multimodal analgesia (OSMMA) in cancer patients.
Authors: Tumanyan Sergey V. , Frantsiyants Elena M. , Rozenko Dmitry A. , Moiseenko Tatiana I. , Menshenina Anna P. , Oros Oksana V. , Popova Natalia N.
Published: June 2022

e17552

Background: Perioperative (PO) pain management is one of the most important issues in cancer treatment. The purpose of the study was to improve the quality of PO analgesia in cancer patients. Methods: A prospective randomized study of the quality and efficacy of various analgesics included 104 patients aged 34 to 77 years who underwent surgical interventions for ovarian cancer. The patients were divided into 2 groups. Group 1 (n = 49): patient-controlled analgesia with trimeperidine and nonsteroidal anti-inflammatory drugs (NSAIDs); group 2 (n = 55): preemptive analgesia based on a continuous infusion of lidocaine, magnesium sulphate, microdoses of fentanyl (4 µg/h) and NSAIDs. Results and pain syndrome were assessed by the visual analogue scale (VAS), personal and reactive anxiety, levels of glucose, cortisol, insulin, lactate, and the Kerdo index. Results: Analgesic effect of trimeperidine was obtained in 85.7% (p < 0.05). However, the effect was less pronounced, compared to OSMMA, and did not reduce the cognitive component of pain after surgical treatment. In group 2, opioid-sparing analgesic effect was 96.4% (p < 0.05). OSMMA limited the increase of cortisol, glucose, insulin, CRP and lactate (p < 0.05) providing effective PO pain relief. OSMMA did not cause residual sedation, anxiety, depressive effects and cognitive impairments, which showed its advantages over trimeperidine. Therefore, despite the minimal doses of narcotic analgesics in group 2, OSMMA improved the quality of pain relief and the well-being of patients in perioperative period being a significant advantage in minimizing the negative effects of opioids. Conclusions: Lidocaine-based PO analgesia with microdoses of fentanyl can significantly limit endocrine and metabolic changes and improve the quality of pain relief contributing to the early rehabilitation of cancer patients.
Impact of tumor percentage on the assessment of homologous recombination deficiency score using a NGS 523 gene panel and a cytogenetic software in the evaluation of epithelial ovarian tumors.
Authors: Navarro Sanchez Janira , Halford Zan , Kar Shing Pon Jason , Woron Amy M. , Terada Keith Y. , Vierkoetter Koah , Lum Christopher A.
Published: June 2022

e17567

Background: Platinum-taxane chemotherapy and surgical debulking are the optimal treatment for patients with advanced ovarian cancer. While initial response rates are above 80%, tumor recurrence occurs in about 70 to 80% of patients. Cells with defects in homologous recombination repair (HRR) are susceptible to cell death induced by Poly (ADP-ribose) polymerase inhibitors (PARPi). These drugs are used to treat recurrent neoplasms that have BRCA1 or BRCA2 mutations or homologous recombination deficiency (HRD). Low tumor percentage in test samples, which is common in clinical practice, is often overlooked when addressing HRD tests. The goal of this study was to determine the optimal tumor content rate needed to detect HRD changes. Methods: A total of sixteen ovarian neoplasms were studied. These samples were sequenced using Illumina TSO500 NGS and interpreted using NxClinical software 6.1. In all cases, HRD scores were evaluated. A score of ≥42 was determined to be HR-deficient and a score < 42 was considered HR-proficient. We aimed to identify the optimal tumor percentage needed for detection of HRD alterations. HRD scores were calculated with tumor percentages of 70%, 60%, 40%, and 20%. Additionally, chemotherapy response scores (CRS) were available in 8 of 16 cases. We correlated the CRS with HRD scores. Results: In this project, visualization of a 523-gene cancer exome panel was shown to be 66.7% sensitive and 100% specific for detecting genomic scars (HRD score). 68.75% of cases showed low HRD score and 31.25% of cases showed a high HRD score. Next generation sequencing (NGS) results for most specimens are adequate with a tumor content rate of 70%. CRS1 cases were HR-proficient. For CRS2 and CRS3 we had mixed results. Conclusions: HRD correlates with platinum sensitivity in epithelial ovarian tumors, which has clinical significance as a predictor of sensitivity to PARPi. During treatment, tissue samples are obtained at different times points and sources, some at diagnosis/surgical debulking and some after neoadjuvant therapy. After neoadjuvant treatment, tumor volume is reduced. Cytology specimens are convenient for obtaining tumoral cells, but tumor volumes are usually small. Profiling tumors of low volume decrease the chances of detecting a patient’s eligibility for targeted maintenance. Our next steps will evaluate the performance of tissue microarrays using the Infinium CytoSNP-850K array compared to NGC cytogenomics at low tumor volumes.
Genomic characteristics of homologous recombination deficiency in ovarian cancer.
Authors: Ma Xiaoxue , Li Mingwei , Lou Feng , Cao Shanbo , Wang Huina
Published: June 2022

