bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary analysis and assessment of breast cancer risk in Japanese women.
Authors: Yamada Michiyo , Ishikawa Takashi , Sugae Sadatoshi , Narui Kazutaka , Arita Eiji , Tonellato Peter , Endo Itaru , Chishima Takashi
Published: September 2018

e13092

Background: No comprehensive breast cancer risk assessment model for Japanese women exists. Consequently, we have collected Japanese women’s data to investigate key BC risk factors with an objective of deriving a Japanese-women specific BC risk assessment model. Methods: We conducted a retrospective case-control study (paper-based with postal survey) at 15 institutions during 2014-2015. A survey was distributed to Japanese females aged 20-80 who had BC check-up. All pertinent data of a total of 34 factors including demographic and reproductive factors, social history and eating habits was collected. Cases and controls were divided into three groups respectively, premenopausal (PRE; 20 ≤ age < 45), perimenopausal (PERI; 45 ≤ age ≤ 55) and postmenopausal group (POST; 55 < age ≤ 80). Cases and control variables were compared by t-test, chi-square test and Wilcoxon rank sum test. Preliminary BC risk was calculated by logistic regression analysis. Results: A total of 3975 female Japanese datasets were collected, of which 2494 were complete (all variables present) with 1401 controls and 1093 cases were used. There were 222 cases and 332 controls for PRE, 404 cases and 537 controls for PERI, and 467 and 532 controls for POST. The univariate analysis demonstrated that BMI was significantly higher in cases than in controls in all groups (P < 0.01) as was “number of deliveries” in PRE and POST (P < 0.001) and Brinkman index in PRE and PERI (p = 0.017). Multivariate analysis revealed that BC risk was positively associated with BMI (OR 1.080, 95% CI 1.017–1.148, p = 0.012) in PRE, BMI (OR 1.121, 95% CI 1.072–1.174, p < 0.01) and brinkman index (OR 1.000005, 95% CI 1.000002–1.000008, p < 0.01) in PERI, age (OR 1.054, 95% CI 1.028–1.081, p < 0.010), BMI (OR 1.153, 95% CI 1.076-1.171, p < 0.01) and family history (OR 1.497, 95% CI 1.103–2.033, p = 0.001) in POST, while negatively associated with regular exercise (OR 0.672, 95% CI 0.517–0.873, p = 0.003) in POST. Conclusions: BMI in all groups, in addition, the Brinkman index in PERI and age and family history in POST are BC risk factors. Exercise is a protective risk factor in POST. However, the preliminary results are incomplete and further analysis will be conducted before a full risk assessment model is proposed for Japanese women.
Effects of county-level attributes on geographic variation in female breast cancer mortality rates across counties in United States.
Authors: Sagiraju Hari Krishna Raju , Jatoi Ismail , Valerio Melissa , Chien Lung-Chang , Gimeno David
Published: September 2018

e13093

Background: Though studies have examined geographic disparities in breast cancer mortality among United States (U.S.) counties, county-level risk factors were not accounted for. The aim of this study is to efficiently map the spatial association between female breast cancer mortality rates & socioeconomic attributes across U.S. counties for identifying high risk geographical clusters in terms of socioeconomic attributes. Methods: County-specific age standardized breast cancer mortality rates for women ≥20 years in the U.S. were obtained for 3,109 counties in 48 contiguous states from Surveillance Epidemiology and End Results program from 1990-2012. County-level attributes such as percentages of Hispanic white, Non-Hispanic white, Non-Hispanic black, < high school education, below 200% poverty, urban, foreign born, language isolation, women aged ≥ 40 years with mammography within last 2 years, and median household income were gathered from U.S. decennial census. Factor analysis condensed county attributes into three factor covariates namely Hispanic immigrants, health care access among urban high socioeconomic population, and non-Hispanic black unemployment. Spatiotemporal analysis was carried out by structured additive regression model to incorporate spatial functions & Markov chain Monte Carlo simulation techniques. Results: Moran’s index suggested existence of spatial dependence for breast cancer mortality among U.S. counties. As mammography screening, %urban population, % with high socioeconomic status and non-Hispanic black unemployment increased in counties of the Southwest region, Rocky mountain region and those in the western border of Midwest region of U.S, risk of breast cancer mortality increased significantly above the national average. As the Hispanic immigrant culture increased, counties of Midwest region of U.S had significantly higher mortality rates compared to national average. Conclusions: These initial results describe socio-economic, cultural, and healthcare access factors for observed geographic variations in female breast cancer mortality, and in turn, could support a stronger theoretical basis for public health policy.
Multiplex ALK, RET, and ROS1 fusion mutation detection in FFPE from lung cancer patients by MALDI-TOF mass spectrometry.
Authors: Su Kang-Yi , Ho Bing-Ching , Chang Gee-Chen , Chen Hsuan-Yu , Yang Pan-Chyr , Yu Sung-Liang
Published: September 2018

