bluuebunny/crossref_metadata_2025_split huggingface dataset:
Technical validation of PD-L1 SP142 assay for TNBC in a large academic center: Unexpected challenges.
Authors: Nofech-Mozes Sharon , Slodkowska Elzbieta 
Published: May 2020

e15253 Background: The IMpassion 130 trial reported that 41-46% of TNBC are positive for PD-L1 SP142 based on centralized testing. While the FDA approved it as a companion diagnostic assay with cut off value of 1%, there are no published guidelines for technical validation in local laboratories. Furthermore, with the need to evaluate staining only in inflammatory cells (IC) the readout becomes particularly challenging for cases around the cutoff point. We report our prevalence of PD-L1 positivity and proportion of borderline cases in our validation. Methods: We ran PDL1 SP142 using the recommended protocol from Roche on the following groups: G1 - 53 consecutive TNBC cases (excisions tumors ≥7mm), G2 - 10 consecutive TNBC cases (breast specimens only) that would have met the inclusion criteria for the trial (LABC with poor NAT response or metastatic), G3 – proficiency testing slide from an EQA provider (4 cores of TNBC 1 negative, 1 borderline low positive and 2 high positive). All cases were read by 2 breast pathologists that received training on PDL1 readout by Roche (one – in class and online, one – online). Results: Borderline staining around the 1% cutoff (11 of 63) and low positive (9 of 63) were encountered in the validation sets more often than shown in training sessions. Classification of borderline cases may have a substantial impact on the rate of PDL1 positivity that potentially could approach 75%. Borderline cases often have IC staining either at the advancing tumor edge, as small collections of highly positive IC or around benign ducts entrapped within the tumor. Conclusions: The prevalence of PDL1 positive TNBC in all comers could be higher than observed in IMpassion 130 (at least 50-60%). Pathologist training in readout is of utmost importance due to high rate of borderline/low positive cases raising the need for central testing in borderline cases. Guideline recommendations for technical validation similar to other class II biomarkers would be useful. Studies on interobserver variability are needed to further address this potential issue. [Table: see text]
Predicting tumor mutational burden in head and neck squamous cell carcinoma based on CT imaging features: A TCGA/TCIA study.
Authors: Luo Yangkun , Li Lu , Yin Gang , Lang Jin Yi 
Published: May 2020

e15254 Background: Immunotherapy has substantially changed the therapeutic strategies for cancers. Unfortunately, only 20–50% of patients with advanced solid tumours respond to treatment. There is therefore a need for the development of methods to identify patients who are most likely to respond to immunotherapy. Tumor mutation burden (TMB) have been served as the most prevalent biomarkers to predict immunotherapy response. This study was designed to investigate the ability of radiomics to predict TMB status in patients with head and neck squamous cell carcinoma (HNSCC). Methods: TMB values were calculated using genomic data obtained from the HNSCC dataset in The Cancer Genome Atlas (TCGA).We identified matching patients (n = 100) who underwent contrast-enhanced CT scan prior to treatment from The Cancer Imaging Archive (TCIA),and patients were grouped based on the cutoff value; high group(>4.2 mutations/Mb) and low group(≤4.2 mutations/Mb). A total of 249 radiomics features(9 non-texture features and 240 scan-texture-parameter features) were extracted from CT images of the tumor. The incorporation of features into multivariable models was performed using logistic regression. The multivariable modeling strategy involved imbalance-adjusted bootstrap resampling in the following four steps leading to final prediction model construction: (1) feature set reduction; (2) feature selection; (3) prediction performance estimation; and (4) computation of model coefficients. The performance was evaluated in terms of area under the curve (AUC), sensitivity, and specificity. Results: Among all the features, twenty features were found to have the most impact on the predictive value; the two top texture parameters were GLCM-Variance and GLCM-Sum Average. In multivariable analysis, the best performance was obtained using a combination of seven texture features that can discriminate between high mutation burden versus low mutation burden. The AUC, sensitivity, and specificity of this model were 0.97 ± 0.01, 0.92 ± 0.04, and 0.92 ±0.01, respectively. Conclusions: The proposed CT-derived predictive model can accurately predict TMB status in patients with HNSCC. It may be helpful in guiding immunotherapy in clinical practice and deserves further analysis.
Identification and validation of stromal immunotype predict survival and benefit from neoadjuvant chemotherapy in patients of breast cancer.
Authors: Ji Fei , Yang Ci-Qiu , Zhang Liulu , Yang Mei , Li Jieqing , Gao Hong-Fei , Zhu Teng , Cheng Min-Yi , Wang Kun 
Published: May 2020

