bluuebunny/crossref_metadata_2025 huggingface dataset:
Some plant metabolites from Petasítes sp. and their effect on cancer cells motility in vitro.
Authors: Timofeeva Sofia V. , Kit Oleg I. , Filippova Svetlana Yu , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Gnennaya Nadezhda V. , Shamova Tatiana V. , Novikova Inna A. , Enin Yaroslav S. , Burov Oleg N. , Zlatnik Elena Yu , Menshenina Anna P. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Zhenilo Oksana E. , Poryvaev Yuriy A. , Myagkova Tatiana Yu. , Pozdnyakova Viktoria V. , Adamyan Meri L.
Published: June 2022

e15077

Background: Plant metabolites are traditionally a valuable source of anticancer drugs. The huge variety of molecular structures found in plants makes it possible to isolate substances that possess not only antimitotic, but also anti-migratory properties on cancer cells. The objective of this study was to evaluate the anti-migratory activity of selected metabolites from Petasítes sp. plants. Methods: Cells of cancer cell cultures PC3 (prostate cancer), A431 (skin cancer), CaCo-2 (colorectal cancer), HeLa (cervical cancer) and T98G (glioma) were seeded in an amount of 15*104 cells per well of a 24-well plate (Biofil, China) in DMEM medium (Gibco, USA) supplemented with 10% FBS (HyClone, USA). After cell adhesion the test substances at a concentration of 40 µM were added, and a wound healing assay was performed according to the standard procedure. The study included the following metabolites: 1) substance 1 (S1) - 2,4-dihydroxy-2,5-dimethylfuran-3(2H)-one; 2) substance 2 (S2) - 5-(hydroxymethyl)furan-2-carbaldehyde; 3) substance 3 (S3) - corynan. The wound area was measured using a Lionheart FX imager (BioTek, USA) at starting time point and after 48 hours of cultivation. Data are presented as mean±95% confidence interval (n = 12). Results: The studied cultures were found to be differently sensitive to the tested substances. Cells of CaCo-2 and PC3 cultures did not demonstrate a significant decrease in mobility, as the degree of scratch overgrowth did not decrease compared to the control without the addition of substances (α = 0.05, df = 22) in all variants of the experiment. However, the A431 skin cancer culture showed reduced motility in all three trials compared to the no-substance control. Namely, the wound area reduction was 81.52 ± 9.6% in the control, 63.77 ± 8.4% in S1 variant, 62.42 ± 6.3% in S2 variant, and 12.05 ± 7.1% in S3 variant. Also, a slowdown in cell motility was observed in HeLa (28.92±5.1% compared to 37.0±6.3% in control) and T98G cells (82.41±9.1% compared to with 97.35±1.9% in control) when incubated with S1. Taking into account the correction for multiple comparisons, only the results for A431 turned out to be significant, but the results obtained for HeLa and T98G cultures were not significant at a corrected significance level (α = 0.003, df = 22). Conclusions: Further studies of 2,4-dihydroxy-2,5-dimethylfuran-3(2H)-one anti-migratory properties are of particular interest, since it showed promising results in three of the five studied cancer cell cultures.
Risk of second primary malignancies among appendiceal cancer survivors in the United States.
Authors: Wong Krista Michelle , Ramsawak Seshma , Abuamsha Hasan
Published: June 2022

e15514

Background: Appendiceal cancer (AC) survival rates have improved over the last decade. The risk of second primary malignancy (SPM) in AC survivors has become an important concern. Therefore, this study aimed to estimate the risk of SPM in patients with primary AC. Methods: We performed a retrospective cohort study of patients ≥18 years of age diagnosed with AC between 2000-2016 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. The study endpoint was the occurrence of SPM diagnosed after two months of the index AC. We calculated the standardized incidence ratio (SIR) with 95% confidence intervals (CI) for SPM in AC survivors by using the SEER software. Results: Of 9578 patients with AC, 598 (6.2%) developed a SPM. The overall risk of SPM for all sites was significantly increased in AC patients (SIR = 1.46, 95% CI 1.34-1.58). The highest risk of developing a SPM was seen in ages < 60 years, females, and Asian/Pacific Islanders, respectively (SIR = 1.84, 95% CI 1.64-2.07; SIR = 1.55, 95% CI 1.38-1.74; SIR = 1.72, 95% CI 1.12-2.52). The SPM sites associated with increased incidences included the small intestine, followed by the appendix, splenic flexure of the colon, and peritoneum/omentum/mesentery. There was an increased risk of developing non-Hodgkin lymphoma, but no elevated risk with developing second leukemias. Surgery and chemotherapy were associated with an increased incidence risk of SPM, respectively (SIR = 1.45, 95% CI 1.33-1.57; SIR = 1.47, 95% CI 1.25-1.71). Conclusions: AC survivors have an increased incidence of developing SPM, most notably in the small intestine, which suggests a pathophysiological process affecting derivatives of similar embryological origin. Long-term surveillance for SPM is recommended for AC survivors, especially those at high risk.[Table: see text]
Impact of hospital teaching status on outcomes of colorectal cancer in hispanic patients: A nationwide analysis.
Authors: Farooq Umer , Franco Diana , Ghous Ghulam , Ma Irene
Published: June 2022

