bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of general anesthetics on the tumor micro-environment in mouse models of breast cancers of spontaneous metastasis.
Authors: Lin Jun , Li Ru , Huang Yujie 
Published: May 2020

e15503 Background: Metastatic breast cancer is a pressing health concern worldwide. Various treatments have been developed but no significant long-term changes in overall survival are observed. Therefore, there is a demand to improve current therapies to treat this disease. Surgical resection of the primary tumors is essential in the treatment. However, accumulating evidence alludes to a role for volatile anesthetics which are used during the surgery in metastatic tumor development, but the mechanism remains largely unknown. We have shown anesthetics exert different effects on lung metastasis in mouse models of breast cancers. This study analyses the effect of general anesthetics in lung microenvironment associated with the increased metastases. Methods: Balb/c mice and NOD-SCID mice were orthotopically implanted with 4T1 cells and MDA-MB-231 cells respectively, in the mammary fat pad to generate primary tumors. Mice were subjected to the tested anesthetic during implantation and/or before and after surgery. Surgical dissection of primary tumor was performed under anesthesia with sevoflurane or an intravenous anesthetic propofol. Survival curve was constructed and analysed. Mice were euthanized to harvest tissues for histology and cell analysis. Results: As we previously reported, surgical dissection of primary tumor in mice under anesthesia with sevoflurane led to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane was associated with increased IL6(Li, Huang, & Lin, 2020). Here we show that anesthesia with sevoflurane resulted in changes of stroma composition in the lung, which was reversed by IL6 pathway interruption. Conclusions: Those results contribute to our understanding of effects of sevoflurane on cancer metastasis and suggest a potential therapeutic approach to overcome the risk of general anesthesia. Li, R., Huang, Y., & Lin, J. (2020). Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models. Nat Commun, 11, 642.
Efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization.
Authors: Zhang Wei , Yan Zhiping 
Published: May 2020

e15504 Background: Effective options for patients with advanced hepatocellular carcinoma (HCC) are urgently needed. Studies have shown that combination of sorafenib with TACE could imorove survival for the treatment of locoregional HCCs. Apatinib is a novel and highly selective inhibitor of VEGFR2 tyrosine kinase. We were aiming to explore the efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Methods: This was a single-center single-arm phase 2 study. The key inclusion criteria included: (1) Histologicaly and cytologicaly diagnosed as Hepatocellular carcinoma of the liver ( HCC ) and with at least one imaging examination of measurable lesions, CT or MR scan long diameter of tumor ≥ 10 mm. (2) BCLC B / C; (3) Progressed after at least twice TACE. Eligible pts received apatinib at 500 mg/day for a maximum after TACE 4-7 days, and TACE treatment was performed after 4 days of discontinuation of apatinib until unacceptable toxicity or tumor recurrence. The primary endpoint was time to progression (TTP), which was defined as the time from enrollment to disease progression. The secondary endpoint was overall survival (OS) and treatment safety. Results: From May 27, 2018 to Oct 12, 2019, 22 pts wereenrolled. 5 pts received TACE more than 5 times, and 17 pts received TACE within 4 times. For 20 evaluable pts, two pts achieved partial response (10%), and 13 patients achieved stable disease. The ORR and DCR were 10% and 75%, respectively. At the cutoff data of Nov 4, 2019, 5 pts were still on treatment. 16 recurrenced and 5 death occurred. The mTTP was 5.09 months (95% CI, 3.48-7.16), and the mOS was not reached. Treatment-related adverse events occurred in 12 pts (60%). Seven grade 3 or 4 adverse events were reported (35%), respectively wereascites (2), platelet count decrease (1), elevated ALT/AST (1), hypertension (1), proteinuria (1) and nausea (1). None of the treatment related AEs was fatal. Conclusions: Apatinib combined with TACE might be effective and tolerant in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Clinical trial information: NCT03510416.
Preclinical study of oncolytic adenovirus-mediated cytotoxic gene therapy with gemcitabine for chemoresistance of desmoplastic tumor.
Authors: Jung Bo-Kyeong , Li Yan , Hong JinWoo , Oh Eonju , Yun Chae-Ok 
Published: May 2020

