bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of clinical efficacy by plasma concentration of apatinib in patients with solid tumor.
Authors: He Hongtao , Wang Lixing , Huang Guanglei , Liu Rongfeng , Yuan Meng , Xing Penghui , Shan Baoen , Shi Jian
Published: June 2021

e15000

Background: To explore the correlation between plasma concentration of apatinib and clinical efficacy. Methods: 42 patients were enrolled. Plasma specimens of all patients were collected. At 7:40 am, fasting blood was drawn as plasma trough concentration (Ctrough). At 8 am, apatinib mesylate (APA-M, 250mg qd) was orally administrated. At 11 am, venous blood was drawn as plasma peak concentration (Cpeak). Each patient has Ctrough and Cpeak samples. A total of 84 plasma samples were obtained. The concentration of APA-M in plasma was determined by UPLC-MS/MS. Results: 1) 42 patients were evaluable. Treatment response was assessed by RECIST1.1. 2 patients achieved complete response (CR), 16 partial response (PR), 12 stable disease (SD) (tumor shrinks), 5 SD (tumor enlargement), 7 progressive disease (PD). Objective response rate (ORR) was 42.9% (18/42) and disease control rate (DCR) was 83.3% (35/42). 2) On day 1 and 456 after oral APA-M from different patients, median trough concentration (Ctrough median) was 264.38 ng/ml (1.18 ng/ml-918 ng/ml), and median peak concentration (Cpeak median) was 543.61 ng/ml (71.11 ng/ml-1609.4 ng/ml), respectively. 3) The Ctrough median in patients with CR, PR and SD (tumor shrinks) was significantly higher than that SD (tumor enlargement) and PD ( P＜0.05). There was significantly difference between CR and PR with SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR ( P＞0.05). (Table) 4) The Cpeak median in patients with CR, PR, SD (tumor enlargement) and PD was significantly higher than that SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR with SD (tumor enlargement) ( P＞0.05). (Table). Conclusions: The plasma Ctrough of Apatinib can predict the clinical efficacy of patients with solid tumor. Perspective clinical studies with adequate sample size are required to validate our results. [Table: see text]
PIK3CA-TP53 co-mutation as a biomarker of overall survival in malignant tumor.
Authors: Wang Hongyan , Zhao Xiaopeng , He Xu , Wang Miao , Zhang Haoran , Cheng Jingge , Wu Yaqing , Luo Ningning , Qi Yingxue , Duan Qianqian
Published: June 2021

e15001

Background: Overall survival (OS) is an important endpoint, with the advantage that there is minimal ambiguity in defining an OS event; the patient is either alive or dead. Some single gene mutations, such as TP53, were identified as important predictors of shorter OS in malignant tumors. However, the relationship between gene co-mutation and OS of malignant tumors is poorly defined. Methods: Genomic and OS data were derived from The Cancer Genome Atlas (TCGA) databases. We defined the double-mutant gene pair as “hit pair” in the specific cancer type if statistically significant OS difference was observed in at least one of three comparison (double-mutant samples vs gene A-only-mutant samples; double-mutant samples vs gene B-only-mutant samples; gene A-only-mutant samples vs gene B-only-mutant samples). Results: PIK3CA-TP53 co-mutation was evaluated as “hit pair” in seven cancer types: GBM (Glioblastoma multiforme), HNSC (Head and neck squamous cell carcinoma), LUSC (Lung squamous cell carcinoma), SARC (Sarcoma), SKCM (Skin cutaneous melanoma), UCEC (Uterine corpus endometrial carcinoma), and UCS (Uterine carcinosarcoma). In SARC and SKCM, the expected hazard ratio was higher in both-mutant group than TP53-only-mutant group, and neither genes were correlated with OS. Especially in SKCM, after we took “neither” group (both genes were wild-type) into comparison, hazard ratio of both-mutant group was significantly higher than neither group. Single-gene mutation didn’t make difference on hazard ratio, which indicated that the both-mutant interaction made the leading contribution. In GBM, LUSC, and UCS, the significant difference of hazard ratio between TP53-only-mutant group and PIK3CA-only-mutant group was neutralized in the both-mutant group, to some extent equivalent to “average effect (OS curve of double-mutant group was between that of only single gene mutant groups)". For PIK3CA-TP53 in HNSC, both-mutant group and TP53-only-mutant group carried with a higher hazard ratio than PIK3CA-only-mutant group. It suggested that the increasing hazard ratio in both-mutant group might be resulted from TP53 mutation. For the circumstance in UCEC, TP53 and PIK3CA were testified to be correlated with higher and lower hazard ratio, respectively and both-mutant group and TP53-only-mutant group both with significantly higher hazard ratio than PIK3CA-only-mutant group, which further verified the greater strength of TP53 than PIK3CA in both-mutant group. Conclusions: In summary, our study identified PIK3CA-TP53 co-mutation as a predictor of OS in seven cancer types: GBM, HNSC, LUSC, SARC, SKCM, UCEC, and UCS, especially in SARC and SKCM.
Anti-PITPNM3 small molecular compounds reverse breast cancer metastasis by targeting PITPNM3.
Authors: Gong Chang , Liu Zihao , Lin Qun , Shi Yu , Luo Qing , Cen Yinghuan , Li Juanmei , Fang Xiaolin , Jiang Wenguo
Published: June 2021

