bluuebunny/crossref_metadata_2025 huggingface dataset:
PIK3CA mutations are distinctive genetic features in non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD): A comprehensive mutational analysis from multi-institutional cohort.
Authors: Sawa Kenji , Kawaguchi Tomoya , Koh Yasuhiro , Kambayashi Satoshi , Asai Kazuhisa , Mitsuoka Shigeki , Kimura Tatsuo , Yoshimura Naruo , Kubo Akihito , Saka Hideo , Matsumura Akihide , Nishiyama Noritoshi , Hirata Kazuto
Published: September 2018

e20060

Background: A mutual developmental mechanism has been proposed between NSCLC and COPD; however, the association is not fully understood. We previously reported that the mutations in PI3K/AKT/mTOR pathway and NFE2L2 were frequently observed and co-existed in NSCLC patients with COPD (Kawaguchi T, J Clin Oncol 34, 2016 [suppl; abstr 8526]). To further validate this finding, a new cohort was added and merged into the original cohort’s study. Methods: A total of 197 surgical specimens of early stage NSCLC including 90 newly added from Osaka City University hospital were collected between 2010 and 2013. Extracted DNAs were deep-sequenced using NGS technologies for somatic mutations in 72 cancer-associated genes for a molecular profiling in NSCLC patients with COPD. We defined COPD as presence of FEV1/FEV < 0.7 and classified the severity based on the Global Initiative for Chronic Obstructive Lung Disease. Results: The COPD group (N = 77) including 56 mild, 21 moderate/severe diseases, had 58 squamous cell carcinoma (SQ) and 19 adenocarcinoma (AD), with 70 smokers. The non-COPD group (N = 120) had 53 SQ, 64 AD and three others, with 78 smokers. The frequency of PIK3CA mutations was higher in COPD (10.4 %) than non-COPD (1.7 %), while in AD KRAS mutations were more frequent in COPD (21.1%) than non-COPD (9.4%). Notably, the frequency of PIK3CA mutations increased parallel to the COPD severity (p < 0.001). Meanwhile, NFE2L2 mutations were observed only in SQ, and no difference in the frequency was observed between the two groups (17.2% vs. 17.0%) unlike our previous analysis. In the multivariate logistic regression model, significantly more PIK3CA mutations were observed in the presence of COPD (Odds ratio = 5.47, 95%CI: 1.04-28.85, p = 0.045) with consideration of age, smoking dose, histology and pathological stage. The most frequent base substitution pattern in PIK3CA mutations was C > T change, suggesting the association with APOBEC-mediated mutagenesis. Conclusions: PIK3CA mutations are distinctive genetic features in NSCLC with COPD, regardless of age, smoking dose, histology and pathological stage.
Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain (TKD) with next-generation sequencing (NGS).
Authors: Stein Matthew K , Morris Lindsay Kaye , Sullivan Jennifer , Fenton Moon Jung , Vanderwalde Ari M. , Schwartzberg Lee Steven , Martin Michael Gary
Published: September 2018

e20506

Background: While conventional organization of EGFR mutations in NSCLC includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to TKD in exons 18-21, NGS raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. Methods: Patients (pts) with lung cancer who received tumor profiling with NGS from 2013-2015 via Caris were identified. EGFR mutations were arranged based upon their known distribution relative to the TKD. In silico analysis was performed with PolyPhen-2 (Harvard) to predict nsSNPs’ pathogenicity. Results: 259 pts (248 NSCLC, 11 SC) had median age 65 years (26-85); 50% female; 64% white, 34% black; 73% with ≥20 pack-years (py), 12% non-smokers; 53% of samples were metastases. 65% NSCLC were adenocarcinoma (A), 21% squamous (S), 8% large-cell; 87% stage IV, 12% III. 44 EGFR variants were seen in 40 pts (15%; 39 NSCLC, 1 SC). While 32 pts had TKD lesions demonstrable through standard testing, 8 had extra-TKD mutations (8/44), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 2 carboxy terminal (CT). Aside from pathogenic ECD mutation G598V, 5/7 extra-TKD nsSNPs were predicted-damaging (pnsSNP) with in silico (Table 1). 7/7 extra-TKD nsSNP+ pts smoked (6/7 ≥20 py) and all 6 NSCLC pts were stage IV; 50% A, 17% S; 83% male. The pt with JM R675Q had erlotinib, 150 mg daily, added following progression of stage IV NSCLC on carboplatin and paclitaxel and had a partial response for 4 months. No other pt received EGFR-directed therapy. Conclusions: 2% NSCLC cases in our cohort had EGFR pnsSNPs located outside of the TKD, representing >18% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. [Table: see text]
Monitoring response of PDL-1 directed immunotherapy in patients with advanced NSCLC using serum CEA levels.
Authors: Roy Rajasree , Chan Wallace , Patel Dilip , Nissel-Horowitz Sandy , Caramalis Angela , Diaz Melanie , Thomas Adrienne , Durban Lawrence H , Mehrotra Bhoomi
Published: September 2018