e15520

Background: Previous studies described lower mortality in teaching hospitals after colorectal surgery. Hispanics represent a growing minority in the USA. Given their scarcity of representation in clinical studies, it is imperative to study the impact of teaching status on hospital outcomes from colorectal cancer (CRC) in the Hispanic population. Methods: We investigated the National Inpatient Sample 2017-2019 using International Classification of Diseases-10 (ICD-10) codes to include adult Hispanics with CRC. Mortality, morbidity, resource utilization, and surgical outcomes were compared stratified by hospital teaching status. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student's t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses. Results: Out of 72,599 included patients, 15,895 were treated at non-teaching and 56,704 at teaching hospitals. Patients treated at teaching hospitals had 21% lower odds of inpatient mortality (Adjusted odds ratio (aOR) for mortality 0.79, 95% confidence interval (CI): 0.64 – 0.97, P= 0.03). There were no differences between markers of resource utilization (length of stay, hospital charges, and ICU admission). Patients at teaching hospitals had higher odds of acute renal failure (aOR 1.15, 95% CI: 1.02 – 1.30, P= 0.02). Rates of acute respiratory failure, lower GI bleeding, and sepsis were comparable between the two groups. Colectomy and procedure-related complication rates (including intubation, post-operative DVT/PE) were equal between the two studied groups except for post-operative adhesions, which were higher at teaching hospitals (aOR 1.29, 95% CI: 1.05 – 1.58, P= 0.01). Conclusions: There appears to be no difference in colectomy rates in teaching or non-teaching hospitals, which results in comparable in-hospital mortality in Hispanics. However, ARF and post-operative adhesions were more in teaching hospitals. Continued efforts are required to provide better access to healthcare and address morbidity disparities while caring for minorities.[Table: see text]
Investigation of the DPYD, TYMS, ENOSF1, MTHFR, CDA, CES2, and UGT1A1 genes in patients who developed fatal fluoropyrimidine-associated toxicity in Northern Brazil.
Authors: Fernandes Marianne R. , Costa Danielle Feio da , Barra Williams Fernandes , Rodrigues Juliana Carla Gomes , Gonçalves Millene Arruda Bechara , Fontoura Raiza Martins , Moraes Francisco Cezar Aquino de , Pereira Esdras Edgar Batista , Burbano Rommel Mario Rodriguez , Assumpção Paulo Pimentel , Latorre-Pellice Ana , Amigo Olalla Maroñas , Guerrero Raquel Cruz , Santos Sidney Emanuel Batista dos , Álvarez Ángel María Carracedo , Santos Ney Pereira Carneiro dos
Published: June 2022

e15532

Background: Fluoropyrimidine-based treatments are still considered challenging due to the wide variability in efficacy and toxicity rates presented by patients. This variability can be explained, partially, by individual genetic differences that contribute significantly to the response of the drug, with 30% of patients experiencing severe toxicity related to dihydropyrimidine dehydrogenase (DPD) deficiency and 5-Fluorouracil (5-FU) metabolism. Methods: This study analyzed the exome of the main genes involved in the fluoropyrimidine metabolism pathway ( DPYD, TYMS / ENOSF1, MTHFR, CDA, CES2, and UGT1A1) in seven patient who developed fatal 5-FU toxicity diagnosed with gastric or colorectal adenocarcinoma and underwent fluoropyrimidine-based cancer treatment. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Results: A total of 74 genetic polymorphisms were identified, 25 of which stand out due to their potential role in the safety of 5-FU administration. Eight variants are exclusive of the studied population (two found in the DPYD gene, two in the MHFR, one in the CES2, and three in the UGT1A1 gene) and 17 have already been associated with fluoropyrimidine efficacy and/or toxicity events: 10 of them are located in the DPYD gene (rs1801159, rs2297595, rs72728438, rs17376848, rs1801160, rs1801265, rs22447512, rs5568, rs56038477, rs56276561, and rs56293913), two in the intergenic region of the TYMS/ ENOSF1 genes (rs11280056 and rs699517), two in the MTHFR gene (rs1801131 and rs1801133) and three in the CDA gene (rs1048977, rs2072671, and rs3215400). Conclusions: The current study has allowed us to obtain a global profile of genetic variants in the pharmacokinetic and pharmacodynamic pathways of fluoropyrimidines in patients with high genetic miscegenation in the northern region of Brazil who have evolved to death due to the fatal toxicity resulting from 5-FU-based therapies. Keywords: Pharmacogenomics; Exome; 5-Fluorouracil; Drug toxicity; Brazil.
Impact of metastasectomy for extrahepatic disease in stage IV colon cancer: A retrospective cohort NCDB analysis.
Authors: Fabregas Jesus C. , Sahin Ilyas , Rogers Sherise C. , Ramnaraign Brian Hemendra , Nassour Ibrahim , Hughes Steven J. , George Thomas J.
Published: June 2022