e15507 Background: Pancreatic cancer is a highly lethal disease. Excessive accumulation of tumor extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. Methods: To overcome the limitations of various conventional therapeutics against desmoplastic pancreatic cancer, we utilized an oncolytic adenovirus (oAd) for combination therapy with gemcitabine, a standard chemotherapeutic for pancreatic cancer treatment. Here, we report the results of preclinical pharmacology and efficology studies conducted in pancreatic cancer model. Results: Efficacy studies in orthotopic pancreatic xenograft tumor model demonstrated that oAd effectively attenuated tumor cell proliferation. oAd further prevented metastasis of pancreatic cancer and sensitized pancreatic tumor to gemcitabine treatment. Furthermore, oAd augmented drug penetration and dispersion within pancreatic tumor xenografts and patient-derived pancreatic tumor spheroids. These results suggest that oAd enhance the therapeutic effect of chemotherapeutic agent in chemo-resistant and desmoplastic pancreatic tumor, thus overcoming the preexisting limitations of standard treatments. Conclusions: Overall, these results demonstrate that local administration of an oncolytic adenovirus with gemcitabine is well tolerated and support moving this investigational approach into human trials.
The KRAS mutation status and resistance to cetuximab in patients with squamous cell carcinoma of oral cavity.
Authors: Lyanova Aza A. , Vladimirova Liubov Yu , Engibaryan Marina A. , Abramova Natalia A. , Popova Irina L. , Ryadinskaya Ludmila A. , Tikhanovskaya Natalia M. , Teplyakova Maria A. , Novoselova Kristina A. , Myagkova Valeriya S , Kutilin Denis S. 
Published: May 2020

e15514 Background: The standard treatment of squamous cell carcinoma of the tongue and the mucosa of the bottom of the oral cavity (SCCTOM) is chemotherapy (CT) in combination with cetuximab (mC, anti-EGFR antibody). However, not all patients manage to achieve positive results. A common cause of resistance to anti-EGFR antibodies is the constitutive activation of mediators of the underlying signaling pathways. Therefore, the aim of the study was to analyze mutations in the KRAS using the Digital Droplet PCR method in patients with SCCTOM on the background of CT in combination with targeted therapy or standard CT. Methods: The study used the QX200 system (Bio-Rad) and the ddPCRtm KRAS Screening Multiplex Kit (7 mutations). The study included 60 patients with T3-4N0-1M0 SCCTOM. The main group consisted of 30 patients (cisplatin, 5-fluorouracil+cetuximab). The control group consisted of 30 patients (CT). For research, cfDNA from blood plasma was used. Analysis of the data was performed using QuantaSoft v1.7.4. Results: The frequency of the KRAS mutant type (mtKRAS) is 43% before treatment and 32% after treatment (n = 60). In the group of patients CT+mC the incidence of mtKRAS before treatment was 40%, after treatment - 20%. In the group of patients CT without mC the incidence of mtKRAS before treatment was 47%, after treatment - 43%. Decrease of 20% (p = 0.00089) in the frequency of mtKRAS after CT+mC was found, while it was 23% (p = 0.00009) lower than the frequency of mtKRAS after CT without mC. After treatment, in the CT+mC group of patients, the number of mtKRAS DNA copies increased 1.5 times (p = 0.048). Analysis of clinical response to therapy allowed us to divide the main and control groups of patients into 2: sensitive and resistant to therapy. After treatment, a change in the mtKRAS ratio was not found in the subgroup sensitive to mC compared with the period before treatment, while the frequency of mtKRAS was reduced by 3 times (p = 0.009). In the mC-resistant subgroup, the mtKRAS ratio increased 1.9 times compared to the period before treatment (p = 0.009), while the frequency of mtKRAS increased 3.5 times compared with the mC-sensitive group (p = 0.0045). Conclusions: Prior to treatment, patients resistant to CT+mC were characterized by an increased occurrence of mutations in the KRAS and an apparently large number of tumor cells carrying mutations. The use of mCs caused a change in the direction of the clonal evolution of tumor cells - leading to an increase in the number of cells carrying mtKRAS (conditions were created for the elimination of cells with mutation in EGFR and KRAS wild type).
A new desensitization protocol, overcoming hypersensitivity reactions to chemotherapy.
Authors: Havasi Andrei Dan , Cainap Calin Ioan , Vlad Ioan-Cătălin , Achimaş-Cadariu Patriciu , Sur Daniel Genel , Meşter (Piciu) Andra , Heputiu-Pater Ana Teodora , Bochis Ovidiu , Balacescu Ovidiu , Crisan Ovidiu , Coza Ovidiu , Balacescu Loredana , Burz Claudia Cristina , Cainap Simona Sorana 
Published: May 2020