e20509

Background: Immunotherapy (IT) response measurements in advanced NSCLC management are evolving. We describe here our retrospective single institutional experience in measuring serum CEA levels as an early response determinant and correlation with radiographic assesment. Methods: Retrospective chart review was performed after obtaining IRB approval. Demographic information, stage, histology, prior treatment, IT agent used, radiographic response assesment and serum CEA levels were recorded. Patients were evaluable if they had elevated baseline serum CEA levels (normal range non smokers: 0-3 ng/ml, smokers 0-5 ng/ml), had recieved at least two cycles of IT and had radiographic response assessment performed. Results: Six eligible patients were identified. Median age 60 yrs; M:F1:5, SCC n=1, Adeno: n=5; Smoking history positive n=4; Stage IV n=6, EGFR mut+ n=2; IT agent used: nivolumab: n=5; atezolizumab: n=1. IT as 1st line of Rx n=1; 2nd line n=3, 3rd line: n=2. On first radiographic assesment: three patients had progressive disease (PD), Two patients had PR, one patient (#1) had an intial PR and subsequently PD with subsequent rise in CEA level to 16.1 corelating with PD on radiographs. Conclusions: Serum CEA levels appear to correlate well with response assesment in patients with advanced NSCLC while being treated with immunotherapy. This small study is hypothesis generating and is currently being evaluated in a larger series. [Table: see text]
Some immunohistochemical markers of angiogenesis in melanocytic skin neoplasms.
Authors: Novikova Inna Arnoldovna , Maksimova Natalia A. , Ulianova Elena Petrovna , Maksimova Maria I. , Shulgina Oksana G. , Grankina Anastasia , Pozdnyakova Victoria V. , Ilchenko Maria G.
Published: September 2018

e21067

Background: The purpose of the study was to analyze the expression of angiogenesis-controlling markers (CD31, VEGF) in tissues of melanocytic skin lesions. Methods: The study included 20 patients with benign pigmented lesions and 15 patients with superficial spreading and nodular melanoma. Immunohistochemical study was performed on sections of paraffin blocks for standard morphological studies using murine monoclonal CD31 and VEGF antibodies. UltraVision Quanto Detection System HRP DAB was used for visualization. Angiogenesis in tumors was assessed by intratumoral microvessel density (iMVD) index. Microvessels were stained with anti-CD31 antibody. The number of vessels was determined in each area of sight using objective lens with 40x magnification and AxioVs40 v-4.8.1.0 program. The tumor was considered VEGF-positive if more than 25% of tumor cells showed positive staining, and percentages of these tumor cells were calculated in each case (in %). Results: Quantitative evaluation of iMVD showed that the median number of microvessels in an area of sight in melanoma and nevi was 10.0±0.9 and 4.1±0.4, respectively, results of CD31 expression were statistically significant (р˂0.05). The numbers of CD31-stained vessels in melanoma ranged from 4 to 18 in one area of sight. 14 nevus cases (70%) showed 4 and less vessels, and only giant-cell nevi (6-30%) demonstrated up to 15 vessels in one area of sight. VEGF expression was found in the cytoplasm of melanoma cells in 100% of cases (15), in nevi – in 65% (13). The expression was not found in nevi cells in 35% (7). The number of VEGF-positive cells varied greatly in both melanomas and in nevi – from less than 5% to 50%. The maximal VEGF expression was observed in melanomas – 32.5±2.9%, while in nevi 23.8±2.1% (р˂0.05). Conclusions: The immunohistochemical study demonstrated a high angiogenic potential of melanoma that can be used as an additional criterion for tumor progression and malignant transformation of melanocytic skin neoplasms and thus contribute to the development of novel approaches to the diagnosis of the disease.
Development and validation of a Medicare health outcomes survey (MHOS) frailty index in multiple myeloma (MM).
Authors: Fiala Mark A , Guerard Emily Jean , Schroeder Mark A. , Stockerl-Goldstein Keith , Vij Ravi , Wildes Tanya Marya
Published: September 2018