e15261 Background: Immune infiltration of breast cancer is associated with clinical outcome. A growing number of research suggests the diversity of functionally distinct cell types that make up the immune response. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast cancer influence survival and treatment response, and construct the stromal immunotype which could improve prediction of neoadjuvant therapy and survival. Methods: A total of 1502 ER negative breast cancers from TCGA and METABRIC cohort were used to infer the proportions of 22 subsets of immune cells, Another 200 ER negative breast cancer patients from Guangdong Provincial People’s Hospital in the validation cohort were also included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method, Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. Results: Of the cell subsets investigated, CD8+ T cells (p < 0.001), CD4+ T cells (p = 0.002), B cells (p = 0.003), M1 macrophages(p = 0.006) were associated with favourable outcome. T regulatory cells(p = 0.005) emerged as the most strongly associated with poor outcome. T regulatory cells were associated with pathological complete response to neoadjuvant chemotherapy (p = 0.012). Using the LASSO model, we classified ER negative breast cancer patients into stromal immunotype A subgroup (CD8+Thigh CD4+Thigh B cellhigh M1 macrophagehigh Treglow) and stromal immunotype B subgroup (CD8+Tlow CD4+Tlow B celllow M1 macrophagelow Treg high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 10-year overall survival (66.2% vs. 49.8%; P < 0.001) and 10-year disease-free survival (63.8% vs. 44.4%; P < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately, and also showed to be related to pCR in neoadjuvant chemotherapy. Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4) expression and three important cytokines expression profiles (IL-2, INF-γ and TGF-β). Conclusions: The stromal immunotypes could predict survival and recurrence of ER negative breast cancer patients effectively. Furthermore, the immunotypes might be a practical predictive tool for immunotherapy.
Oncolytic activity of a new group of non-classified rotavirus of Reoviridae family on human epidermoid carcinoma A431 growth.
Authors: Kolpakov Sergey A. , Kolpakova Elena P. , Zlatnik Elena Yu. , Nepomnyashchaya Evgeniya M. , Shulgina Oksana G. , Sitkovskaya Anastasia O. , Kit Oleg I. 
Published: May 2020