e15005

Background: Recent studies highlight the fundamental roles of PITPNM3 in breast cancer metastasis. PITPNM3 is identified as the functional receptor of CCL18 and promotes breast cancer cell invasion and metastasis by binding with CCL18. Since anti-CCL18 neutralized antibodies shows medium binding affinity which restricts their clinical application, small molecular inhibitors targeting PITPNM3 are needed to be further investigated. Therefore, we identified several first in class small molecular inhibitors potentially targeting PITPNM3 and can inhibit breast cancer metastasis conducted by PITPNM3 activation. Methods: We performed computer-assisted drug design by constructing PITPNM3 homology model, characterizing potential binding pockets and docking preselected high diversity structured small molecule compounds into the static PITPNM3 model. Top 100 small molecules in silico scores were selected and screened through basic experiments. After screening, the anti-metastasis effects of selected compounds were tested through transwell migration and invasion assay. Immunofluorescence and qPCR were applied to confirm the expression of vimentin and CDH1. Western blot were used to clarify the inhibition effects of selected compounds on PITPNM3 signaling pathways. Results: By using homology remodeling, we successfully constructed the PITPNM3(680-920aa) protein model. The PITPNM3(680-920aa) domain is responsible for interacting with PYK2 and phosphorylating PYK2. The phosphorylation of PYK2 conducted by PITPNM3 signaling pathway will lead to metastasis and epithelial-mesenchymal transition (EMT) of breast cancer cells. We then characterized the potential binding pockets of this static model and a druggable site was founded. More than 50K molecules with high diversity were docked into this druggable site and scored through their docking performance. Finally, top 100 scored small molecules were selected. In addition, through 1 rounds of toxicity screening, 1 round of transwell migration assay screening and 1 round of transwell invasion assay screening, 4 small molecules with higher bioactivity is identified and 1 compound with the highest bioactivity as well as docking performance among 50K small molecules is chose. This compound can inhibit CCL18 treatment as well as tumor associated macrophage co-culture mediated migration and invasion. Besides, it can also inhibit the phophorylation of PYK2 and Src without inhibition the expression of PITPNM3. Conclusions: Our findings identify the first-in-class anti-PITPNM3 small molecule inhibitors. These compounds can inhibit PITPNM3 signaling pathway and reverse breast cancer metastasis.
The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.
Authors: Mohiuddin Md , Kimura Hideharu , Watanabe Satoshi , Abo Miki , Sone Takashi , Saeki Keigo , Terada Nanao , Tanimura Kota , Kasahara Kazuo
Published: June 2021

e15009

Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.
Antitumor efficiency of combination of bortezomib and themosolomide on subcutaneous PDX-model of human glioblastoma.
Authors: Volkova A. V. , Evgenievich Rostorguev Eduard , Goncharova Anna S. , Mindar M. V. , Zaikina Ekaterina V. , Khodakova D. V. , Lukbanova Ekaterina A. , Kurbanova L. Z. , Khatyushin Vladislav E. , Kavitskiy Sergey E.
Published: June 2021