e21519

Background: Increasing age is associated with poorer outcomes in MM. However, biological aging (BA) is heterogeneous and does not correlate perfectly with chronological age (CA). A recently developed frailty of CA, functional status, and comorbidities is more predictive of toxicity, progression-free and overall survival (OS) than CA alone (Palumbo et al Blood 2015). We sought to apply the Rockwood Accumulation of Deficits approach to develop and validate a frailty index (FI) for older adults with MM. Methods: MHOS, a random survey of HRQOL (health related quality of life) in Medicare Advantage HMO enrollees, data were obtained from 1,747,042 non-cancer patients (pts) and 340 with newly diagnosed MM 1997-2011 from the SEER-MHOS linked dataset. In creating the FI, we considered only variables available throughout all 4 survey versions used since its initiation in 1998. We identified 34 variables including items related to function/mobility, comorbidities, and mental health. The FI was calculated as the number of deficits present, divided by the number total number of possible deficits, with possible scores ranging from 0 to 1 and higher values indicating more frail. Missing data points were excluded from the FI calculation. Cox regression analysis was performed to determine the association of the FI with OS, controlling for CA, gender, and race. The FI was first derived in the non-cancer cohort then applied in the MM cohort. Results: The median age was 72 for non-cancer pts and 75 for pts with MM; the median FI was 0.308 and 0.368, respectively. Among non-cancer pts, each 10% increase in FI (~3-4 more deficits) was associated with a 35% increased risk for death (aHR 1.352, 95% CI 1.350-1.354, p < 0.001); among pts with MM it was associated with a 15% increased risk (aHR 1.147, 1.065-1.236, p < 0 .001). Median OS for pts with MM in the lowest tertile of FI was 48 months (95% CI 42-56) compared to 23 months (17-33) for the highest tertile. Conclusions: Here we present a MHOS-based FI. The FI was more prognostic among non-cancer pts than among pts with MM, presumably because stage and tumor characteristics also contribute to OS in MM pts. Further exploration of the MHOS-FI in MM and other cancers is warranted.
Ability of individual patient health parameters to predict malnutrition among elderly stem cell transplant patients.
Authors: Bhulani Nizar , Holmes Holly Michelle , Morgan Robert
Published: September 2018

e21521

Background: Increasing number of geriatric patients are now being considered as suitable candidates for allogeneic hematopoietic cell transplantation (HCT). Malnutrition being a common comorbidity in older cancer patients with no gold standard in malnutrition screening tools, it warrants for a better understanding of the health of geriatric cancer patients from a nutrition stand point. This study was pursued to evaluate individual patient parameters to predict malnutrition among elderly stem cell transplant patients. Methods: A retrospective cohort analysis was conducted on patients eligible for allogeneic HCT at the MD Anderson Cancer Center. Nutrition was assessed using the Mini Nutritional Assessment tool. Individual parameters to predict malnutrition included body mass index of less than 24 and weight loss of more than 3 kgs in the past 3 months. Statistical analysis was conducted using SPSS, version 23. Results: Mean age of the study participants was 65 years. Majority of the study population had the diagnosis of acute myelogenous leukemia (AML) at the time evaluation. The mean BMI of the study participants was 28.91 +- 4.77 while the mean MNA score was 24.95 +- 3.39. There was no association found between patient characteristics and history of weight loss or abnormal BMI. There was a significant association (p < 0.001) found between loss of more than 3 kg weight and an abnormal MNA score. There was no association found between any of the patient characteristics and abnormal BMI with abnormal MNA. The sensitivity of weight loss in comparison with MNA score was 62.5% and the specificity was 91%, thus, having a positive and negative predictive value of 77% and 84% respectively. Given that 86% of our patients were either overweight or obese at the time of evaluation, from those who were under weight, 100% had an abnormal MNA and 50% of normal weight patients had an abnormal MNA. Conclusions: The significant association between weight loss and poor MNA status shows that we are moving in the right direction to provide answers to nutrition status using individual patient health parameters.
Hair loss associated with aromatase inhibitor treatment among breast cancer patients.
Authors: Gallicchio Lisa , Calhoun Carla , Helzlsouer Kathy J.
Published: September 2018