e15523 Background: Despite the progress for cancer treatment, some drugs remain a cornerstone for an optimal approach. Hypersensitivity reactions to chemotherapy may render these essential chemotherapeutic agents useless and for some types of cancer continuing the therapeutic scheme could be crucial. Various regimens for desensitization to allow chemotherapy administration through the time were conceived, with different dilutions, time and settings of administration. Methods: A prospective study of patients with systemic treatment for histopathologically confirmed cancer in our Oncological Institute „Prof. Ion Chiricuta” Cluj-Napoca, with an allergic reaction during treatment being the keys inclusion criteria in the analysis. Patients were administered a three days desensitization regimen from the following cycle of treatment with blood samples that were taken to observe the predictive value of biological markers. Results: Eighty-two patients were the initial pool, with a median age of 56 years. Platin derivates containing regiments were responsible for an allergic reaction for 75 out of 82 patients. Four of them were known with a previous allergic reaction for chemotherapy in their personal medical history, and 56 of them had more than one chemotherapy line in their treatment. More than 688 desensitization cycles were administrated during our study with a rate of failure of 1.3 %. The main reason for discontinuation was disease progression or adjuvant character (limited duration) of the chemotherapy administration. Conclusions: Allergic reaction does not impede the administration of the responsible drug. A 3-day inpatient regimen could be a valuable option with a successful rate of administration without the need for ICU monitoring.
Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy.
Authors: Cao Hua , Liu Xinyi , Chen Yixin , Yang Pan , Huang Tanxiao , Song Lele , Xu Ruilian 
Published: May 2020

e15524 Background: Colorectal cancer (CRC) is a highly lethal disease worldwide. The majority of patients receiving targeted therapy or chemotherapy develop drug resistance, while its molecular mechanism remains to be elucidated. The plasma circulating tumor DNA (ctDNA) exhibited the potential in identifying gene variations and monitoring drug resistance in CRC treatment. Methods: In this study, we monitored the ctDNA mutational changes in advanced CRC patients underwent first-line therapy with bevacizumab and cetuximab combined with chemotherapy. The mutation spectrum of 43 patients was established by a 605-gene next-generation sequencing (NGS) panel. Results: The baseline measurement shows that genes with the highest mutation frequency were TP53 (74%), APC (58%), KRAS (40%), SYNE1 (33%), LRP1B (23%), TOP1 (23%) and PIK3CA (21%). Mutations in TP53, APC and KRAS were detected in 29 paired plasma and tissue samples with the consistency of 81%, 67% and 42%, respectively. Clinically targetable gene mutations, such as APC, RNF43, SMAD4, BRAD1, KRAS, RAF1, and TP53, were also identified in ctDNA. The overall consistency between ctDNA and tissue samples was 54.6%. Alleviation of mutational burden in BRAF, KRAS, AMER1 and other major driving genes was observed following the first-line therapy. Patients with KRAS and TP53 mutations in tissues appeared to benefit more than the wild-type counterpart. The dynamic change of plasma mutation status was consistent with the tissue tumor burden and was closely correlated with disease progression. Conclusions: ctDNA monitoring is a useful method for molecular genotyping of colorectal cancer patients. Dynamic changes in resistance can be sensitively monitored by gene variation status, which potentially helps to develop treatment strategy.
Effect of local activation via SQ3370 on the safety of chemotherapy with concomitant anti-tumor immune response.
Authors: Srinivasan Sangeetha , Yee Nathan A. , Mahmoodi Amir , Zakharian Michael , Mejia Oneto Jose Manuel 
Published: May 2020