e13103

Background: Approximately 3-7% of lung tumors harbor anaplastic lymphoma kinase (ALK) fusions in the subgroup of non-small cell lung cancer (NSCLC). In addition to echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion, TRK-fused gene (TFG)-ALK, kinesin family member 5B (KIF5B)-ALK and kinesin light chain 1 (KLC1)-ALK had been reported in lung cancer. On the other hand, RET proto-oncogene (RET) and ROS proto-oncogene 1 (ROS1) fusion proteins also have prevalence in lung cancer. Food and Drug Administration (FDA)-approved several target drugs are available to treat patients with fusion mutations. Therefore, the diagnosis of ALK, RET or ROS1 fusion genes shows quite important. However, nowadays methods of detecting fusions such as fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are limited to technique, low sensitivity, sample quality as well as subtype classification. Methods: We established nucleotide MALDI-TOF mass spectrometry based multiplex detection platform to distinguish major types including 9 types of EML4-ALK, 5 types of ALK, 5 types of RET and 8 types ROS1 fusions. Results: The detection limitation was about less 1% mutant cells among wild-type cells. In the pilot testing, we used 2 patients’ cell cDNA and 4 patients’ lung FFPE samples cDNA, which had been diagnosed as ALK fusion before, to be detected by this panel, and then identified their variant types successfully. Furthermore, one patient harbored CCDC6-RET fusion mutation was identified by our platform and confirmed by Sanger Sequencing. Conclusions: Taken together, this new panel has high sensitivity and allows little and poor quality samples for detecting. The correlation between clinical characteristics and fusion subtypes can be further investigated by utilizing this platform in the future. Also, the detection panel can be revised based on clinical needs by removing/adding probes.
BRCA 1/2 mutations by next-generation sequencing testing in 200 Romanian high-risk patients with breast cancer.
Authors: Eniu Alexandru E. , Antone Nicoleta Zenovia , Stoian Andrei , Dronca Eleonora , Matei Ramona DOINA , Ligtenberg Marjolijn , Ouchene Hicham , Eniu Rares , Pop Laura
Published: September 2018

e13116

Background: To determine types and frequencies of BRCA 1 (B1) or BRCA2 (B2) mutations in high-risk Romanian breast cancer patients, as there is no data published in this population. Methods: This prospective study evaluates the germline BRCA1/BRCA2 mutations in 200 Romanian high-risk breast cancer patients tested between February 2015-January 2017 at IOCN. Inclusion criteria selected patients diagnosed with breast cancer before 40 years, triple negative breast cancer under the age of 50, or having conventional family history criteria. All patients signed an informed consent. BRCA1/BRCA2 testing was performed using an AmpliSeq-based sequencing analysis, on the Ion Torrent Personal Genome Machine (Life Technologies) at RCFG. The pathogenic mutations were validated using Sanger technology. MLPA was performed for all 200 patients. Results: We analyzed 200 high-risk breast cancer patients and found 32 (16%) patients with pathogenic mutations, 23 (11.5%) patients with B1 and 9 (4.5%) patients with B2 mutations. The majority of patients (99.5%) presented normal MLPA results; only one sample (0.5%) presented a deletion at CHEK2-9(10). The frequency of class 5 mutations identified in B1 gene were c.1687C > T (1%), c.181T > G (2%), c.3607C > T (3.5%), c.4218delG (0.5%), c.5329_5330insC (c.5266dupC) (4.5%) and for the B2 gene c.1528G > T (0.5%), c.4022C > G (0.5%), c.7007G > A (0.5%), c.8695C > T (0.5%), c.9253 delA (0.5%), c.9371A > T (2%). Conclusions: Frequency of deleterious BRCA mutations in our cohort was 11.5% for BRCA1 and 4.5% for BRCA2. This prospective study presents the first extensive results on frequency and types of germline BRCA1/2 mutations in Romanian high-risk breast cancer patients. Clinical trial information: NCT02317120. [Table: see text]
Mutational profiling of Chinese ROS1 positive non-small cell lung cancer patients with required resistant to crizotinib by next generation sequencing.
Authors: Wang Wen-xian , Xu Chunwei , Fang Meiyu , Zhu You-cai , Chen Yan-ping , Chen Yu , Liao Xing-hui , Zhuang Wu , Lin Gen , Chen Xiao-hui , Huang Yun-jian , Xu Hai-peng , Du Kai-qi , Guan Yan-Fang , Yi Xin , Chen Gang , Lv Tangfeng , Song Yong
Published: September 2018

e13120

Background: The ROS1 rearrangement has been identified in 1%-2% of NSCLC cases, these patients would benefit from the inhibitor of crizotinib. But the resistance to crizotinib inevitably developed in the patients with ROS1+ NSCLC and shown a response to crizotinib initially. The mechanism of acquired resistance to crizotinib for the patients with ROS1+ NSCLC is not identified completely now. In this study, we performed mutational profiling in a cohort of 16 ROS1+NSCLC patients at diagnosis and acquired resistance to crizotinib using targeted NGS. Methods: A total of 16 patients with stage IIIb-IV ROS1+ NSCLC were undergoing tumor biopsies or blood withdrawing by the time of acquiring resistance to crizotinib, including 4 formalin-fixed paraffin-embedded (FFPE) samples, 9 serum samples and 3 serous effusions. We used targeted NGS to detect genes status of patients. Results: In total, we identified 62 genetic alterations with a median of 3.9 mutations per patient. 93% of patients still exhibit fusions, and 31% of patients acquired ROS1 required point mutations. Besides other known resistance mechanisms, we identified CDKN2A mutations in 19% of patients. Interestingly, we also observed TERT, PTPRD, NFE2L2 and OR5L2 mutations in ROS1 required point mutations negative patients, which were restricted to crizotinib resistance. Conclusions: Our study uncovered mutational profiles of ROS1+NSCLC patients with crizotinib resistance with potential therapeutic implications, and this study also depicted the genetic landscapes comprehensively in Chinese ROS1+NSCLC population resistant to crizotinib. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression.
Pattern of blood count change during craniospinal irradiation and the effect on progression free survival in medulloblastoma adult patients.
Authors: Dibs Khaled Nabil , Jaradat Imad A. , Khader Jamal , Al Khairi Laith , Sarhan Nasim , Mohammad Ahmad , Sulaiman Awf , Amoudi Mohammad , Ismael Yousef , Hijlih Ramiz , Ghatasheh Hamza , Al-Mousa Abdelatif
Published: September 2018