e15548

Background: Stage IV colon cancer has a dismal prognosis with a 5-yr survival rate of only 14%. The role of liver metastasectomy is well established. However, it is not clear if there is a survival benefit for metastasectomy in cases of extrahepatic disease. Methods: We conducted a retrospective cohort study, US hospital-based. The NCDB version 2017 was accessed. Exposure variable: metastasectomy for extrahepatic distant disease, analyzed as binary. Outcome: overall survival. Kaplan Meier curves and log rank test were used for survival analysis. The primary endpoint was to estimate the association between metastasectomy and survival. Covariates demographic factors, age, sex, race, insurance status, site of metastatic disease – lung, liver, bone, brain. A Cox proportional hazards model was used to evaluate the impact of metastasectomy of extrahepatic disease in patients with stage IV colon cancer. 95% confidence intervals and p values of less than 0.05 were used for statistical significance. Missing data as handled with complete and available case analysis. Statistical analysis was done using Stata 16. Results: A total of 68,334 adult patients with stage IV colon cancer diagnosed in from 2010 -2016 were included in the final analysis. Median age was 64 years (SD 14.1). Prevalence of metastases in this stage IV population was as follows: Liver 72.12%, Lung 20.12%, Bone 5.06%, Brain: 1.6%. A total of 10,595 patients (15.5%) had metastasectomy. Median overall survival were as follows: Lung, 21.59 months with surgery vs 8.41 months no surgery. Bone, 7.03 mo vs 4.53 mo respectively; Brain 9.3 mo vs 3.15 mo; Liver 33.28 mo vs 10.97 mo. In univariate analysis, patients with lung metastases had an improved survival if they had metastasectomy (vs no surgery, HR 0.58, p < 0.0001, 95% CI 0.52 – 0.60). The same benefit was observed in patients with bone (HR 0.80, p 0.001, 95% CI 0.69 – 0.91) and brain metastases (HR 0.56, p < 0.001, 95%CI 0.49 – 0.65). In multivariable analysis the survival advantage was still significant. In a sensitivity analysis, excluding patients with liver metastases, the improvement in survival persisted. Conclusions: Metastasectomy for extrahepatic disease improved overall survival in patients with colon cancer in this retrospective analysis. Further research is needed before routinely incorporating it in clinical practice.[Table: see text]
Irinotecan combined with Panitumumab or cetuximab as third-line treatment for metastatic colorectal cancer.
Authors: Braghiroli Maria Ignez , Vicentini Maria Fernanda Batistuzzo , Fonseca Leonardo Gomes da , Souza Karla Teixeira , Bonadio Renata Colombo , Braghiroli Oddone Freitas Melro , Mathias Maria Cecília Machado , Talans Aley , Zambrano Mendoza Maria Elizabeth , Martins Juliana Goes , Sabagga Jorge , Moniz Camila Venchiarutti Motta Venchiarutti , Hoff Paulo Marcelo
Published: June 2022

e15551

Background: Literature suggests that the addition of cetuximab can overcome the resistance to irinotecan treatment for metastatic colorectal cancer (mCRC). It is unknown if the combination of panitumumab with irinotecan could also revert treatment resistance and offer a better response rate after progression on irinotecan monotherapy. In this study, we aim to compare the impact of panitumumab plus irinotecan (P+I) or cetuximab plus irinotecan (C+I) on overall survival as a third line mCRC treatment. Methods: This is a single institution, retrospective cohort analysis, evaluating the overall survival of mCRC patients exposed to an anti-EGFR antibody plus irinotecan, upon progression on irinotecan monotherapy. Overall survival function was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: We identified 460 patients with mCRC that fulfilled inclusion criteria, treated between July 2008 and April 2018. One hundred eighty-three (183) patients received (I+C), and 277 received (I+P). Upon diagnosis, the median age was 55.9 years (range, 19 - 83 years), with a male to female ratio of 1.3:1. All patients received the combination of irinotecan and anti-EGFR targeting antibodies for at least one cycle (D1 and D15). Partial response occurred in 22.6% of patients [23.5% for (I+C) and 22.0% for (I+P)], and 25,2% had stable disease [27.8% for (I+C) and 23.6% for (I+P)]. Interestingly, response rate in patients with right-sided tumors was 3.3% in the (I+C) regimen and 14.3% in the (I+P) regimen. The disease control rate was 50.3% in the (I+C) combination and 45.7% in the (I+P) combination (p = 0.358). The median overall survival (mOS) for all patients was 9.63 months, 8.97 to the group C+I and 10.74 to P+I (p = 0.73). Regarding primary tumor location, the mOS was 6.34 mo for right-sided tumors and 10.74 mo for left-sided tumors (p = 0.022). The 3-year survival rate was 5.6% for the (C+I) treated patients and 3.2% for (P+I). Conclusions: (P+I) and (C+I) combinations showed similar response rate and mOS as a third-line treatment for mCRC, suggesting that both anti-EGFR agents can be used in this setting. A perceived tendency for a superior response with the (I+P) regimen in right-sided tumors might warrant further investigation in prospective studies.
Comprehensive landscape of tumor angiogenesis via integrating RNA sequencing and three-dimensional microphysiological system.
Authors: Ko Jihoon , Hyung Sujin , An Minae , Park Se Hoon , Kim Seung Tae , Kang WonKi , Jeon Noo Li , Lee Jeeyun
Published: June 2022