e15272 Background: Significant increase of malignant tumors` incidence all over the world in spite of vast arsenal of anticancer drugs and their combinations challenges the oncologists to develop new approaches to tumor treatment. Application of oncolytic virus is considered to be rather promising. Here we studied two strains of the new group of non-classified rotavirus of Reoviridae family (RVK): 100 and 228 ( http://jbks.ru/archive/issue-10/article-6 ). RVK are attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·109 per 1 ml. The aim of the study was to assess the effect of two RVK strains (100 and 228) on the growth of human epidermoid carcinoma A431 transplanted to nude mice in vivo. Methods: Mice Balb/cNude 22-24 g body weight (n = 13) were injected with 4х106 cells of human epidermoid carcinoma A431 subcutaneously in SPF-area of vivarium. After formation of palpable tumors (1 week after transplantation) administration of alive RVK strains 100 and 228 was performed. The 3rd group was the control one and received 0.85% NaCl. The injections were performed once a week 0.3 ml. Tumor growth rate and its` volume were measured. 1 week after the completion of the course mice were sacrificed, tumors were weighted and their morphology was studied. Results: In mice injected with RVK tumor growth inhibition developed in early date after the injection and was statistically significant within 30 - 40 days of monitoring only after the administration of strain 100. In these animals tumor weight was 2.6 times lower than in control mice (6.3±3.0 и 16.6±2.3 g respectively, р < 0.05), in mice having received strain 228 it was 1.7 times less tan in controls. Layers of high-grade sqamous carcinoma cells without keratinization with inflammatory and necrotic foci were observed in tumors of control mice while in tumors inhibited by RVK dystrophic changes and fragmentation, inflammation in places severe and necrotic foci were seen. Implication of the strain 100 resulted in 2-3 time reduction of tumor size, decrease of tumor cells` layers, mononuclear infiltration. Conclusions: In the in vivo model of human epidermoid carcinoma A431 transplanted to nude mice the inhibition of tumor growth under RVK administration was established. Our results confirm the oncolytic activity in RVK, particularly in strain 100.
VEGF-A polymorphisms affect the pharmacologic effect of bevacizumab on VEGF-A levels in patients with metastatic colorectal cancer.
Authors: Papachristos Apostolos , Kemos Polychronis , Kalofonos Haralabos , Sivolapenko Gregory 
Published: May 2020

e15505 Background: Bevacizumab treatment presents large interpatient variability in efficacy. Mutations in VEGF-A rs699947 are associated with longer overall survival and progression free survival in bevacizumab-treated metastatic colorectal cancer (mCRC) patients. The aim of the present study was to investigate correlations between VEGF-A polymorphisms and VEGF-A levels in patients receiving bevacizumab for mCRC. Methods: 46 patients were studied. Blood samples were collected for VEGF-A (rs2010963, 1570360, rs699947) genotyping, and measurement of bevacizumab and VEGF-A levels. The Spearman's rank correlation coefficient was used to study the correlation between VEGF-A and bevacizumab levels. For the multiple analysis, we used linear regression with residual analysis and considering multicollinearity while the effects are reported with 95% confidence intervals. Results: In total 171 samples for VEGF-A and 157 for bevacizumab levels were analyzed. A very strong negative correlation between bevacizumab and VEGF-A levels (coef. = -0.625, p < 0.000001) was noted. Interestingly, VEGF-A rs699947 plays an important role in the model (p = 0.0002, 95% CI 32.5-58.1) and as VEGF-A levels were found to be significantly lower in patients with mutant rs699947 (p < 0.0001, 95% CI 25.2 - 53.8). Conclusions: In conclusion, genetic factors significantly affected the effect of bevacizumab on VEGF-A levels. Significantly lower VEGF levels were measured in carriers of mutant rs699947. These results may explain the favorable clinical outcomes reported in this sub-group of patients. These findings might enable clinicians to distinguish patients, who may benefit more and in a long-term. Finally, can be used to design individualized dosing schemes for bevacizumab.
A rare case of metastatic testicular adult granulosa cell tumor.
Authors: Natoli Guido , Metovic Jasna , Taraglio Stefano , Miraglia Stefania , Misischi Francesca , Delsedime Luisa 
Published: May 2020

e15506 Background: Adult granulosa cell tumour (AGCT) is a rare disease that develops in the testis, composed of sex cord cells, accounting for less than 0.5% of all sex cord-stromal neoplasias (WHO 2016). To our knowledge, 48 cases of AGCT of the testis have been published up to date reporting follow-up (Table 1). Infrequently, these tumors can metastasize, usually to retroperitoneal lymph nodes, but also liver, lungs and bones. Methods: In 2015 a 60-year-old Caucasian male with unilateral, painless slowly growing mass underwent to orchioectomy. A diagnosis of malignant ADTC was rendered. After 19 months metestatic spread to lung was hystologically confirmed. After cytotoxic treatment a compassionate use of pazopanib was sterted and the was in complete response today. Results: The patient is still on pazopanib treatment with complete response that is well tolerated and has improved quality of life 55 months after the initial AGCT diagnosis. Conclusions: Our case report could offer an important source of information for clinicians who are currently facing this rare entity. In summary in case of tumor larger than 4-5 cm adjuvant treatment may be considered and, more importantly, systemic treatments, including pazopanib, could be suggested as a treatment apporach to a metastatic AGCT patient. In the future, other reports containg long-term follow up will be of vital importance to understand the best management of patient with AGCT.
Stability and visual compatibility of daunorubicin and cytarabine during Y-site administration with selected drugs.
Authors: Sicard Guillaume , Donnette Mélanie , Pourroy Bertrand , Fanciullino Raphaëlle 
Published: May 2020