e13500

Background: The primary treatment of medulloblastoma in adults is surgery followed by radiotherapy. Craniospinal irradiation in such patients holds a clinical significant effect on blood count drop, as more than 50% of bone marrow is irradiated during CSI. Precise guidelines on how often a patient's peripheral blood count should be monitored are yet to be established. Methods: A retrospective analysis of blood count data on 42 adult medulloblastoma patients who underwent surgical resection followed by CSI as 36-39.6Gy over 20-22 fractions followed by boost to posterior cranial fossa up to 54Gy and spinal boost up to 45Gy. The manner of blood count cells during radiotherapy and the correlation between WBC drop and outcome were examined. Results: Our study showed a drop in WBCs to 4 and below in 64% of patients during CSI. Eight patients (19%) had Hb drop below 12. There was no grade 3 or 4 anemia. Significant drop in neutrophils below 1500 was observed in 8 patients (20%), with 2.4% had grade 3 neutropenia. In 26 patients (62%) who developed platelets drop, three patients (7%) had platelets of less than 50000 (grade 3 and 4 thrombocytopenia). The Hb, lymphocyte, neutrophils, and platelets nadirs were 8.7 g/dL, 42 cells /microL, 720 cells /microL, and 1000 platelets/microL, respectively. The minimum interval between the nadir and starting radiotherapy for Hb, WBCs, and platelets were 13, 6, and 11 days, respectively. The median interval between the nadir and starting radiotherapy for all cells was 3 weeks. The median WBCs percentage drop was 71%. In 23 patients who had non-metastatic disease, the estimated three year progression free survival was 70%. In those who had WBC drop below 2.7 the PFS was 100% vs. 46%. (P value = 0.042). Conclusions: Some institutions reduced monitoring of CBC during conventional radiotherapy may result in financial saving; however, our study suggests the need for weekly CBC for patients receiving CSI irradiation. Fortunately, no one developed serious infection during radiotherapy, but a precaution should be there. A WBCs change during radiotherapy could reflect the outcome and may suggest more aggressive treatment in patients who had a nadir of 2.7 and above.
Expression of metabolic enzymes as predictors of prognosis in patients with aggressive primary brain cancers.
Authors: Schwartz Kenneth A. , Noel Mary , Shaik Mohammed , Chang Howard , Olson L. Karl
Published: September 2018

e13529

Background: Aggressive primary brain cancers like glioblastoma multiforme (GBM) are metabolically active tumors. We hypothesis that abnormalexpression of metabolic enzymes may be useful in predicting survival. Methods: 60 patients (45 with GBM, 11 with anaplastic gliomas and 4 with gliosarcoma) were evaluated using Immunohistochemistry (IHC) to measure the relative expression of metabolic enzymes known to be predictors of prognosis including hexokinase-II (HK2) and mutated isocitrate dehydrogenase-1 (IDH1-R132H) as well as several ketolytic enzymes including cytosolic type 2 (R)-beta-hydroxybutyrate dehydrogenase (BDH2)..The tumors were graded based on the percentage of immunoreactive tumor cells: Positive (≥20%), Negative ( < 20%). Survival was calculated using Kaplan Meier (KM), and an age adjusted hazard ratio (aHR) for death was obtained using cox proportional analysis for enzyme expression. Significance p ≤0.05. Results: Demographics for 60 patients; 19 females and 41 males, median age 62 years, and median survival for all the patients 5.9 months. Univariate analysis showed positive HK2 and negative BDH2 expression had decreased survival with (HR of 1.8 p = 0.06 and 2.6 p = 0.01), respectively. In a multivariate analysis after adjusting to age, histology and other enzyme expression, positive HK2 and negative BDH2 expression were statistically associated with decreased survival (aHR of 11.3 p = 0.001 and 32.6, p = 0.0004), respectively. The group with favorable prognosis (negative HK2 and positive BDH2 expression) (n = 36) had a median survival of 9.7 months (95% CI 4.2 -13.5) whereas the group with non-favorable prognosis (neither a negative HK2 nor a positive BDH, n = 24) had a median survival of 3.1 months (95% CI 1.8 – 5.8). Because only 3 patients had GBM that were positive for the IDH1-R132H mutant protein, IDH1-R132H was not used as a statistically valid predictor in this study. Conclusions: Our current result confirms the poor prognosis associated with positive expression of HK2, and suggests that negative IHC expression of BDH2 may be a new indicator of poor prognosis for patients with aggressive primary brain cancers.
Comparison of early versus late onset of cellular immunotherapy in glioblastoma multiforme WHO IV.
Authors: Nesselhut Jan , Marx Dagmar , Cillien Nicole , Chang Raymond Y. , Brockmann Wulf-Peter , Martin Michael , Nesselhut Thomas
Published: September 2018