e16058

Background: The prognosis of gastric cancer (GC) patients with peritoneal metastasis with malignant ascites is very poor. We developed an in vitro tumor angiogenesis platform “TumorAngioChip” to reproduce tumor angiogenesis in 45 gastric cancer patients and mapping their angiogenesis characteristics. This platform, which can predict the features of tumor angiogenesis and drug responsiveness in patient’s samples, opens up potential for a variety of combination therapies, including ramucirumab. Methods: We built a PDC library for the study based on samples of 45 GC patients receiving treatment at Samsung Medical Center. For all patient samples, whole exome and transcriptome sequencing was performed for subtype clustering. TumorAngioChip was fabricated by design prototyping through 3D printing and mass production through injection molding. Patient-derived tumor angiogenesis reconstructed on TumorAngioChip was analyzed using an algorithm for morphological image processing of 3D images obtained through confocal microscopy. Results: Of 45 GC patients, we investigated TumorAngioChip analysis and transcriptome sequencing to classify them as KDR-High (N = 24) and KDR-Low (N = 21) ( P = 4.481e-08, Wilcoxon signed-rank test). In the TumorAngioChip–patient mapping analysis, we clearly demonstrated that GC patients with high KDR level regardless to their GC TCGA subtype had high index of tumor-induced angiogenesis and cancer invasiveness measured by TumorAngioChip ( KDR-High vs. KDR-low group; mean sprouting length: 1.455 × 103 vs. 0.946 × 103, respectively, P < 0.0001; vessel density: 3.470 vs. 2.637, respectively, P < 0.0001; sprouts number: 219 vs. 111, respectively, P < 0.0001; vessel total length: 4.931 × 104 vs. 3.919 × 104, respectively, P = 0.0011). Conclusions: This study is the first attempt to elucidate cancer angiogenesis in large-scale GC patients via a microfluidic-based in vitro system. By integrating transcriptome sequencing and TumorAngioChip-based 3D morphological image processing, we demonstrated tumor angiogenesis mapping for GC patients and further revealed the benefits of ramucirumab in individual patients. The application of TumorAngioChip shows its potential as a novel preclinical drug screening platform to identify effective angiogenesis inhibitors reflecting TME for the first time.
Alofanib in subsequent therapy for advanced gastric cancer: Final results from the phase Ib clinical trial.
Authors: Tsimafeyeu Ilya , Vladimirova Liubov Yu , Mochalova Anastasia , Besova Natalia , Statsenko Galina , Rykov Ivan , Utyashev Igor A. , Raskin Grigory , Kazey Vasily , Artamonova Elena , Moiseyenko Vladimir , Tjulandin Sergei
Published: June 2022

e16077

Background: Alofanib (RPT835) is a first-in-class allosteric inhibitor that induces conformational changes in the extracellular domain of FGFR2. Here, we present the final results of the phase Ib clinical study (RPT835GC1B) of alofanib. Methods: Patients with metastatic gastric adenocarcinoma resistant to standard therapy with measurable disease were eligible. The dose finding part used a 3+3 design, starting with a dose level of 50 mg/m2, intravenously, 5 days on, 2 days off. Five dose levels were foreseen. Primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included toxicity, PK, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: 21 patients were enrolled. 4 (19.1%), 14 (66.7%), 9 (43%), 3 (14.3%), and 12 (57%) patients had ECOG PS 2, ≥2 metastatic sites, liver metastases, bone metastases, and 3-6 lines previous therapy, respectively. The MTD has not been reached and dose of 350 mg/m2 has been declared as recommended phase II dose. With median follow-up of 13.0 months 15 (71.4%) patients had any grade treatment related adverse events (TRAE). Grade 3-4 TRAE occurred in 6 (28.6%) patients. Two (9.5%) patients discontinued treatment due to grade 3 diarrhea and grade 4 reactions immediately after injections. There were no treatment-related deaths in the study. One partial response (5.26%) with a duration of 18.53 months was identified. Disease control rate (DCR) was 68.4% and median duration of stable disease was 4.91 months. Median PFS was 3.63 (95% CI 1.58–5.68) months. Median OS was 7.0 (3.82–10.18) months. 6-month OS rate was 57.1%. OS was almost 2 times better in patients with DCR (median 10.05 vs. 5.9 months) and without bone metastases (8.6 vs. 3.1). Only one patient (4.8%) had FGFR2 amplification (time to death was 7 months). PK parameters linearly changed depending on the dose level, but no correlation with efficacy was found. Table summarizes rate of TRAE and DCR in dose cohorts. Conclusions: Alofanib was feasible and showed early signals of efficacy in heavily-pretreated patients with metastatic gastric cancer. A phase 2 randomized trial is planned. Clinical trial information: NCT04071184. [Table: see text]
Global multi-center phase I trial of the intraperitoneal infusion of anti-EpCAM x anti-CD3 bispecific antibody catumaxomab for advanced gastric carcinoma with peritoneal metastasis.
Authors: QI Changsong , Wu Shikai , Kim In-Ho , Cai Shirong , Wang Jufeng , Kim Seung Tae , Wang Jaw-Yuan , Bai Li-Yuan , Lin Cheng-Yao , Liang Zhezhao , Wei Jian Xin , Shen Lin
Published: June 2022