e15011

Background: Poor clinical effects of standard treatment for glioblastoma determine the need for the development of new therapeutic strategies. Aberrant functioning of the proteasome system, as well as activation of the HIF-1α signaling pathway, are characteristic of glial tumor cells; they can be considered as potential therapeutic targets in the treatment of malignant brain tumors. One of the possible options for improving the results of glioblastoma treatment may involve strategies for inhibiting the HIF-1α pathway. Bortezomib, a proteasome inhibitor, can block the biological effects of HIF-1α. Bortezomib showed a pronounced antitumor effect in in vitro testing on various models of solid malignant tumors, giving grounds for further studies of its effectiveness in vivo. Patient-derived xenograft (PDX) models are characterized by a variety of cell subclones and are therefore considered the most reliable tool for predicting therapeutic responses. Methods: A PDX model of glioblastoma was created in 20 Balb/c Nude mice implanted with a subcutaneously inoculated human glioblastoma. Temozolomide (0.5 mg/kg), bortezomib (0.25 mg/kg), or a combination of temozolomide and bortezomib were administered intraperitoneally daily for 21 days. The tumor histotype was confirmed by histological analysis (staining with hematoxylin and eosin). The antitumor effect was determined by the inhibition of tumor growth (ITG%), the volume of tumor nodes, and the index of tumor growth. Results: The highest value of the inhibition of tumor growth (ITG%) was registered in the group of animals receiving a combination of temozolomide and bortezomib – 85.38%. The values in the groups receiving temozolomide or bortezomib monotherapy were 57.32% and 63.11%, respectively. Conclusions: An analysis of the antitumor efficacy of bortezomib combined with temozolomide in human subcutaneous PDX-glioblastomas demonstrated their synergistic effect.
Cell-surface vimentin positive circulating tumor cells as a diagnostic and prognostic indicator in pediatric sarcoma patients.
Authors: Dao Long , Ragoonanan Dristhi , Foglesong Jessica , Batth Izhar Singh , Zaky Wafik Tharwat , Gill Jonathan Benjamin , Liu Diane D. , Albert Aisha , Gordon Nancy Beatriz , Huh Winston W. , Harrison Douglas James , Herzog Cynthia E. , Kleinerman Eugenie , Gorlick Richard Greg , Daw Najat C. , Li Shulin
Published: June 2021

e15022

Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains only reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods: Here, we enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients. Results: We discovered the CSV+CTC could serve as a possible biomarker of disease with sensitivity of 85.3% and specificity of 75%. Significantly, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative (773 days vs 2622 days). Addition of readily available genetic analyses improved the sensitivity in both diagnostic and prognostic tests. Conclusions: Our findings indicate that CSV+ CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.
Significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China.
Authors: Song Yuntao , Liu Jie , Wang Weiran , Ma Tonghui
Published: June 2021

e15028

Background: Ultrasound and ultrasound-guided fine needle aspiration (US-FNA) are a preferred method for judging benign and malignant thyroid nodules. For thyroid nodules that can’t be determined by FNA, molecular markers of thyroid cancer can be detected as assistant method. This study aim to verify the significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China. Methods: We carried out a prospective study of 383 FNA samples of thyroid nodules, and performed targeted multi-gene NGS on most samples with FSZ-Thyroid NGS Panel V1, the result of which would be incorporated into the reference index for clinicians to decide whether a patient should undergo surgery. And postoperative pathology were followed up. The NGS targets were divided into three categories: high risk (BRAF V600E, TP53, PIK3CA, AKT1, CTNNB1, RET, KRAS with VAF≥30%, HRAS with VAF≥30%, NRAS with VAF≥30%, RET fusion, NTRK1 fusion, NTRK3 fusion, ALK fusion, BRAF fusion), low risk (BRAF non-V600E, EIF1AX, GNAS, TSHR, TERT, KRAS with VAF < 30%, HRAS with VAF < 30%, HRAS with VAF < 30%, PPARG fusion, THADA fusion), benign like (EZH1, SPOP, ZNF148 or no mutations). Results: Among the 383 FNA samples, 333 of them were sequenced with FSZ-Thyroid NGS Panel V1, and 211 thyroid nodules were resected. Finally, postoperative pathology showed that 180 nodules was malignant and 31 was benign. Among the 180 malignant tumors, BRAF V600E (71.1%), RET fusion (7.8%), and TERT mutation (2.8%) were the top three most mutated genes; and there were also significant differences in frequency of some mutations between malignant tumors in different BSRTC class, including more BRAF V600E (83.6%) in class VI malignant tumors, more gene fusions (26.1%) in class V malignant tumors which was significantly higher than that in class VI (7%). And, the frequency of RAS mutations (8.3%) in class III and IV malignant tumors was higher than that of class V and VI. Here a test was considered as positive if a genetic alteration was annotated with High-Risk, and negative if Low-Risk or Benign-Like, the sensitivity and specificity for detecting malignant tumors in BSRTC class III-IV were 66.7% and 100%, respectively, and the total sensitivity and specificity for BSRTC class I-VI malignant tumors were 85.6% and 100%. In addition, 21 of 383 patients underwent Re-FNA. Among these 21 patients, 11 patients detected high risk mutations and 90.9% (10/11) underwent upgrade of BSRTC class on Re-FNA. As a comparation, among the remaining 10 patients who detected low risk or benign like sites, only 30% (3/10) underwent upgrade of BSRTC class on Re-FNA which suggested that the detection of high risk sites might predict the upgrade of BSRTC class on Re-FNA. Conclusions: Molecular testing can distinguish between benign and malignant thyroid nodules and predict the upgrade of BSRTC class on Re-FNA which could provide the reference for treatment decision-making of thyroid nodules in China.
Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.
Authors: Kharbanda Surender , Mohammad Anees , Tiwari Sachchidanand , Mehrotra Neha , Appajosyula Sireesh , Laumas Sandeep , Singh Harpal
Published: June 2021