e13531

Background: Glioblastoma multiforme (GBM WHO grade IV glioma) is an aggressive disease with an unfavorable prognosis. The current first line treatment comprises radical operation and radiotherapy combined with temozolomide chemotherapy (Stupp protocol). After failure of first-line therapy there is currently no effective therapy. Here we report that dendritic cell therapy prolongs the survival for patients with newly diagnosed GBM V. Preliminary results show that adding checkpoint blockade with Nivolumab may cause a secondary therapy response. Methods: After isolating monocytes from peripheral blood of n = 11 patients with stage IV GBM, who underwent primary surgery and first-line radio-chemotherapy and from n = 34 patients, who failed first line therapy MoDC were generated using standard protocols. In 5 patients checkpoint blockade with Nivolumab was added after failure of DC therapy. Results: With a median overall survival of 41 months there is a clear improvement of the overall survival in patients, who received DC therapy after having finished the Stupp-protocol. The 3- year-survival rate after primary diagnosis is 46% (n = 5) and 1 patient is still alive after 81 months. In this patient a secondary therapy response of 16 months could be induced by adding low dose Nivolumab (1mg/kg body weight) after failure of DC therapy. The median survival after onset of DC therapy in patients who failed first line standard therapy is 10 months. The 3-year overall survival rate is 9% (n = 3). In 4 patients therapy with Nivolumab was combined causing only a limiting effect on the survival (4 to 10 months). Conclusions: Dendritic-cell based immune therapy started immediately after primary standard therapy has a clear impact on the overall survival of patients with newly diagnosed GBM IV. Whereas the therapeutic effect for patients after failure of first-line therapy is limited. Nivolumab may cause secondary therapy response in certain patients.
Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG).
Authors: Desjardins Annick , Sampson John H. , Vlahovic Gordana , Peters Katherine B. , Randazzo Dina , Threatt Stevie , Herndon James Emmett , Bullock Chevelle A , Miller Elizabeth S , Boulton Susan , Lally-Goss Denise , McSherry Frances , Lipp Eric S , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Gromeier Matthias
Published: September 2018

e13533

Background: The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. The original two-step continual reassessment method dose escalation was amended to decrease to dose level(DL) -1 and DL -2 after observing prolonged steroid use in patients treated on higher DLs. Results: As of 2/01/2017, 52 pts were treated on study (1 each at DL1 and DL3, 7 at DL2, 2 at DL4, 4 at DL5, 24 at DL -1 and 13 at DL -2). Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Grade 3 or higher adverse events possibly, probably or definitely related to PVSRIPO include: lymphopenia (grade 3, n = 1), steroid myopathy (grade 3, n = 1), cerebral edema (grade 4, n = 1), headache (grade 3, n = 1), dystonia (grade 3, n = 1), pyramidal tract syndrome (grade 3, n = 6), seizure (grade 3, n = 1; grade 4, n = 1), delusions (grade 3, n = 1), hypertension (grade 3, n = 1), and thromboembolic events (grade 3, n = 2). At a median follow-up of 20.1 months, 20.8% of pts remain alive at 36-month post PVSRIPO infusion, compared to 4% of an historical control. Four pts remain alive more than 22 months post treatment without having received any additional intervention following PVSRIPO at 57.5+, 56.4+, 27.9+ and 23.2+ months. Conclusions: Infusion of PVSRIPO via CED is safe and encouraging efficacy results are observed. The dose finding study is now completed and we are initiating clinical trials evaluating combination of PVSRIPO with other therapies. Clinical trial information: NCT01491893.
3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.
Authors: Bota Daniela Annenelie , Yan Huaming , Romero-López Monica , Benitez Lesli , Di Kaijun , Frieboes Hermann , Hughes Christopher C.W. , Lowengrub John S
Published: September 2018

e13535

Background: Glioblastoma (GBM), the most aggressive brain tumor in human patients, is highly heterogeneous and intensively vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and by promoting resistance to therapy. Recently, crosstalk between GSCs and vascular endothelial cells that line capillaries has been shown to considerably promote GSC self-renewal and tumor progression. GSCs have been shown to also transdifferentiate into bona-fide vascular endothelial cells (GEC). GECs inherit mutations present in GSCs and are resistant to traditional anti-angiogenic therapies. Methods: We develop a multispecies mathematical model to investigate the 3D spatiotemporal dynamics of vascularized GBM progression and response to cancer therapies. Results: The model predicts GSCs drive invasive fingering and that GECs spontaneously form a network within the hypoxic core, consistent with published experimental findings. We demonstrate that standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies reduce GBM tumor sizes but increase invasiveness. Anti-GEC treatments block the GEC support of GSCs and reduce tumor sizes but can lead to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness and sizes, but are ultimately limited in reducing tumor sizes because GECs can maintain GSCs. Anti-GEC therapies are required to remove the tumor completely. Conclusions: Our results suggest that a combinatorial regimen targeting the vasculature, GSCs and GECs, using drugs already approved by the FDA, can reduce both tumor sizes and invasiveness and could lead to tumor eradication without recurrence when the treatment is stopped.
The association and prognostic significance of programmed death-ligand 1 (PD-L1) and isocitrate dehydrogenase (IDH-1) mutation in glioblastome multiforme(GBM) patients.
Authors: Sener Dede Didem , Tatlı Doğan Hayriye , Asan Fatma Betul , Gumuskaya Berrak , Ayik Sule , Sendur Mehmet Ali Nahit , Ulas Arife , Bilgin Burak , Hizal Mutlu , Akinci Bulent , Silay Kamile , Yalcin Bulent
Published: September 2018