e16102

Background: Advanced gastric cancer (GC) patients (pts) have high incidence of peritoneal metastasis (PM), resulting in ascites, cachexia and poor life quality. EpCAM is highly expressed on GC but no on peritoneum. Catumaxomab intraperitoneal infusion (i.p.) was previously demonstrated to eradicate EpCAM+ cancers and control the malignant ascites in Europe (Heiss. Int. J. Cancer.2010). We present initial safety, pharmacokinetics (PK), and efficacy from the multi-center phase I trial of Catumaxomab on GC pts with PM in Asian population (NCT04222114). Methods: GC pts who had progressed on at least two prior standard systemic therapies with peritoneal metastasis were enrolled. Pts received Catumaxomab i.p. of 10 μg, 20 μg, 50 μg and 150 μg on days 1, 4, 8 and 11, respectively in the 1st cycle. From the 2nd cycle, Pts received Catumaxomab i.p. of 20 μg, 50 μg, 150 μg on days 1, 4 and 8, respectively. The cycle was 42 days in Cohort A, and 28 days in Cohort B. Catumaxomab PK were evaluated, tumor measurements and quantification of ascites by five-point method (Oriuchi, JJCO,2005) were performed Q6W. The primary endpoint was overall survival (OS); secondary endpoints were response rate of ascites, progression-free interval of peritoneal metastatic lesions and puncture-free survival (PuFS); Data cut-off date was Jan 29,2022. Results: 17 pts from 14 sites (median age: 52.5 yr, ECOG PS: 0 [n=2], 1 [n=14], 2[n=1], Cohort A:9, Cohort B:8) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was pyrexia (76.5%) and abdominal pain (58.8%). Grade ≥3 treatment related adverse events (TRAE) of abdominal pain (23.5%), bilirubin conjugated increased (23.5%), lymphocyte count decreased (17.6%), ALT increased (11.8%), and AST increased (11.8%) were reported. No treatment related death or neurotoxicity occurred in the study. Median overall survival was 102 days (95%CI: 38-166), with 10 (58.8%) deaths observed. For ascites, CR+PR was observed in 4 cases (33%), no PD case was reported. No therapeutic ascites drainage was recorded after cycle 1. Median PuFS was 116 days (95%CI: 28-157). Median progression-free interval of peritoneal metastatic lesions was 102 days (95%CI: 38-166). PK: Catumaxomab concentrations in plasma increased in a dose-dependent manner and were similar to Caucasian population in Europe. Conclusions: This clinical study indicated that multiple cycles of Catumaxomab i.p. were safe and well tolerated in Asian population. PK profile was similar. Early efficacy signals were promising, especially in pts with ascites, which will be further investigated in phase 3 study. Clinical trial information: NCT04222114.
Comprehensive molecular characterization of Chinese patients with biliary tract cancers.
Authors: Liu Daren , Ye Dan , Wu Jinhong , Yu Yangyang , Zhao Lele , Xiao Mingzhe , Qi Chuang
Published: June 2022

e16153

Background: Biliary tract cancers are clinically heterogenous with poor prognosis. The traditional location-based classification of biliary tract cancers is helpful while the boundary between subtypes is still ambiguous. We hereby analyzed the comprehensive molecular characterizations across different types among biliary tract cancers and further to identify the similarities and differences and help with the individualized treatment. Methods: Tumor tissue samples from 219 Chinese biliary tract cancer patients were profiled by next generation sequencing with a 539 gene panel by the Illumina NovaSeq 6000 (Illumina, San Diego, CA, USA) sequencing platform. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. Results: A total of 219 biliary tract cancer (BTC) patients with a median age of 61 years(range 29–83 years) were enrolled, including 147 gallbladder cancer (GBC), 51 intrahepatic cholangiocarcinoma (iCCA) and 21 hilar cholangiocarcinoma (hCCA). These samples consisted of 93 males and 126 females. The most frequent mutated genes were TP53 (73%), ARID1A (18%), MUC16 (16%) in GBC, TP53 (57%), KRAS (35%), ARID1A (16%), PIK3CA (16%) in iCCA, TP53 (48%), KRAS (29%), ARID1A (14%) in hCCA. The mutation of BCORL1 (P = 0.002) and IRF4 (P = 0.006) had a significant association with age. The median TMB was 4.26 mutations/Mb in GBC, 2.94 mutations/Mb in iCCA and 2.84 mutations/Mb in hCCA. Patients with ATM mutation and FAT1 mutation had a significant higher TMB level (P＜0.001). The mutations of common target genes in different types of BTC were analyzed. The mutations of IDH1, target gene of Ivosidenib, were detected in 4 (1.83%) patients (1 in GBC, 2 in iCCA, 1in hCCA). The mutations of FGFR1/2/3/4, target gene of Erdafitinib, were detected in 10 (4.57%) patients (8 in GBC, 2 in iCCA, 0 in hCCA). The most frequently affected pathways in GBC, iCCA and hCCA were TP53 (78.2%, 60.8%, 47.6%), RTK-RAS (52.4%, 64.7%, 47.6%), PIK3 (34%, 39.2%, 33.3%). Conclusions: The genomic profiling and molecular characterization among different anatomic locations could support the exploration of tumor development mechanism and provide theoretic basis for developing diagnosis and treatment methods for biliary tract cancers patients.
GATA6 amplification is associated with improved survival of TP53-mutated pancreatic cancer.
Authors: Yang Jung-In , Ha Taehoon , Zhou Edward , Tzanavaris Chris , Deschênes Astrid , Boyd Jeff , Hollweg Christopher , Zhu Xinhua , King Daniel
Published: June 2022