e21619

Background: Hair loss and thinning have been reported by breast cancer patients treated with aromatase inhibitors (AIs); these side effects are documented to be reasons that patients discontinue their AI therapy and have been shown to be associated with a decrease in quality of life. Despite this knowledge, there is a paucity of detailed data on hair changes over the course of AI therapy. The purpose of this study was to examine hair changes and risk factors for hair loss among breast cancer patients initiating aromatase inhibitor therapy and followed for one year. Methods: Data were analyzed from a cohort of 146 breast cancer patients initiating AI therapy and followed over the first year of their AI treatment. At baseline (prior to AI therapy) and at 1-year, a questionnaire was administered that ascertained data on demographics, health behaviors, and symptoms. Detailed hair loss questions, including those pertaining to family history and specific location of hair loss, were added during the study period when study staff noticed that hair loss and thinning were commonly being reported on the symptom checklist after initiation of AI therapy. Multivariable logistic regression analysis was conducted to examine factors related to AI-attributed hair loss. Results: Among the 86 breast cancer patients who completed the detailed hair loss survey at 1-year (mean age = 63y), 43% reported experiencing hair loss after the initiation of AI therapy. The most frequently reported time period of onset of the AI-attributed hair loss was between 3 and 6 months post-AI initiation (43.2%), with 67.6% of patients noting hair loss in the mid-scalp (top of head). Factors significantly associated with AI-related hair loss at 1-year were: hair loss prior to AI therapy, having a BMI > 30 kg/m2(odds ratio (OR) = 6.5), being a current smoker (OR = 7.8), and maternal history of hair loss or hair thinning (OR = 9.1). ORs were similar when patients with prior chemotherapy were excluded. Conclusions: Hair loss is a common side effect of AI therapy that can negatively affect a patient’s quality of life and potentially lead to treatment discontinuation. Treatment options for this AI-related side effect should be explored, especially for patients who are at increased risk.
Prognostic factors for mortality in malignant pleural effusion: Is it possible to predict survival?
Authors: Abrao Fernando , de Oliveira Mariana Campello , Garcia Geisa , Abreu Igor , D'Alpino Renata D'Alpino , Sardenberg Rodrigo Afonso , Marciano Carolina , Toledo Mariana Belaunde , Younes Riad N.
Published: September 2018

e21638

Background: The aim of this study was to identify predictors of overall survival (OS) following palliative pleural procedures in patients with malignant pleural effusion (MPE). Methods: Data was collected from our database between January 2012 and December 2016 including all patients with MPE. All patients were followed-up for at least 30 days after the pleural procedure. We evaluated radiological aspects, biochemical and hematologic parameters as well as clinical features. For OS analysis, patients were divided into two groups. Group I included OS < 30 days and Group II included OS > 30 days. Prognostic factors for OS were identified by univariate analysis, using Fisher's exact for the categorical variables and Student's t-test for the quantitative ones. The cutoff points for any significant continuous variables were determined by the ROC curve. Subsequently, significant variables were entered into a multivariate logistic regression analysis ( p < 0.05). Results: A total of 238 patients were included in the analysis (37,6% males). Median age was 62 year-old (range 24-965) and median follow-up time for surviving patients was 127 days. Median OS was 83 days for therapeutic pleural aspiration (TPA), 353 days for pleurodesis, 135 days for VAT drainages without pleurodesis due to trapped lung and 39 days for indwelling pleural catheter. Regarding primary site, median OS was 170 days for lung (n = 91), 253 days for breast (n = 70), 90 days for gynecological (n = 18), 33 for gastrointestinal (n = 34) and 305 days for others (n = 26). Factors affecting OS in univariate analysis with p < 0.0001 were ECOG, procedure, protein, albumin, neutrophil to lymphocyte ratio(NLR) and hemoglobin, pulmonary infiltrate (p < 0.0438), hematocrit (p < 0.0002), and chemotherapy line (p < 0.0229). In multivariate analysis the following variables were identified as independent prognostic factor: ECOG 3/4 (p < 0.0095), pulmonary infiltrate (p < 0.0011), albumin < 2.5 (p < 0.0325), and hematocrit < 35 (p < 0.0055). Conclusions: Patients with MPE who presented with ECOG 3/4, pulmonary infiltrate, albumin < 2.5 and hematocrit < 35 had shorter OS. The identification of these prognostic factors may assist physicians in choosing the optimal palliative technique.
Impact of measuring quality of life in oncology practice: A prospective study.
Authors: Castillo Cecilia , Alfonzo Ana Laura , Camejo Natalia , Schiavone Andrea , Diaz Mariana , Camano Ivanna , Camblor Maria Eugenia , Delgado Lucia Beatriz , Dapueto Juan
Published: September 2018