e15047

Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.
Cardiovascular toxicities associated with ibrutinib in elderly patients.
Authors: Yudiono Jason , Sorooshian Hormozan
Published: June 2021

e15061

Background: Ibrutinib is as a first line treatment option for chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström’s macroglobulinemia. It is also FDA approved as a subsequent therapy for mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease. Cardiovascular (CV) toxicities, such as atrial fibrillation (afib), are some of the most common reasons for modifying ibrutinib therapy and tend to occur within the first few months of initiation. There is currently no FDA approved recommendation to reduce the dose of ibrutinib in the elderly, despite the greater incidence of afib in this patient population. It is unclear if this increased incidence leads to subsequent treatment modification in the elderly. Thus, further review of CV toxicities amongst Kaiser Permanente members may provide evidence to offer a reduced starting dose of ibrutinib in the elderly. Methods: This retrospective, multi-center study evaluated patients who started ibrutinib between January 1, 2014 and January 1, 2020 at an FDA approved dose per indication. Patient charts were reviewed from the time of treatment initiation up to one year of treatment or death, whichever came first. Data such as demographic information, diagnosis, adverse events, and ibrutinib treatment modifications were collected from chart review. The primary objective of this study was to determine if elderly (70 years or older) patients starting ibrutinib experienced a greater incidence of CV toxicities resulting in treatment modification and/or death. CV toxicities were only included if they occurred within the first year after starting ibrutinib. Results: Of the 50 patients included in this study, 23 (46%) patients initiated ibrutinib at an elderly age (70 years or older). Three (11.1%) non-elderly and two (8.7%) elderly patients underwent treatment modifications due to CV toxicities (p=0.78). Three additional patients experienced CV toxicities without further treatment modifications. Two (one per patient group) patients had already suspended ibrutinib for hepatic and/or hematological toxicities when they experienced afib. One non-elderly patient was hospitalized for afib but continued ibrutinib as originally prescribed. Conclusions: This study did not detect a significant difference in CV toxicities between elderly and non-elderly patients. Cardiac arrhythmia rates appeared slightly higher than those reported in clinical trials, but this may be due to the smaller sample size of this study. At this time, further evidence is needed to support a lower starting dose for elderly patients on ibrutinib.
Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.
Authors: Xu Libin , Liu Ming , Duan Jingxian , Wang Tao
Published: June 2021

e15072

Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]
Potential of 1.3-diethylbenzimidazolium triiodide in experimental therapy for lung cancer.
Authors: Shikhlyarova Alla I. , Trepitaki Lidia K. , Kaplieva Irina V. , Frantsiyants Elena M. , Kharagezov Dmitry A. , Milakin Anton G. , Leyman Igor A. , Stateshny Oleg N. , Volkova Viktoriya L. , Lazutin Yuriy N.
Published: June 2021

e15094

Background: The practice of thoracic oncology demonstrates that the lungs often become affected by cancer. The antitumor effect of chemoradiation therapy can be poor, and surgical treatment is associated with reduced functionality of the organ and therefore reduced quality of life of patients. Therefore, nonspecific agents are required that combine a pronounced antitumor effect and, at the same time, restore pulmonary tissue. Our purpose was to study the effects of 1,3-diethylbenzimidazolium triiodide in a rat model of lung cancer by morphological analysis of pulmonary tissues. Methods: An experimental model of lung cancer was created in 60 male and female rats by subclavian infusion of sarcoma 45 cell suspension in the saline at a dose of 0.5 ml (2×106). Iodine-containing preparation was administered enterally at 0.4 mg/kg daily for 5 days with a 2-day interval; treatment was started immediately after the intravenous injection of malignant cells, the therapy lasted for 8 weeks. The morphological control of the lungs was performed at decapitation of animals, tissue processing and staining, by light microscopy using the LEICA DM LS2 microscope with magnification of up to x100. Results: Hematogenous introduction of tumor cells into the lung caused hemorrhage, “acute swelling” of the alveoli, microabscesses, distelectasis, colonization of interalveolar septa with tumor cells and the formation of large metastatic foci. Involutive changes in the tumor tissue were noted together with signs of pulmonary regeneration: after 5 weeks of the treatment – pronounced activation of immune cells and occurrence of elastic fibers with reserve tortuosity; after 8 weeks - active proliferation of epithelial elements that form the bronchial-alveolar apparatus, an increase in surfactant activity in hypertrophied alveoli, and a significant strengthening of the elastic and collagen framework of the alveolar walls. Conclusions: Morphological correlates of the experimental effect of 1,3-diethylbenzimidazolium triiodide indicate its strong antitumor properties and potential for improving the recovery capabilities of the structure-forming elements of the lung.
Healthcare utilization and outcomes in HIV versus non-HIV patients with anal cancer: A nationwide analysis.
Authors: Achebe Ikechukwu , Asotibe Jennifer C , Sherazi Syed Ali Amir , Obi Okechukwu , Attar Bashar , Gupta Shweta , Mullane Michael Russell
Published: June 2021