e16285

Background: Recent investigation in pancreatic adenocarcinoma (PDAC) demonstrates an association of molecular subtype with chemosensitivity and prognosis. TP53 and GATA6 are two genes independently associated with worse survival in PDAC. Here, we evaluated treatment outcome by genetic alterations of TP53 and GATA6 among patients with pancreatic cancer across New York’s largest health care system. Methods: This is a retrospective analysis of patients at Northwell Health diagnosed with PDAC between 2014 to 2021. Surgical status was used to segregate patients into two groups: resected and unresected. TP53 and GATA6 mutation status was compared for disease-free survival (DFS) (resected) or progression-free survival (PFS) (unresected), and for overall survival (OS). Additionally, patient survival by type of chemotherapy administered was evaluated. The Kaplan–Meier method was used to determine overall survival (OS), and the Wilcoxon test was used to compare survival curves. Results: Tumor mutational profiling data were available for 129 patients. TP53 mutations were found in 105 patients (81.4%), GATA6 amplifications were found in 18 patients (14.0%), and 16 patients had both mutations. TP53 mutations were associated with a worse OS compared to the wild-type TP53 population (n = 24) (median OS 22.7 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.5 to 80.3, HR 1.97, p = 0.048). Among patients with a TP53 mutation, a survival advantage was observed in those who had a GATA6 amplification compared to those who did not (median OS 25.5 months, 95% CI 10.9 to 44.6, vs. 22.1 months, 95% CI 12.6 to 51.5, HR 1.68, p = 0.038). In patients with unresected PDAC, the survival advantage of GATA6 amplification within TP53 mutated group was more prominent than the absence of the amplification (median OS 23.8 months, 95% CI 10.0 to 56.5, n = 12 vs. 10.5 months, 95% CI 4.4 to 24.8, n = 55, HR 0.52, p = 0.008). In the TP53 mutation group, among 33 patients who received Gem/NabP as the first-line chemotherapy, patients with GATA6 amplification (n = 8) had significantly improved survival compared to those without GATA6 amplification (n = 25) (mean OS 23.1 months, 95% CI 8.5 to 63.0, vs. 9.4 months, 95% CI 3.44 to 26.6, HR 0.51, p = 0.027). Conclusions: Genetic mutations in TP53 were associated with shorter OS than wild-type TP53. Contrary to our initial expectation that co-mutation would be associated with even worse survival, we found that GATA6 amplification appeared to attenuate poor prognosis observed in TP53-mutant patients. Additionally, GATA6 amplification may be a predictive marker for better responses to Gem/NabP chemotherapy.
Prognostic value of CA 19-9 and carcinoembrionic antigen (CEA) in duodenal adenocarcinoma (DA): An institutional retrospective cohort study.
Authors: Altshuler Ellery , King William , Richhart Raymond , Hones Keegan , Mathavan Akash , Mathavan Akshay , Leach Daniel F. , Murtaza Yasmeen , Lee Jimmy , Manfrini Denise , Mathavan Mohit , Chowdhury Zahara , Rogers Sherise C. , Nassour Ibrahim , Ramnaraign Brian Hemendra , Sahin Ilyas , Franke Aaron J , George Thomas J. , Hughes Steven J. , Fabregas Jesus C.
Published: June 2022

e16306

Background: Duodenal adenocarcinoma (DA) is a rare malignancy with poor outcomes. Tumor markers are used to assess disease response and to monitor for recurrence. Specifically, CA-19-9 and CEA have been validated for use in pancreatic cancer and colorectal cancer, respectively. However, these tumor markers have never been validated in patients with DA. We aim to assess the association of these biomarkers with clinical outcomes in patients with DA. Methods: This is a retrospective cohort study. After obtaining IRB approval (IRB202102705), we accessed the University of Florida medical records of patient treated for DA from January 1, 2006, until December 31, 2021. CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal CA 19-9 < = 35 U/ml; CEA < = 3 ng/ml). Analysis was conducted using Kaplan Meyer curves, log-rank test and Cox proportional hazards model. Results: A total of 68 patients were included in the final analysis. Median age was 67 years and median follow-up was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. Patients with an elevated CA 19-9 had a median overall survival (OS) of 8.5 months vs. 27.4 months in patients with normal levels (HR 1.67; 95%CI 0.94–2.99; p = 0.081). Patients with an elevated CEA had a median OS of 13.4 months vs. 16.8 months in patients with normal level normal levels (HR 1.43; 95%CI 0.81–2.52; p value = 0.221). In a sensitivity analysis, a concomitant elevation of both tumoral markers was significantly associated with worsened OS (HR 1.9; 95%CI 1.05–3.06; p = 0.035). Conclusions: In patients with duodenal adenocarcinoma, elevation of both CA 19-9 and CEA was associated with a statistically significant worse overall survival. CA 19-9 level had a higher prognostic impact on OS than CEA levels. To our knowledge, this is the first study to evaluate the role of CA 19-9 and CEA in patients with DA. Further research is required for validation.[Table: see text]
In vitro and in vivo investigations of anlotinib in bladder cancer treatment.
Authors: Meng Zeji , Pei Xinqi , Gu Yanan , Li Lei , He Dalin , Wu Kaijie
Published: June 2022

e16505

Background: Bladder cancer is one of the most common malignancy in urinary system. Fibroblast growth factor receptor 3 (FGFR3) is the most common alteration gene in bladder cancer, occurring in approximately 70% of non-metastatic bladder cancer and 20% of metastatic bladder cancer. Anlotinib is a potent oral, multi-target tyrosine kinase inhibitor with a favorable safety which mainly targets vascular endothelial growth factor receptor (VEGFR), FGFR, platelet-derived growth factor receptors, and c-kit. This study aims to investigate the role of anlotinib in bladder cancer compared with FGFR3 inhibitor erdafitinib i n vitro and in vivo. Methods: MTT, colony formation, and Transwell assays were performed on bladder cancer cells (SW780 and UMUC14) to confirm the effects of anlotinib and erdafitinib on proliferation, migration and invasion. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the protein and mRNA were examined by RNA-seq, Western blotting and RT-qPCR. Finally, mice with palpable xenografts were treated either with anlotinib and erdafitinib for 8 days before they were sacrificed for measuring the sizes and weights of the tumors. Results: To assess the roles of anlotinib in bladder cancer, we treated SW780 cell line which had FGFR3-BALAP2L1 fusion mutation and UMUC-14 cell line which had a FGFR3 (MuS247C) mutation with DMSO, anlotinib and erdafitinib. As seen in MTT, colony formation and Transwell assays, anlotinib repressed cell proliferation, migration and invasion as erdafitinib. Compared with vehicle, Anlotinib promoted cell apoptosis of bladder cancer cells. To further explore the mechanism, anlotinib and erdafitinib suppressed p-Erk1/2 and p-AKT, while only anlotinib inhibited the expression of VEGF-a. Compared with erdafitinib, the inhibitory ability of anlotinib was weaker than that of erdafitinib in cell line with FGFR3 (MuS247C) mutation, on the contrary, it was much stronger in cell line with FGFR3-BALAP2L1 fusion mutation. In addition, the in vivo data from xenagrafts also supported that anlotinib could significantly repress tumor growth with FGFR3 fusion mutation, and the efficacy was better than erdafitinib. Conclusions: Anlotinib could repress the proliferation, migration and invasion of bladder cancer cells by inhibiting the phosphorylation of Erk1/2 and AKT, and the suppression VEGF-a expression, whose effects was better than erdafitinib in bladder cancer with FGFR3 fusion mutation. Therefore, anlotinib might be a potential novel targeted agent to treat the bladder cancer patients with FGFR3 fusion mutations, and clinical trials are needed for further investigation.
VISIOCYT1 clinical trial: Artificial intelligence for the diagnosis of bladder urothelial lesions.
Authors: Lebret Thierry , Radulescu Camélia , Guy Laurent , Roumiguié Mathieu , Courtade-Saïdi Monique , Piaton Eric , Verhoest Gregory , Rioux Nathalie , Savareux Laurent , De Vergie Stéphane , Renaudin Karine , Kandel Christine , Gonzalez Samia , Borgès Ruth , Cochand-Priollet Béatrix , Nivet Sebastien , Pignot Geraldine
Published: June 2022