e15525 Background: With systemic chemotherapy, only 1-2% of the dose given reaches a local tumor, while the remaining leads to off-target toxicities. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our approach (SQ3370) consists of: 1. SQL70 - drug-activating biomaterial carrying 2. SQP33 - chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. Methods: SQL70 is injected at the tumor site followed by SQP33 given systemically. The prodrug is captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects. Results: We have shown that the greater safety of SQ3370 allows significantly higher doses to be administered compared to conventional Dox. PK studies in rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to active Dox. A single SQL70 injection selectively activated multiple doses of SQP33 at the target site, maximizing the local therapeutic index. Additionally, SQP33 was capable of being activated by SQL70 injected in various regions in the body, including peri/intratumoral, intraperitoneal, subcutaneous and intramuscular sites. SQ3370 treatment also enhances efficacy in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 significantly improved anti-tumor response and overall survival compared to conventional Dox. In mice bearing two tumors, SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. This technology also enabled a sustained anti-tumor response upon rechallenge with MC38 tumor cells, without additional treatment. Furthermore, SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors, suggesting that SQ3370 can induce an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Conclusions: SQ3370 enables delivery of cytotoxic drugs to multiple target sites while limiting off-target exposure, leading to improved safety and efficacy. A multicenter, first-in-human, Phase 1 dose-escalation clinical trial (NCT04106492) in patients with advanced solid tumor malignancies is planned to commence enrollment in April, 2020.
Assessment of mutation burden after clinical intervention in pancreatic ductal adenocarcinomas (PDAC), and biliary tract cancers (BTC) via profiling circulating tumor DNA (ctDNA).
Authors: Pittella-Silva Fabio , Motoya Masayo , Kimura Yasutoshi , Nakamura Toru , Low Siew-Kee Kee , Nakamura Yusuke 
Published: May 2020

e15529 Background: PDAC and BTC have very poor prognosis with limited treatment options. Blood-based monitoring of ctDNA may have great potential to improve early detection of relapse or failure to chemotherapy and to possibly identify actionable genetic alterations. Methods: We performed targeted sequencing using NGS with Ion S5 Oncomine PanCancer gene panel to investigate mutations in 52 genes in 42 PDAC and 24 BTC patients. Blood samples were obtained from PDAC and BTC cases before the first intervention (baseline) as well as 2-4 weeks later to evaluate cfDNA mutations after surgery or chemotherapy. Actionable alterations with potential therapeutic relevance was defined as those with possible treatments within OncoKB system. We also compared the amount of cfDNA and mutant allele detection rates in pre-, intra- and post-operative samples. Results: Overall detection of ctDNA alterations in baseline samples was 74% (31/42) in PDAC cases. Alterations including SNVs and CNVs were detected among 15 genes; mutations in TP53 (53%), KRAS (41%) and SMAD4 (10%) were most commonly identified. Overall detection rate in BTC patients was 83% (20/24) comprising 9 genes; frequent mutations were observed in TP53 (58%) and KRAS (33%). Decrease in MAF (mutant allele frequency) was observed in 64% (18/28) of PDAC cases after the treatment and that of CA19-9 was observed in 50% (14/28) of the cases. In BTC pts, reduction of MAF was observed in 60% of the cases after surgery. Potentially actionable mutations were observed in 38% of PDAC samples and in 25% of BTC samples. Interestingly, the amounts of cfDNA were 4-fold higher in intraoperative samples compared to pre- and post-operative samples indicating release of cfDNA during surgery, possibly by tissue damage. Conclusions: We have shown the feasibility to assess minimum residual tumor cells or drug response by liquid biopsy in both PDAC and BTC which may improve the clinical management.
Correlation of CTCs with disease progression in Indian oral cancer patients.
Authors: Khandare Jayant , Qayyumi Burhanuddin , Bharde Atul , Aland Gourishankar , Jayant Sreeja , Tripathi Swati , Singh Nitin , Badave Reecha , D'Souza Alain , Singh Balram , Arora Smriti , Kale Narendra , Vasudevan Aravindan , Ashturkar Amrut , Prabhash Kumar , Chaturvedi Pankaj ,   Actorius
Published: May 2020