e15505

Background: Anal cancer (AC) is the most common HPV-associated cancer in men with HIV. Nearly one third of men with anal cancer have HIV with HPV accounting for 88% of cases. Studies have reported mixed outcomes in HIV-Anal Cancer (HIV-AC) compared to non-HIV-AC patients with most studies being small and retrospective. There were no clear explanations for the differences in the outcomes in both groups. We studied HIV-AC patients from a national database and compared the outcomes and healthcare utilization with non-HIV AC cohort. Methods: We identified all adult patients with AC, with and without HIV, between 2016-2018 from the Healthcare Cost Utilization Project (HCUP) National Inpatient Sample (NIS) database. The groups were compared for socio-demographic differences, inpatient mortality, length of stay (LOS) and total hospital charges (THC). Secondary outcomes studied were rate of acute kidney injury (AKI), tumor lysis syndrome (TLS), lower GI Bleed (LGIB), anemia, tumor lysis (TLS), sepsis, septic shock (SS), neutropenia and protein energy malnutrition (PEM). Statistics was performed using the t-test, univariate and multivariate logistic regression using Stata software. Results: A total of 1235 inpatient admissions with HIV-AC and 10,415 with non-HIV-AC were identified. HIV-AC patients were significantly younger (mean age 50.2 vs 63 years, p < 0.0001) with few over 65 years (8% vs 44.2%, p < 0.0001), more men (82.6% vs 30.8%, p < 0.001), more likely African Americans (AA) (47.8% VS 11.2%, p < 0.0001) and significantly more likely to be treated at a teaching hospital (90.7% vs 9.3%, p < 0.0001) compared to non-HIV-AC cohort. HIV-AC patients had significantly lower odds of inpatient mortality (aOR= 0.26, CI = 0.093 – 0.705, p = 0.008) but higher LOS (7.4 vs 6.5 days, p = 0.02) and higher THC ($74,131 vs $60,864, p = 0.005). Rates of sepsis were higher in HIV-AC (OR = 2.11, CI = 1.465 - 3.028, p < 0.0001) compared to non-HIV-AC, but odds of AKI, TLS, LGIB, SS, anemia, neutropenia and PEM were similar. Conclusions: HIV-AC patients are more likely to be younger, AA, men and have significantly lower inpatient mortality compared to non-HIV-AC, despite higher rates of sepsis. HIV-AC patients being younger and overwhelmingly (90%) treated at teaching hospitals may be contributing to the observed lower mortality. However, the HIV-AC cohort was also a high inpatient healthcare utilizer with significantly increased hospital charges amounting to over $16 million over 3 years. The reversal of sex incidence likely reflects the different exposure to HPV in HIV and non-HIV cohorts. Prospective studies are needed to further evaluate outcomes in HIV-AC patients and identify underlying contributors of higher utilization.
Circulation of tumor cells to destroy correlations in immune system of colorectal cancer patients.
Authors: Sitkovskaya Anastasia O. , Zlatnik Elena Yu. , Kit Oleg I. , Novikova Inna A. , Bondarenko Elena S. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Vereshchak Maksim A. , Katelnitskaya Oksana V. , Savchenko Dmitriy A. , Tolmakh Roman E.
Published: June 2021