e13536

Background: We aimed to assessed thePD-L1, PD-1 expression, TILs and IDH-1 mutation associations and their prognostic importance in GBM. Methods: Newly diagnosed and all were operated GBM patients who folllowed between February 2006 to February 2017 were included retrospectively in the study. We assessed the PD-L1, PD-1 expression, CD4(+) ve CD8(+)TILs, IDH-1 mutation in initial tumor specimens. Immunohistochemistry was performed using Ventana® antibody (clon-SP263, ROCHE) for PD-L1 and PD-1, real time PCR used for IDH-1 mutation analysis. Intensity was graded as low, moderate, dense for PD-1, CD4, CD8 TILs. PD-L1 evaluated in percents. The cutoff value assumed as ≥5% for PD-L1 positivity. We used Kaplan Meier, Cox regression tests and SPSS 23. Results: Fourty eight patients included in the study. The mean age was 54± 14,4 and 34 (70%) patients were male. Thirty (70 %) patients were received chemoradiotherapy with temozolamide and 20 (41%) of them also received chemotherapy.We identified two different staining pattern of PD-L1 expression as diffuse fibrillary [13(27%)] and membranous staining [14(29%)]. IDH-1 mutation was found in 30 (62%) patients. We found that TILs were more intensely located in the perivascular area than intratumoral area and in that TILs, PD-1 intensity were dense. We also found a correlation between the percentages of PD-L1 positivity and the density of TILs in the intratumoral and perivascular areas (p < 0,002, r = 0,46). The intensity of both TILs in perivascular areas were significantly lower in PD-L1 (-) tumors than in PD-L1 (+) tumors (p < 0,001). We didn’t find any association between IDH-1 and PD-L1 or TILs. According to survival and multivariate analysis; age, sex, PD-L1 positivity and IDH-1 mutation status did not appear to have a significant effect on survival. (log rank 0,08; 0,30; 0,89; 0,14 respectively) The presence of dense intratumoral CD8(+) and PD-1 (+)TILs were found as positive; advanced age and membranous PD-L1 staining was found as negative independent prognostic factors. Conclusions: Different staining pattern of PD-L1 in tumor tissue and PD-1 positivity in TILs may be a prognostic importance in GBM
Comparison of tissue DNA to circulating tumor DNA in patients with brain metastases.
Authors: Lanman Tyler A. , Kesari Santosh , Patel Sandip Pravin , Bazhenova Lyudmila , Parker Barbara A. , Daniels Gregory A. , Fanta Paul T. , Plaxe Steven C. , Schwaederle Maria Clemence , Kurzrock Razelle , Piccioni David Eric
Published: September 2018

e13546

Background: Brain metastases are often a late complication of cancer, not easily amenable to biopsy, and may contain additional molecular alterations not found in the original tumor. We sought to analyze the concordance between tissue DNA and cell-free circulating tumor DNA (ctDNA) in patients who developed brain metastases, and determine how the ctDNA profile changed with time. Methods: We retrospectively analyzed 31 patients with brain metastases who underwent next-generation sequencing (NGS) from both ctDNA and tumor tissue DNA. Breast, lung, ovarian, renal, melanoma, and colon primaries were included (42, 32, 13, 7, 3, and 3%, respectively). Tissue DNA was from primary tumor, systemic metastasis or brain (39, 39, and 7%, respectively). A median number of five alterations was found in each tissue group. Alterations in ctDNA were compared to tumor DNA and analyzed for relative frequencies, concordance, and novel alterations. Overall survival (OS) and time between DNA sample collections was analyzed. Results: All 31 patients had detectable mutations in tumor tissue. 25 patients (80.6%) had detectable ctDNA alterations and 14 patients (45.2%) had at least one identical ctDNA alteration that was concordant with tissue DNA. The most commonly altered genes (in both ctDNA and tissue DNA) were TP53 and EGFR. Breast cancer had both the highest proportion of patients with ≥ 1 ctDNA alterations (92.3%) and the highest proportion of patients who had ≥ 1 alterations in common with tissue DNA (61.5%). 23 of the 25 patients (92%) with detectable ctDNA alterations had additional alterations not found in tissue DNA, which increased with time from tumor DNA sampling. Median time between ctDNA extraction and tissue biopsy was 6.5 months for cases with common alterations, and 12.4 months for those without common alterations. There was trend to decreased OS with increasing ctDNA burden. Conclusions: We found that ctDNA is comparable with tissue DNA sequencing in patients with brain metastases. This concordance decreases with increasing time from tissue diagnosis, reflecting the changing nature of tumor genetics and highlighting the utility of ctDNA as a feasible way to monitor changes and identify additional potentially targetable alterations.
EGFR/CD16A tetravalent bispecific antibody AFM24 to engage NK-cells to kill EGFR expressing tumor cells and safety results in cynomolgus monkey studies.
Authors: Kerber Anne , Kluge Michael , Reusch Uwe , Ellwanger Kristina , Fucek Ivica , Weichel Michael , Haneke Torsten , Knackmuss Stefan , Rajkovic Erich , Treder Martin
Published: September 2018