e15516 Background: Vyxeos is a daunorubicine plus cytarabine liposome indicated in adults patient with newly diagnosed acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML). The standard protocol is an induction phase on D1, D3 and D5 at 100 mg/m² (expressed in cytarabine) during 90 minutes followed by 2 consolidation cures at 65 mg/m² on D1 and D3. Data provided from manufacturer indicate stability over 4 hours for diluted solution of daunorubicine plus cytarabine. AML-Patients are all receiving complex infusion increasing the risk of Y site incompatibilities. However, there is a lack of data on Y site compatibility of daunorubicine plus cytarabine with others drugs while these phenomena are well described with cytarabine and daunorubicine. The aim of this study was to evaluate stability and container-content interaction over time and visual Y site compatibility with selected drugs. Methods: Physicochemical stability over time was evaluated by Dynamic Light Scattering (DLS) (particle size) and by LC-MS/MS analysis (determination of cytarabine concentration). Daunorubicine plus cytarabine diluted solutions in 0.9% NaCl, final concentration 0.17 mg/mL were stored at 4°C during this study. Container-content interaction was evaluated comparing glass bottle and free-PolyVinylChloride (PVC) bag. Regarding Y site compatibility, a total of 33 drugs were tested. Medication mixtures were analyzed immediately after contact (T=0) and 90 minutes after, stored at room temperature (i.e., 25°C). The particle analyses were performed visually and by DLS. Drugs couple were classified in three categories: compatible, incompatible and variable compatibility when dubious phenomenon was observed. Results: No significative difference was found over time (120h) in term of particle size and chemical stability of cytarabine encapsulated, regardless of the container. This suggests that stability of daunorubicine plus cytarabine could actually be much longer than manufacturer’s recommendations. Most of the tested drugs were compatible. Still, three drugs exhibited visual incompatibilities at T = 0 and T = 90 minutes. However seven drugs presented incompatibilities using LDS. Two combinations presented conflicting data and thus classified as variable compatibility. Conclusions: Polypharmacy is a major concern in AML patients and knowledge and management of daunorubicine plus cytarabine stability and Y site compatibilities are critical to ensure a maximum safety at bedside. At least 10 drugs frequently used in oncology present a variety of incompatibilities with daunorubicine plus cytarabine and therefore should not be co-administered on Y site.
Abscopal effect induced intratumoral injection of chemotherapy drugs with hapten and tumor microstructure changes with protein expression of distal untreated tumors in mice.
Authors: Yu Baofa , Gao Feng , Jing Peng , Liu Jian , Zhang Jian , Li Bian , Yang Huanzhen , Han Yan , Wu Yanfei , Fu Qiang ,   Shandong Baofa Cancer Therapeutic Systems
Published: May 2020