e15508

Background: The most important stages of metastatic cascade are extravasation and invasion of malignant cells and their surviving in blood. The vast majority of circulating tumor cells (CTC) is destroyed by immune cells. The role of immune system which is able to play not only antitumor but also prooncogenic role is manifested both on local and systemic levels. We studied correlations between lymphocyte subsets` content in blood and in tumor of colorectal cancer patients (II, III, IV stages) with and without CTC. Methods: 60 colorectal cancer patients with II (n = 20), III (n = 20) and IV (n = 20) stages underwent surgery without previous chemotherapy. CTC were measured in blood by CellSearchSystem™ (JanssenDiagnostics, LLC), cell-mediated immunity was assessed in blood by flow cytometry (BD Canto II) and in tissue after surgery by immunohistochemistry; some markers of proliferation and epithelial-mesenchimal transition (EMT) in tumor cells (Ki-67, E- and N-cadherins) were also studied. Criteria of CTC-positive and CTC-negative samples were > 3 and ≤3 respectively. Correlative analysis was performed between the data of the patients with and without CTC in each stage, r was counted. Results: In CTC-positive patients with all the stages the number of strong and moderate correlations between system immunologic factors involving CD8+ appeared to be fewer than in CTC-negative ones (7 vs 19). On the contrary, the number of correlations with T regs in CTC-positive was increased: 5 vs 3 in CTC-negative patients. In patients with CTC > 3 fewer correlations were noted between factors of local and systemic immunity than in CTC-negative ones (9 vs 4 in II stage) and total disruption of all the correlations between system immunologic factors and proliferating tumor cells in III and IV stages was established. Some pathologic correlations appeared in CTC-positive patients like moderate direct one between activated T-lymphocytes` amount and Ki-67+ tumor cells. The number of correlations between intratumoral lymphocytes and tumor cells expressing proliferation and EMT markers in CTC-positive patients was decreased in comparison with CTC-negative ones (4 vs 10 in II stage, 1 vs 9 in III, 2 vs 9 in IV stage). Conclusions: The presence of CTC in colorectal cancer patients rather than tumor stage is associated with imbalance of their systemic and local immunologic factors. This provides some evidence that disruption of interactions in the immune system is at least partly due to CTC.
Analysis of LRP1B as a potential biomarker for colorectal cancer immunotherapy.
Authors: Liu Ruiting , Duan Qianqian , Zhang Qin
Published: June 2021

e15521

Background: Low-density lipoprotein receptor-related protein 1B (LRP1B), a putative tumor suppressor, is one of the most frequently altered gene in cancer. Recently, there are emerging evidences that LRP1B is involved in sensitivity to melanoma and non-small cell lung cancer immunotherapy. Here we explored the relationship between LRP1B mutation and potential effect of immunotherapy for colorectal cancer (CRC) based on multidimensional data. Methods: Next-generation sequencing (NGS) data of CRC patients (n = 536) from TCGA and Chinese clinical dataset (n = 249) was used to evaluate tumor mutational burden (TMB) differences between LRP1B mutation group and wildtype group. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Neoantigens of CRC samples (n = 214) were obtained from The Cancer Immunome Atlas. In addition, we investigated the association of LRP1B mutation with 30 immune-related genes, which were classified into 3 categories: immune checkpoint, T-effector and interferon-γ gene signature, and T cell receptor. Results: 22.95% (123/536) patients in TCGA harbored LRP1B mutation. In the Chinese cohort, the LRP1B mutation ratio (24.50%, 61/249) was similar to TCGA. The TMB level of LRP1B mutation group in both TCGA and Chinese cohort was significantly higher than wild-type group (P < 0.001). The TNB between two group is also showed a significant difference (P < 0.001) in TCGA. Of the 30 immune-related genes, 27 (90.0%) genes are differentially expressed (P < 0.05) and all 27 differentially expressed genes have higher expression levels in LRBP1-mutated samples in comparison with wild-type ones. Conclusions: LRBP1-mutated CRC patients have a higher TMB, TNB and show higher expression level with immune-related genes. These results indicated that LRP1B mutation may serve as a potential biomarker of ICI benefit in CRC patients. Moreover, further clinical insights and prospective validation studies are warranted.
Associations between age and stage at presentation among black and white colorectal cancer patients.
Authors: Starks Victoria , Mitchell Edith P.
Published: June 2021

e15542

Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites. It is suggested that the etiology of this disparity may be inadequate screening for colorectal cancer among racial communities. However, little is known about the correlations between age and stage at presentation among black and white colorectal cancer patients at Thomas Jefferson University Hospital (TJUH). Objective: The objective of this study is to explore diagnostic trends that may unveil differences in age and stage at presentation between black and white colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n= 529) included newly diagnosed colorectal cancer patients treated at TJUH from 2015-2019 and included information regarding race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. The cohort was divided by age (<50, 50-65, >65). Patient age was compared against AJCC stage at presentation. Results: Findings reveal 12.38% of blacks & 14.29% of whites presented before age 50. 36.19% of blacks and 30.19% of whites presented between ages 50-65. 51.43% of blacks & 55.42% of whites presented after age 65. Additionally, the average age at presentation among blacks was 62.71 years vs. 65.71 years among whites. Lastly, the average stage at presentation among blacks was between 2C and 3A while the average stage at diagnosis among whites was between least 2B and 2C. Conclusions: Within this population, similarities exist among age at presentation between black and white patients, however, differences in stage at presentation exist between blacks and whites. Further research is needed explore how these findings inform the poor clinical outcomes seen among black colorectal cancer patients. Future analysis of this cohort will explore trends regarding time to treatment and treatment received after diagnosis, as similar studies have found differences among racial populations.
A cohort study on the molecular mechanism of distinct therapeutic effects and prognosis in Chinese colorectal cancer patients who underwent neoadjuvant or surgical therapies.
Authors: Xu Ye , Mu Tianhao
Published: June 2021