e16558

Background: Voided urinary cytology is a non-invasive test, but it suffers from a lack of sensitivity (Se), particularly in low-grade urothelial lesions, and it remains pathologist-dependent. In order to improve the performance of urinary cytopathology, the VitaDX company (France) developed a medical device which uses whole-slide digitalization and artificial intelligence algorithms to identify tumor cells. The device allows complete analysis of morphological characters of voided urothelial cells, such as the shape, size and color of the nuclei. Methods: VISIOCYT1 is a prospective, multicenter clinical trial involving 319 patients divided into two groups: 1) patients with non-muscle invasive bladder tumors (NMIBC) confirmed by histology, and 2) control patients with negative urinary cytology and cystoscopy. The primary objective of the study was to evaluate the Se of the VisioCyt test. Specificity (Sp) and comparison of Se and Sp of conventional urinary cytology vs. the VisioCyt test were also calculated. Results: A total of 319 patients were included (170 in the NIMBC group vs. 149 controls). Overall Se was 80.9% and 45.9% for VisioCyt test and conventional urinary cytology, respectively (p = .002). Negative cytology being an inclusion criterion, a 100% Sp was attributed to the control group. It was calculated at 61.8% for the VisioCyt test. Concerning grade, the VisioCyt test allowed higher Se to be obtained in the low grade tumor category (66.7% vs. 26.1% for conventional urinary cytology, Mc Nemar test, p < .0001). A higher Se was also observed in high grade tumors: 93.7% vs. 62.8% (p < .0001). Conclusions: The VisioCyt test greatly improves the performance of urinary cytopathology in the diagnosis of urothelial bladder tumors, particularly in low grade, pTa lesions. Its implementation could dramatically reduce the need for cystoscopy in patients followed after conservative treatment of bladder cancer. Clinical trial information: NCT02966691. [Table: see text]
Combining IL-12 immunocytokine (M9241) with docetaxel in metastatic prostate cancer: A phase I study.
Authors: Atiq Mohammad O. , Chandran Elias Bin Aris , Meininger Luke , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Strauss Julius , Redman Jason , Floudas Charalampos S. , Pastor Danielle M. , Owens Helen , Hankin Amy , Williams Monique , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit
Published: June 2022

e17033

Background: M9241 is an immunocytokine that targets single- and double-stranded DNA which allows the treatment to localize IL-12 to necrotic tumor (Xu, CCR 2017). M9241 was well-tolerated as a monotherapy in a Phase I study with solid tumors (Strauss J, CCR 2019). Additional preclinical data has demonstrated synergy of M9241 with cytotoxic therapy. This is the first study to examine the safety of a novel combination of chemotherapy and immunocytokines in metastatic prostate cancer. Methods: This safety analysis included patients with mCSPC or mCRPC. Patients were enrolled in a 2-dose level (DL) escalation cohort of M9241 (DL 1: 12mcg/kg, DL 2: 16.8mcg/kg) combined with docetaxel (75mg/m2) with 6 patients planned per DL. A third DL of 8mcg/kg will enroll 6 more patients after the 16.8mcg/kg DL has fully enrolled. All patients were treated with ADT. Patients were initiated on treatment with docetaxel with a plan for mCSPC patients to receive six 3-week cycles of combined treatment and mCRPC patients to continue until progression or unacceptable toxicity. M9241 was given starting with the second cycle of treatment for each patient. Dose-limiting toxicity (DLT) was evaluated in the first 6 weeks after start of docetaxel (from cycle 1 day 1 through the end of the first cycle with M9241). Results: The study has enrolled 10 patients out of a planned 18 for the safety portion. Age range is 58-82 with a median of 69 years. Race distribution is 80% White and 20% Black. Gleason scores for patients were 8 (40%), 9 (40%), and 10 (20%). No DLTs were seen with either dose-level. Only 1 patient had a Grade 4 AE, neutropenia. Grade 3 toxicities included anemia, diarrhea, leukopenia, and hypotension (each occurring in 10% of the patients). The most frequent adverse events (AEs) of any grade were anemia (40%) and lymphopenia (40%), followed by fatigue (30%), diarrhea (20%), and fever (20%). Conclusions: We established a safe dose-level of M9241 at ≥ 12mcg/kg. Updated clinical data from the safety cohort (n = 18) will be presented. This demonstrates that an immunocytokine and chemotherapy can be safely combined for treatment in metastatic prostate cancer. Two planned expansion cohorts will evaluate docetaxel and M9241 in mCSPC and mCRPC, respectively. Clinical trial information: NCT04633252.
Systematic review of real-world evidence studies in women’s cancer at key congresses and factors related to high tier acceptance.
Authors: Szamreta Elizabeth A. , Modi Mansi , Periyasamy Ramu , Yamsani Bhavani , Kulkarni Sumedha , Monberg Matthew J.
Published: June 2022