e14001

Background: The epidermal growth factor receptor is a target for the treatment of solid tumors, like CRC, HNSCC and NSCLC. Therapeutic success of EGFR-targeting agents depends on mutations defining resistance to these agents, thus an effective EGFR-targeting therapy overcoming resistance would offer an attractive new treatment option. Natural killer (NK-) cells play a central role in the innate immune system and can destroy cancer cells. NK-cell-engaging bispecific antibodies may offer a safe and effective therapy to target EGFR-expressing tumor cells irrespective of their mutational status. Methods: AFM24 was generated using proprietary human anti-EGFR and anti-CD16A variable domains and characterized for binding, stability, manufacturability, efficacy and safety in biophysical and functional assays in vitro and in vivo. Assays for binding to target/effector cells and cytotoxicity were performed in the presence of physiologically relevant IgG levels using EGFR+ tumor cell lines with and without RAS. The safety profile of AFM24 was investigated in vitro for off-target activity and in vivo in cynomolgus monkeys. Results: AFM24 showed excellent biophysical properties and picomolar EC50 values in cytotoxicity assays. It was more potent than cetuximab, or an antibody with cetuximab-derived anti-EGFR variable domain. Importantly, AFM24 was less prone to IgG interference and eliminated cell lines harboring negative predictive biomarkers in in vitro cytotoxicity assays, even in the presence of relevant serum IgG levels. AFM24 demonstrated in vivo efficacy in a humanized hu-NOG mouse model. Furthermore, AFM24 exhibited a favorable safety profile in cynomolgus monkeys. It was well tolerated up to 94 mg/kg in a single dose, maximum tolerated dose study (MTD) when administered as a 2 hour infusion. Conclusions: Our data suggest that AFM24 is a highly potent and potentially safer drug candidate suitable for the treatment of EGFR-expressing cancers with the potential to overcome resistance to other EGFR-targeting agents and to avoid toxic side effects seen with other anti-EGFR therapeutics.
Pritumumab binding to glioma cells induces ADCC and inhibits tumor growth.
Authors: Kesari Santosh , Babic Ivan , Mukthavaram Rajesh , Jiang Pengfei , Nomura Natsuko , Pingle Sandeep C. , Juarez Tiffany , Yang Junbao , Yenugonda Venkata , Nurmemmedov Elmar , Glassy Mark Charles
Published: September 2018

e14004

Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumumab binding to glioma cells. Xenograft studies demonstrated pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Intact cell-mediated immunity was necessary for pritumumab’s anti-tumor effect. Analysis of a blood brain barrier model showed significant binding of pritumumab in brain tumor areas and minimal distribution in normal brain tissues suggesting the antibody can cross the blood brain barrier. Conclusions: Our data demonstratepritumumab binds glioma cells in vitro and can induce ADCC. In addition, pritumumab can limit the growth of xenograft glioma tumors in vivo only in the presence of intact cell-mediated immunity. Together these data suggest pritumumab is suitable for development as an anti-tumor therapeutic.
A randomized, double-blind, single dose comparison of pharmacokinetics and safety of FKB238 with bevacizumab.
Authors: Kaito Hidekuni , van den Berg Frans , Niewiarowski Andrew , Boyce Malcolm
Published: September 2018

e14007

Background: Bevacizumab is a recombinant humanized monoclonal antibody that binds selectively to vascular endothelial growth factor-A (VEGF-A). Bevacizumab was first approved for treatment of metastatic colon cancer under the brand name Avastin; it has since been approved for treating various other cancers. FKB238 is being developed as a biosimilar to Avastin. In this first-in-human study, safety, pharmacokinetics (PK) and immunogenicity of FKB238 were compared to those of branded Avastin from US and EU market. Methods: Ninety nine healthy male subjects were randomly assigned to receive a single 5 mg/kg intravenous infusion of either EU Avastin, US Avastin or FKB238 in a 1:1:1 ratio. Safety, PK and immunogenicity (anti-drug antibodies - ADA) were assessed up to 99 days after the infusion. Each PK parameter (AUC0-inf and AUC0–t as primary; Cmax and t1/2 as secondary) was analysed to assess similarity between FKB238 and EU Avastin, FKB238 and US Avastin, and EU Avastin and US Avastin. PK similarity is established if for each of the 2 primary PK parameters, the 90% confidence interval (CI) of the ratio of geometric means for the said 3-way comparison falls within 0.80-1.25. Results: A total of 99 subjects were randomized and 96 completed the study. The 90% CI for the ratio of geometric LS means of all 3 comparisons (FKB238/EU Avastin, FKB238/US Avastin and US Avastin/EU Avastin) for all 4 PK parameters were entirely within the pre-defined equivalence margin (0.80-1.25). Overall, 81% of subjects experienced an adverse event (AE) after treatment (FKB238: 97.0%; EU Avastin: 76.5%; US Avastin: 71.9%). Most AEs were mild or moderate in intensity (Grade 1 or 2 by CTCAE ver. 4); the most common were headache (16.2%), epistaxis (8.1%) and fatigue (5.1%). There were no serious AEs. All subjects had a negative ADA against study drug at their last visit. Conclusions: The study demonstrated PK similarity of FKB238, EU Avastin and US Avastin in healthy male subjects. FKB238 was well tolerated, with no serious AEs. All three study compounds showed comparable safety profile with no significant AEs or evidence of a propensity to form ADAs. This results support further development of FKB238 as a proposed biosimilar to Avastin. Clinical trial information: 163882.
SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/neu expression.
Authors: Menderes Gulden , Bonazzoli Elena , Bellone Stefania , Black Jonathan , Altwerger Gary , Pettinella Francesca , Masserdotti Alice , Zammataro Luca , Buza Natalia , Hui Pei , Wong Serena , Litkouhi Babak , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Santin Alessandro
Published: September 2018