e15518 Background: To observe the abscopal effect by intratumoral injection of chemo drugs with hapten on tumor, and analyze the difference in expression of bilateral tumor proteins and the inhibition of tumor growth on the opposite side. Methods: Balb/c mice 45, H22 ascites were inoculated in left forelimb armpit. When longest diameter of about 4-5mm randomized (day 0); the next day, intratumoral injection different combination drugs, the three days later in the right armpit mice were inoculated inoculated 0.2ml (105/ml) H22 cells, the seven days later of secondary administration, while observing the contralateral sides, especially tumor growth. 15 days after first treatment each group were sacrificed 6 mice, tumor tissue on both sides for immunohistochemistry, quantitative RNA PCR quantitative determination. Results: It showed an upward trend in body weight in mice, 15 days after administration of DNP sustained release drug group and PYM control group of mice were significantly lower than the body weight of the negative control group, the difference between groups (P<0.05); three groups of mice after administration of tumor volume on the left. On the 15th day after the administration, the left and right tumors in DNP group were significantly smaller than those in PYM group and negative control group, and the difference was statistically significant (P < 0.05); the left tumors in PYM group were significantly smaller than those in negative control group, and the difference was statistically significant (P < 0.05). After administration PYM control group’s Col1a1, CD4, Il12aA, TGF, Ela, NFKB, Cox2, CD11c, CD8, TNFa expression was significantly lower than the negative control group and DNP sustained-release drug group; DNP sustained-release drug group’s Col1a1, CD4,Il12aA, TGF, Elastin, NFKB, CD11c, CD8 expression was significantly lower than the negative control group. A large number of cell disintegration phenomenon, observed lymphocytes, leukocytes, the presence of high electron density granular, suggesting that there may be drugs enter into cancer cells. Conclusions: Intratumoral injection of chemotherapy drugs with hapten can exhibit significant anti-tumor effect. In the DNP sustained-release drug group, abscopal effect is more obvious. After the use of PCR quantitative detection of various tumors and fibroplasia, inflammatory factors and immune-related factors have changed significantly to further confirm abscopal effect by intratumoral injection of combination drugs.
Morphology classification of circulating tumor cells could be a predictor of recurrent disease in patients with non-small cell lung cancer after surgery.
Authors: Wu Yun , Niu Yuxu , Lv Fanzhen , Gao Wen , Shen Xiaoyong 
Published: May 2020

e15530 Background: CTCs have been widely used in monitoring the efficacy and prognosis of lung cancer. However, CTCs number count alone cannot accurately predict the recurrent disease in patients. In this study, we investigate whether the morphology classification of CTCs could be as a prognostic marker for increased risk of recurrence after surgery. Methods: In this study, 105 lung cancer patients (median age 68y) who underwent surgery were prospectively enrolled in this study. Samples were obtained before, after, and serially up to 24 months after surgery. CTCs were collected and morphology classified by utilizing a CTC test workflow which uses negative enrichment and immunofluorescence methods to capture and identify CTCs from blood sample. Captured CTCs (epithelial type) were screened with a customized imaging analysis pipeline, a cytological profile of each CTC was created, including cell size, shape, fluorescent intensity and texture etc. Results: The CTC detection rate was 78.1% (78 of 105) prior to surgery, and a total of 726 CTCs were enumerated. Median CTC count number was 3. 5 classes of CTCs with distinct morphological features were observed in lung cancer patients’ CTC tests, briefly, CTC class I and class II possessed large nuclei but relatively lower epithelial expression level, CTC class III, IV, V possessed small nuclei but relatively higher epithelial expression level, CTC class III possessed irregular shaped nuclei, CTC class V possessed relatively lower nuclei/cytoplasm ratio. Class III accounted for the highest proportion of captured CTCs III, about 35.5% with Class I 14.8%, Class II 15.3%,Class IV 17.8% and Class 5 16.6%. Postoperative recurrence and metastasis were observed in 16 patients. CTCs positive were found in 14 patients (87.5%). 145 CTCs were collected, Median CTC count number was 3,Cluster III accounted for 47.3%, with Class I 11.8%,Class II 13.3%,Class IV 14.5% and Class V 11.8%; Patients with Cluster 3 dominant were associated with increased risk of local recurrence ( p < 0.05) and distant metastasis ( p < 0.05). Conclusions: Small and irregular nuclei CTC is significant associated with increased risk of recurrence disease. Morphology Classification of circulating tumor cells is feasible in monitoring the recurrence of disease and may potentially identify the patients who may benefit from further therapy.