e15544

Background: Colorectal cancer is one of the most common and lethal types of cancer in the world. However, the molecular mechanism of colorectal cancer and predicting biomarkers for prognosis are still not fully understood. Methods: Here, we investigated a cohort study to explore the genetic alteration of Chinese colorectal cancer patients. Primary tumors and metastatic tumors were collected and performed with whole exome sequencing. Distinct therapeutic effects of patients were recorded and analyzed. Overall survival of patients was also collected. Results: 57 patients with colorectal cancer (CRC) were enrolled in this study. The mutation landscape of primary tumors showed that the TOP 10 most frequently mutated genes were APC, TP53, KRAS, FRG1, SOX9, PIK3CA, MUC12, SMAD4, MUC4, and DNAH9. The main genetic mutation type was missense. Both primary tumors and metastatic tumors shared the feature of mutated TP53, APC, and KRAS. However, the primary tumors harbored higher mutated FMN2, PLXNB2, DSCAM, SSPO, and PCDHA13, while the metastatic tumors harbored RYR2, RAB15, WNK1, MUC16, and HERC2. Moreover, APC mutation showed a better overall survival (p = 0.029). Co-mutation of APC and FRG1 also presented a better overall survival than one-mutation or none-mutation types (p = 0.029). In contrast, ARID3A mutation (p < 0.001), NUDT6 mutation (p < 0.0099), ZNF717 mutation (p = 7e-04). Curative surgery showed better overall survival than palliative surgery (p = 0.042). However, EBV infection showed no significant relation to overall survival (p = 0.89). In addition, patients harboring FRG1 or CEL mutation were more sensitive to chemotherapy (p = 0.01 and p = 0.02 respectively), while TMB was not significantly related to the effects of chemotherapy. Interestingly, somatic mutations, including NEURL4, DLGAP5, EML1, MBD3L1, SETBP1, TMC4, YTHDC1, PLXNB2, ARHGAP8, and CHD2 were found to be significantly related to patients with family histories (p < 0.05). Conclusions: In this study, we investigated the mutation landscape of primary tumors and metastatic tumors of Chinese colorectal cancer patients. Moreover, the associations between prognosis and different factors, including genetic mutations, surgery strategies, TMB, EBV, and family histories were explored, which may help shed light on better clinical treatment for colorectal cancer in the future.
A phase I study of SHR7390 plus camrelizumab in advanced/metastatic colorectal cancer.
Authors: Wei Xiao-li , Zhang Yang , Zhao Hongyun , Wang Zhiqiang , Li Yu-Hong , Wang Feng , Wang Fenghua , Fang Wenfeng , He Ming-ming , Luo Huiyan , Qiu Miaozhen , Zou Ben-Yan , Xie Jie , Jin Chunlei , Xu Rui-hua
Published: June 2021