e14009

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. HER2 overexpression/amplification in EOC show considerable variation ranging from 8% to 66%. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to compare the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1) in EOC. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of effector cells [i.e., peripheral blood lymphocytes (PBL)] against EOC cell lines with high, moderate and low HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1. Specifically, in HER2/neu 1+ cell lines the mean IC50’s were 0.072 µg/mL and 3.035 µg/mL for SYD985 vs T-DM1 (p < 0.0001), in HER2/neu 2+ cell lines 0.054 µg/mL and 1.168 µg/mL, (p < 0.0001) and in HER2/neu 3+ cell lines 0.024 µg/mL and 0.088 µg/mL, respectively, (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in EOC and effective against HER2/neu 3+ xenografts. Additional (HER2/neu 2+ & 1+) EOC xenograft studies are ongoing. Conclusions: SYD985 is a novel ADC with remarkable in vitro activity against EOC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it may be active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in EOC patients harboring chemo-resistant disease are needed.
A clinical study to evaluate the efficacy and safety of docetaxel with ribavirin in patients with progressive castration resistant prostate cancer who have previously received docetaxel alone.
Authors: Kosaka Takeo , Maeda Takahiro , Shinojima Toshiaki , Nagata Hirohiko , Mizuno Ryuichi , Oya Mototsugu
Published: September 2018

e14010

Background: We have previously reported a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting cancer stemness related gene network and identified ribavirin as a candidate drug for overcoming docertaxel resistant castration resistant prostate cancer.This non-randamized and open-labelled pilot clinical study explored the safety and efficacy of ribavirin, anti-virus drug, in combination with docetaxel in patients with progressive CRPC. Methods: In this clinical study, patients received intravenous docetaxel 60-70 mg/mm2 on day 1 of 3-6 weeks cycles plus Ribavirin 600 mg twice daily. The primary endopoint was safety, PSA response and objective response rate. Secondary end ponts included health-related quality of life overall survival.Patients with progressive CRPC based on PSA and/or radiographic criteria, PS 0-1, normal renal and hepatic function were eligible. Results:Five patients were enrolled in this study. Medium age was 73. Median serum PSA concentration was 53.1 ng/ml (range: 5.1-370.5).The median cycle and total dose of docetaxel received before the study was 31 cycles and 3625 mg, respectively. 80% of patients who had disease progression during docetaxel treatment. The median time from last docetaxel dose to disease progression before the participation was 1.5 months.Safety: Medium number of treatment cycles were 7 (range: 3-8) cycles. Grade 3/4 adverse events requiring dose modification were not observed. Grade 3 anemia and neutropenia were seen in two patients. Common adverse events were less than Grade 2. Efiicacy: 3 (60%) had some degree of PSA decline and 2 (40%) had a decline of ≧30 %. Median follow-up was 10.0 month. Median progression free survival was 6 month. Conclusions: This combination was well tolerated with promising response rate, justifying further investigation in docetaxel resistant CRPC. Clinical trial information: UMIN000012521.
Bayesian AI to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase I study of BPM31510 (ubidecarenone) in solid tumors.
Authors: Sarangarajan Rangaprasad , Subbiah Vivek , Hong David S. , Kiebish Michael , Vishnudas Vivek , Grund Eric M , Miller Gregory M , Rodrigues Leonardo O , Dion Hedy , Stevens Janice , Akmaev Viacheslav R , Narain Niven R.
Published: September 2018