e17575

Background: HRD score correlates with sensitivity to PARP inhibitors (PARPi). BRCA1/2 mutations are well-known causes of HRD, but other genetic abnormalities of the homologous recombination repair (HRR) pathway could also cause HRD, although no consensus has been reached. We aimed to analyze HRD score and its relationship with genetic characteristics in ovarian cancer, particularly the HRR-related genes mutations. Methods: Matched tumor/normal DNA from Chinese patients with ovarian cancer (N = 181) were analyzed by Acornmed panel with 98 cancer-related genes. The HRD score is the sum of these scar signature scores, namely, the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). HRR genes mutations and clinical outcomes from the TCGA cohort were included. Results: In our cohort, 44.2% patients exhibited HRR genes mutations, yielded an increment of 12.2% than BRCA mutants. The most frequently mutated HRR genes were BRCA1 (25.0%), BRCA2 (8.0%), CDK12 (4.0%), and RAD51D (4.0%). Chinese cohort contained frequently somatic mutation of HRR genes compared with TCGA cohort (22.7% vs 13.6%, p < 0.010). Germline mutations of HRR genes and non-HRR genes occurred in 21.5% and 2.8% of cases detected, respectively. HRD score in HRR-related genes wildtype was lower than tumors with BRCA1/2 mutation and HRR genes mutation without BRCA1/2 carriers (median HRD score 33, 72 and 64; p < 0.001). Interestingly, no difference was observed in HRD scores between patients with somatic BRCA-mut and germline- BRCA mutants. The median HRD score in our cohort was 65 (range from 0 to 96), and 58.6% patients were HRD-high with the cutoff of HRD score ≥ 42. The HRD-high patients covered 89.7% of the BRCA-positive cases, besides, approximately 77.3% of the BRCA-wt/HRR-mut patients also harbored high HRD scores. Six mutated genes were significantly different between HRD-high and HRD-low group. ARID1A was frequently mutated in patients with HRD-low, while significantly more mutations in TP53 were identified among HRD-high patients. Interestingly, in the TCGA cohort, patients with TP53-mut (p = 0.024) and individuals without ARID1A mutation (p < 0.001) had remarkably high survival rates, as compared with the rest of these patients.Furthermore, tumors with HRD-high had a bit higher TMB (median TMB 4.56 vs 2.91, p = 0.018). Conclusions: Our data suggest that HRR genes mutations strongly affect HRD score, which may increase the number of patients who may benefit from PARPi treatment, and combining gene mutations and HRD score could optimize prognosis stratification in ovarian cancer. In addition, the molecular features of HRD provide new opportunities to predict the tumor response to multiple treatments.
Early mortality in epithelial ovarian cancer.
Authors: McMinn Erin , Nasioudis Dimitrios , Latif Nawar A. , Cory Lori , Ko Emily Meichun , Giuntoli Robert
Published: June 2022

e17585

Background: Investigate the prevalence and characteristics of patients with epithelial ovarian carcinoma (EOC) who experience early mortality defined as death within 90 days of diagnosis. Methods: The National Cancer Database was accessed, and patients diagnosed with a pathologically confirmed EOC between 2004-2015 were identified. Patients who died within 90 days from diagnosis were identified. Clinico-pathological characteristics were compared with the chi-square and Mann Whitney U test. Results: A total of 150064 patients diagnosed with EOC were identified; 13561 (9%) patients died within 90 days from diagnosis with a decreasing incidence per year of diagnosis (from 9.8% in 2004 to 8% in 2015). These patients were older (median 76 vs 61 years, p < 0.001), more likely to be Black (11.4% vs 7.1%, p < 0.001), have government-issued insurance (75.6% vs 45.4%, p < 0.001), median income < 48000$ (45.1% vs 37.9%, p < 0.001), comorbidities (35% vs 19.1%, p < 0.001), reside closer to treatment facility (median 8 vs 12.3 miles, p < 0.001) and present to non-academic facilities (68.5% vs 58.1%, p < 0.001). Incidence of early mortality was 3.6% for patients aged < 65 years, 11.2% for those 65-79 years and 28.6% among those > = 80 years. For patients who experienced early mortality, 6067 (44.7%) did not receive any treatment, 2969 (21.9%) received chemotherapy only, 3345 (24.7%) underwent surgery only and 1180 (8.7%) received both. The rate of patients who did not receive any treatment was higher for patients aged > = 80 years (25.6%) compared to those aged 65-79 (6.9%) and < 65 years (2.5%), p < 0.001. For patients who underwent surgery, median inpatient stay was 9 days while unplanned readmission rate within 30-days from discharge was 10.8%. After controlling for insurance, type of treatment facility, comorbidities, income, race, and stage, octogenarians had higher odds of early mortality (OR 6.02, 95% CI: 5.65, 6.41) compared to those aged < 65 years. Higher odds of early mortality were also observed among octogenarians who received chemotherapy (OR 4.28, 95% CI: 3.84, 4.77) or surgery (OR 5.72, 95% CI: 5.15, 6.35) compared to those < 65 years, after controlling for the aforementioned confounders. Conclusions: Approximately 1 in 10 patients diagnosed with ovarian cancer will expire within 90 days from diagnosis. These patients are older and more likely to have medical comorbidities. More than 1 in 4 octogenarians with ovarian cancer will die within 90 days of diagnosis. Some of these patients may not be candidates for active treatment; however, interventions that facilitate timely presentation, target frailty, and allow medical optimization are greatly warranted.