e15553

Background: PD-1 antibody monotherapy has shown durable response in colorectal cancer (CRC) patients (pts) with microsatellite instability (MSI) high status, who account for only 10–15% of all CRC pts. Preclinical studies revealed that inhibition of MAPK pathway with MEK inhibitors can increase T-cell infiltration into tumors and therefore might enhance the antitumor activity of immune checkpoint inhibitor. Thus, this study was conducted to evaluate the safety and antitumor activity of SHR7390, a MEK1/2 inhibitor, plus camrelizumab (anti-PD-1) in pts with CRC. Methods: In this single-arm, open-label, phase I study, pts with treatment-refractory advanced or metastatic CRC were enrolled to receive SHR7390 in an accelerated titration scheme at doses of 0.125, 0.25, and 0.5 mg orally qd, plus camrelizumab at a fixed dose of 200 mg IV q2w. Eligible pts were given a single dose of SHR7390, observed for 7–10 days, and then treated continuously with SHR7390 and camrelizumab in 28-day treatment cycles until disease progression, intolerable toxicities, or withdrawal of consent. A recommended dose for expansion was determined based on the safety and tolerability of the dose escalation stage. The primary endpoints were dose limiting toxicity (DLT) and maximum tolerated dose (MTD). This study is registered with ClinicalTrials.gov, number NCT03182673. Results: At data cutoff on May 30, 2020, 22 pts were enrolled. The median follow-up duration was 6 months. Seven pts had received ≥3 lines of prior treatment. MSI status were available in 21 pts (MSS/MSI-L, n = 18; MSI-H, n = 3). There were two pts each in the SHR7390 0.125 and 0.25 mg cohorts, and 0.5 mg cohort was expanded to 18 pts. One DLT (grade 3 rash) was reported in a pt in the 0.5 mg cohort and the MTD was not reached. Grade 3–4 treatment-related adverse events (TRAEs) were rash (n = 4), increased lipase, oedema peripheral, face oedema, and anemia (n = 1 each). One pt reported a grade 5 TRAE (increased intracranial pressure). Five pts (23%) achieved partial response (0.125 and 0.25 mg cohorts, n = 1 each; 0.5 mg cohort, n =3), including one out of three pts with MSS/MSI-L & BRAF mutant tumors (response lasting 13 months), one out of 15 pts with MSS/MSI-L & BRAF wild type tumors (response lasting 8 months), and all three pts with MSI-H tumors (responses lasting 31, 11, and 10 months, respectively). Three pts with MSS/MSI-L achieved stable disease, and the overall disease control rate reached 36%. Conclusions: SHR7390 plus camrelizumab showed a tolerable safety profile. Preliminary clinical activity was reported regardless of BRAF and MSI status, and future studies are warranted to further evaluate these results. Clinical trial information: NCT03182673.
A retrospective analysis of real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in third line.
Authors: Gathirua-Mwangi Wambui , Yang Tony , Khan Taha , Wu Yixun , Afable Manuel
Published: June 2021

e15575

Background: Colorectal cancer (CRC) is the 3rd leading cause of cancer-related deaths in the US. Anti-epidermal growth factor receptor agents improve outcomes of patients with metastatic CRC (mCRC) and are used in multiple lines of therapy. However, real-world time on treatment (TOT) and overall survival (OS) of cetuximab in third-line (3L) have not been described. Therefore, we sought to evaluate TOT, OS, and associated factors in a retrospective study. Methods: A total of 617 patients diagnosed with mCRC and received 3L treatment with cetuximab containing regimens regardless of prior therapies were selected from the nationwide Flatiron electronic health record database (January 2013 - August 2020). TOT was defined as the time from initiation of cetuximab in 3L (index date), to the last recorded date of cetuximab administration. End of therapy was defined if the patients progressed to subsequent line of therapy, or had a record of death. OS was calculated from the index date to date of death or censored to last visit date available. The Kaplan-Meier estimates, and stepwise Cox models were adapted to identify and calculate hazard ratios (HR), and 95% confidence intervals (CI) for factors associated with TOT and OS. Results: Majority of patients receiving 3L treatment with cetuximab containing regimens were: treated in the community setting (96%), less than 65 years old (58%), overweight with a median body mass index (BMI) of 26.2 kg/m² and, received FOLFOX regimens in 1L (46%) and FOLFIRI in 2L (47%). The most common cetuximab containing regimens were cetuximab+irinotecan (36%) and cetuximab+FOLFIRI (34%) and cetuximab monotherapy. The median TOT (mTOT) for patients receiving 3L cetuximab containing regimens was 3.48 months (median interquartile range (mIQR) 3.02-4.17). Higher BMI (obese vs. underweight HR = 0.44, 95% CI 0.28-0.68) was associated with a longer mTOT, while having an ECOG score ≥1 was associated with a shorter mTOT (vs. ECOG = 0, HR = 1.37, 95% CI 1.10-1.72). Also, of all cetuximab containing regimens in 3L cetuximab + FOLFIRI (vs. cetuximab monotherapy) was associated with a longer mTOT (4.63 months, mIQR 3.45-5.55). The median OS (mOS) for patients receiving 3L cetuximab containing regimens was 11.99 months (mIQR 10.87-12.94). Similarly, higher BMI (obese vs. underweight HR = 0.25, 95% CI 0.16-0.40) and 3L cetuximab + FOLFIRI (mOS= 14.3 months, mIQR 11.66-16.85) vs. cetuximab monotherapy were associated with a longer mOS. OS did not differ by patients geographic region (South vs Midwest, p-value 0.35). Conclusions: In this real-world retrospective analysis cetuximab + irinotecan and cetuximab + FOLFIRI were the most common 3L cetuximab regimens. The most common treatment regimens in 1L and 2L were FOLFOX and FOLFIRI respectively. Overall, BMI and treatment regimens received in 3L were associated with mTOT and mOS.