e14042

Background: BPM 31510 is a ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses Warburg effect. This Phase 1 study is evaluating safety of 144-hour infusion of BPM 31510 as a single agent and in combination with 3 standard chemotherapy regimens. The molecular adaptive study design enabled longitudinal multi-omic molecular profiling to delineate personalized cause-and-effect networks relating patient biology to clinical outcomes using unbiased Bayesian statistics based bAIcis Artificial Intelligence (AI) technology Methods: Eligible pts (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM31510 for 144-hour infusion in 28d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed with BPM 31510 for 3 wks followed by weekly dosing in a 6wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Clinical information was processed and integrated with multi-omic molecular data (metabolomics, lipidomics and proteomics), utilized bAIcis to learn relationships and extract actionable information from pt records, molecular features and corresponding clinical response. Results: As of 10 Dec 2016, 97 pts have been enrolled. Hematologically-related DLTs were reported at 171mg/kg in monotherapy and 137mg/kg in the BPM31510+gemcitabine arm (maximum administered dose). The bAIcis-generated set of predictors defining coagulation-related events in the clinical trial population include proteins, lipids, and metabolites, the levels of which can potentially predict undesirable events prior to and 24h after the 1st treatment with BPM 31510. Conclusions: BPM31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents. Molecular signatures of susceptibility have been identified through use of multi-omic based AI analysis. Molecular signatures predictive of coagulation-related events will be assessed in Phase 2 and 3 trials to guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.
Tolerability of paclitaxel/carboplatin (PCb) in solid tumor patients (pts) infected with HIV.
Authors: Haigentz Missak , Moore Page C. , Ratner Lee , Henry David H. , Rubinstein Paul G. , Ramos Juan Carlos , Rudek Michelle A. , Eng Yoko , Cooley Timothy Patrick , Deeken John F. , Little Richard F. , Mitsuyasu Ronald T. ,   AIDS Malignancy Consortium
Published: September 2018

e14077

Background: Although cancer has long been a recognized hallmark of the HIV epidemic, the preservation of immunologic health with modern antiretroviral therapy (ART) and aging has resulted in a population increasingly susceptible to cancers not traditionally associated with advancing immunosuppression. Several of these cancers (including lung, anal and head & neck) are seen in excess compared to the background population. Defining tolerability of standard treatments and analyzing potential interactions between ART and chemotherapy provides evidence necessary to mitigate treatment disparities. Methods: We conducted a study to evaluate the tolerability of PCb in HIV+ cancer pts. AMC-078 (NCT01249443), originally designed as a phase I of vorinostat in combination with fixed doses of P (at 175mg/m2) and Cb (AUC 6) every 3 weeks, was amended to study pts treated with PCb alone after phase III testing in the background population was negative for the combination in lung cancer. Eligibility criteria: PS ≤ 2, advanced solid tumor and normal organ function, including CD4 count > 100 cells/mcL on stable ART. Up to 6 cycles of PCb were permitted. Clinically significant adverse events (AE) in prior cycles were managed by dose reductions. Results: 17 pts (10M/7F; median CD4, 389/mcL) were accrued, including lung (9) and anal (3) cancers; 8 pts had ritonavir (potent CYP inhibitor)-containing ART. 65 PCb cycles were administered to 16 evaluable pts, for a mean of 4+ cycles/pt; only 2 pts were treated with vorinostat. AE of special interest included ≥G3 (febrile) neutropenia and ≥ G2 neuropathy, below. 4 pts had partial responses (3 confirmed). Pharmacokinetic analyses (7 pts) are pending. Conclusions: PCb has similar toxicity profile in fit pts with HIV infection. No signal for worse myelosuppression or neuropathy was observed by ART regimen. Routine use of GCSF or empiric dose reduction for presumed risk is unjustified. Results support standard cancer treatment for this underserved population. Clinical trial information: NCT01249443. [Table: see text]
Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes.
Authors: Albitar Maher , Sudarsanam Sucha , Ma Wanlong , Jiang Shiping , Chen Wayne , Funari Vincent Anthony , Agersborg Sally
Published: September 2018

e14500

Background: PD-L1 expression as detected by immunohistochemistry (IHC) is significantly lower in colorectal cancers (CRC) when compared with lung cancer or other types of cancer. We explored if mutations in the RAS/RAF gene family, TP53 or PIK3CA can define a subgroup of CRC that express PD-L1. Methods: Tissue samples collected from 107 patients with CRC were studied for the expression of PD-L1 using clone SP142. The same samples were also tested for mutations in NRAS, KRAS, HRAS, BRAF, TP53, and PIK3CA using Next Generation Sequencing (NGS). Results: Of the 107 CRC samples only 15 (14%) showed PD-L1 positive tumor cells (≥1%) and 8 of the 15 (7.5% of total) had PD-L1 in ≤5% of tumor cells. Detected mutations in these samples were as follows: TP53 65%, KRAS 49.5%, PI3KCA 22.5%, NRAS 5%, HRAS 1%, and BRAF 17%. There was no correlation between PD-L1 expression and mutation status in any of the RAS/RAF genes. There was also no correlation between TP53 mutation and PD-L1 expression. This was true irrespective if PD-L1 expression is considered as a continuous variable or when cut-off points of 5%, 20%, or 50% were used. However, patients without any mutation in RAS or TP53 had significantly (P = 0.005) more expression of PD-L1 when cut-off point of 5% is used. This remained true if PD-L1 expression is considered as a continuous variable (P = 0.04). There was no correlation between PIK3CA and PD-L1 expression. Conclusions: PD-L1 expression is significantly more common in CRC that lack mutations in RAS or TP53. PD-L1 expression is detected in 31% of patients with wild-type RAS/TP53 as compared with 12% in patients with RAS/TP53 mutations (P = 0.04). If a cut-off point of 5% is used, 31% of RAS/TP53-wild-type CRC were positive for PD-L1, while only 6% of RAS/TP53- mutant CRC were positive for PD-L1 (P = 0.005). This suggests that in CRC without RAS/TP53 mutation, the PD-L1 may play a more important role in oncogenesis. Exploring immunotherapy in this group of CRC patients might be justified.