e17533

Background: Real-world evidence (RWE) studies complement clinical trials (CT) and address a variety of issues, such as adherence, cost, comparative effectiveness, and treatment patterns. This systematic review assessed prevalence and characteristics of RWE presented at oncology congresses. Methods: Data on women’s cancers (cervical, ovarian, endometrial, and multiple [gyn/other]) work were extracted from the databases of American Society of Clinical Oncology (ASCO) and The Society of Gynecological Oncology (SGO) congresses (2018-2020). The primary objective was to identify the proportion of CT vs RWE. Secondary objectives were to: a) describe the tier of acceptance for RWE vs CTs; b) describe prevalence of types of RWE; c) analyze the characteristics (data source, design, authorship, outcome(s) assessed, and presence of statistically significant results) associated with RWE acceptance. Results: Of 3163 abstracts screened, 2271 were included (1756 RWE vs 515 CTs). RWE represented a higher proportion of work at SGO vs ASCO (90% vs 59%). Overall, more RWE vs CTs was accepted as a poster (75% vs 60%) or publication only (19% vs 11%), while less was accepted for oral presentation (4% vs 20%). Among RWE, 90% had academic author(s), 44% used clinical data, around one quarter used another data repository/registry, and about 14% used medical record or chart review data. Nearly two thirds of RWE studies reported significant results, while 6% contained no significant results. There was no clear association between authorship or significance of results and tier of acceptance. About 60% of RWE studies were retrospective, 9% were prospective, 4% focused primarily on PROs, and 2% were economic models. The most common outcomes assessed in RWE studies were molecular analyses (18%) and survival based on treatment efficacy (13%). Among molecular analyses, most (68%) were accepted as a poster, with 26% accepted as publication only and 4% as oral. An even greater fraction (77%) of survival/efficacy analyses were accepted as a poster, 18% as publication only and even fewer (2%) as oral. Conclusions: RWE was more frequently presented than CTs at both ASCO and SGO. However, across congresses and cancer types, a smaller proportion of RWE vs CT work was accepted as an oral presentation. Results indicated high interest in CTs; RWE studies utilizing clinical data or data repository/registry data, and those with molecular and/or survival outcomes, were most common. The results demonstrate that while RWE studies are prevalent and provide valuable data for healthcare decision-making, they do not always achieve the visibility of CTs.[Table: see text]
PACSIN3 is a novel biomarker for platinum resistance BRCA mutated platinum resistance epithelial ovarian cancer.
Authors: Han Gwan Hee , Cho Hanbyoul , Yun Hee , Kim Jae-Hoon
Published: June 2022

e17540

Background: Mutations in breast cancer susceptibility gene type 1 and type 2 (BRCA1 and BRCA2) put women at a higher risk of developing epithelial ovarian cancer (EOC). In individual carrying BRCA1 mutation has about 39-49% of the probability developing EOC in a lifetime. With BRCA2 mutations, the probability of developing EOC is about 11- 18 %. EOC patients with BRCA mutations shows an advanced histological grade compared to patients with BRCA wile type and respond better to platinum therapy, showing better survival. Patients with BRCA mutation shows better response to the platinum therapy, because in the absence of functional BRCA protein, cells fail to repair intra-strand crosslinks formed by DNA cross linking agents such as platinum drugs, leading to apoptotic cell death. However, despite the good response to platinum-based chemotherapy, EOC patients inevitably develop resistance to platinum drugs resulting in disease recurrent and is a major roadblock in a clinical management of cancer that carry BRCA mutation. Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing. Methods: RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients were analysed with various bioinformatic tools including Spatial Analysis of Functional Enrichment (SAFE) analysis, and the bioinformatic analysis result was verified with variuos ovarian cancer cell lines and public data. Results: Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients. The results of our study showed 308 total differentially expressed genes (DEGs) with 138 upregulated genes and 170 downregulated genes. By applying Spatial Analysis of Functional Enrichment (SAFE) analysis, we investigated that G2/M transition of mitotic cell cycle, MAPK cascade, double strand break repair via homologous recombination were the enriched pathways with upregulation of PABPC1, DCAF13, RAD21, PACSIN3 and downregulation of GCG11, HECW2, PSMA1. Their altered expression was verified in ovarian cancer cell lines and public database which showed the significant altered expression of PACSIN3 was observed in ovarian cancer cell lines suggesting as a potential biomarker for EOC treatment. Conclusions: Platinum resistance BRCA mutation EOC is an important issue to overcome the low survival rate for EOC patients. However, until now, there was relatively not much studies in discovring the biomarker or candidate gene of target therapy. Therefore, here we suggest the PACSIN3 as a new candidate gene for target therapy in platinum resistance BRCA mutation EOC.