e15541 Background: Head and neck squamous cell carcinoma is leading cancer in the India with Oral squamous cell carcinoma (OSCC) as the most frequent subtype. OSCC is classified as a locoregional disease and its increased frequency is attributed to lack of good biomarkers compared to other epithelial cancers. At the time of diagnosis, above 50% of cases present the manifestation of advanced-stage disease, and are predisposed to disease failure in spite of appropriate treatment. Thus, early diagnosis of OSCC can significantly reduce the disease burden. Here we describe regulatory approved method to establish Circulating tumor cells (CTCs) presence in OSCC Indian patients and its positive correlation with various clinicopathological parameters, suggesting the potential use of CTCs as a significant parameter to stratify oral cancer with respect to the disease advancement. Methods: In a cross-sectional observational study, 230 OSCC patients at the different pathological stage of the disease and treatment mode were enrolled. CTCs were isolated using approved OncoDiscover liquid biopsy technology (Drug controller general of India approved), platform technology based on immunomagnetic CTC enumeration. CTCs were detected for CK18 presence and well-defined, DAPI-stained nuclei. Enumerated CTC subsequently analyzed for various clinic-pathological parameters such as pstage, extra-capsular spread (ECS), lymphovascular emboli (LVE), perineural invasion (PNI) and depth of invasion (DOI). CTC cut off values were obtained to differentiate early vs advanced stages with respect to different clinical stages and parameters. Results: CTCs of OSCC patients correlated positively with the cancer stages (clinical as well as pathological) as well as aggressive pathological features. The presence of aggressive pathological features that often suggest the poor outcome of the disease, we observed a 25-50 % increase in CTC number. Early stage, treatment naïve patients had lower number of CTCs. Mean CTC number in advanced-stage patients was 50 % higher than early-stage OSCC patients. Conclusions: Considering a positive correlation of CTC number with various pathophysiological features, CTC can be contemplated as a reliable parameter to predict the disease outcome in oral cancer. The consistent presence of CTC across all disease stages also suggests a probable nature of OSCC as a biological systematic disease. Clinical trial information: CTRI/2018/03/012905.
Performance of a Nu.Q H3.1 assay for lung cancer detection.
Authors: Sibille Anne Louise Louise , Henket Monique , Herzog Marielle , Hardat Natalie , Corhay Jean-Louis , Louis Renaud , Duysinx Bernard 
Published: May 2020

e15542 Background: Lung cancer diagnosis relies on invasive methods and often occurs at a late stage of disease, explaining its poor outcome. Nucleosomes are DNA fragments wrapped around histones. They may constitute a non-invasive and early diagnostic method for lung cancer. We investigated the clinical and statistical performance of nucleosome assay levels alone and in combination with cytokines in plasma from untreated lung cancer (LC) patients and what their discriminant power was towards chronic obstructive pulmonary disease (COPD) and healthy (H) subjects. Methods: 142 plasma samples were prospectively collected: H, n = 45; LC, n = 44 and COPD, n = 53. The circulating level of intact nucleosomes containing the histone H3.1 isoform (Nu.Qª-H3.1) was individually tested and in combination with cytokines for its performance in discriminating subjects for their underlying condition. Then, statistical performance of each model was tested with binary logistic regression models for the best combination of biomarkers for the following groups: cancer vs control (group A), cancer vs COPD+control (group B) and for cancer vs COPD (group C). The best model for each group was then applied to two independent biobank cohorts for validation. Results: Results for Nu.Q-H3.1 was an area under the curve (AUC) of 0.79, for group A, B and C; a sensitivity of 68%, 66% and 66% for group A, B and C, respectively, for 80% specificity. For group A the H3.1+IL-10 model achieved a sensitivity of 77% for 80% specificity with an AUC of 0.88 (R² = 55.8%). For group B the H3.1+IL-6+IL-10 model achieved a sensitivity of 70% with an AUC of 0.85 (R² = 40.6%). For group C the H3.1+IL-6+IL-10 model achieved a sensitivity of 79% with an AUC of 0.85 (R² = 46.1%). The validation cohort performed similarly. Results for the 3 cohorts taken together were: AUC of 0.83, 0.87 and 0.90 for group A, B and C, respectively; sensitivity of 75%, 76 % and 84% for group A, B and C, respectively, for 80% specificity. Conclusions: Nucleosomes are detected in the plasma of H, LC and COPD patients. Combination with cytokines as described in these models allows for a good power ofdiscrimination between the three groups. Based on these encouraging results, we believe further studies with larger numbers of patients should be performed to confirm and validate the usefulness of these biomarkers and models.