e21663

Background: To assess the impact of incorporating systematic quality of life measurements in oncology practice on the quality of care and well-being of patients; to assess physician's level of satisfaction with this instrument and detectable changes in clinical practice Methods: In a prospective study, 67 patients (pts) diagnosed with cancer, undergoing cancer-specific treatments, were randomized into a intervention and control group. In the intervention group , pts had regular completion of touch-screen health-related quality of life (HRQL) questionnaires (European Organization for Research and Treatment of Cancer–Core Quality of Life Questionnaire version 3.0, and Hospital Anxiety and Depression Scale) and feedback of results to physician and then were followed up with a phone call where HRQL was measured by the Functional Assessment of Cancer Therapy–General questionnaire (FACT-G). In the control group, pts were regular followed with a phone call to answer FACT-G questionnaire. Physicians completed a visit-specific questionnaire after each visit of pts from intervention group. Results: 58 pts were included, 36 in the intervention group and 22 in the control group. Median age was 59 years. The results of the patient-reported data were found to be very useful to quite useful by 87.5% of physicians (14/16), and 56.3% of them considered that there was no difference in the length of visits. Completing the HRQL questionnaires on a touch screen was easy to very easy for 97.1% of patients, and 97.1% found that important questions were asked and that they would be willing to complete the questionnaires. FACT-G scores and subscale scores were higher in the intervention group, but differences were not statistically significant (76.44 v 72.60; p 0.388). Conclusions: HRQL assessments had a positive impact on physician-patient communication. It made it possible to learn how cancer and its treatments affected pts not only physically, but also on functional and psychological states and social relationships. They helped us improve therapeutic interventions and specialist referrals, thus achieving positive changes in the well-being and satisfaction of pts.
Evaluating financial toxicity (FT) interventions.
Authors: De Souza Jonas A. , Proussaloglou Ellie , Nicholson Laura , Wang Yichen
Published: September 2018

e21673

Background: FT has been defined as an adverse event of cancer treatments. Several patient (pt)-level interventions have been developed to mitigate FT. However, due to the lack of longitudinal studies, the impact of these interventions has not been established. Methods: Pts with cancer receiving Co-Pay Assistance (CPA) from the Patient Access Network Foundation were approached at baseline, 1 and 3 months post-CPA. We assessed the use of pt navigators, social workers, financial counselors, support groups, and transportation vouchers by pts. The outcomes were improvements in disease-specific HRQoL measures, global HRQoL measure (FACTG, lower values are worse) and improvement in FT, as measured by the COST (lower values are worse). Multivariable regression was used to identify whether these interventions were associated with the outcomes. Results: 308 pts with cancer were assessed at baseline (prior to CPA) and at 1 and 3 months after. 275 pts (89%) had an improvement in their FT over 3 months. A majority of these pts had multiple myeloma (MM, 86 pts, 28%). Navigators were used by 179 pts (42%), social workers by 106 (34%), financial counselors by 107 (35%), support groups by 94 (31%), and transportation vouchers by 50 (16%). None of these interventions increased the odds of FT or HRQoL improvement at the 0.05 significance level. Conclusions: The selected population of cancer pts who received CPA for their treatments had a significant improvement in FT over time. Yet, this improvement was not associated with additional interventions, suggesting CPA as the main intervention. The FT improvement was not clearly translated into significant HRQoL improvements, likely due to the multidimensional HRQoL construct (which includes other symptoms) versus the unidimensional aspect of a financial event. [Table: see text]
Barriers and solutions of long-term follow up of childhood cancer survivors in Turkey: A questionaire survey.
Authors: Tacyildiz Nurdan , incesoy Ozdemir Sonay , Unal Emel Cabi , Dincaslan Handan , Yavuz Gulsan
Published: September 2018

e22020

Background: The population of childhood cancer survivors has grown with 80 % cure rates. Our aim was to establish the barriers of longterm followup (LTFU) in Turkey. Methods: An e-mail questionnaire survey has been sent to 33 pediatric oncology centers (POC). Questionnaire compossed of 3 sections: 1- Description of the center; yearly new patients number, follow-up period, etc. 2- Methods for follow-up of late effects Content of provided information to the families related cancer treatment & side effects & healthy life style, missing parts of LTFU 3- Transition problems of survivors to adult survivorship programs. Educational problems of Hematology/Oncology Fellows (HOF) Suggestions for improvement of LTFU. Results: 21 of 33 centers (63%) responded the questionnaire. Experience as POC: 2-50 years (median: 23). New patients / each year: 8 - 300 (median: 68). Most of the centers accepting patients up to 18 years, only 4 center providing lifelong LTFU. No Available Risk Adapted LTFU guideline at 21 center. LTFU provided by pediatric oncologist at the pediatric oncology outpatient clinic with transition problems to adult clinic. All centers were following Cardiotoxicity, Secondary cancer,and Kidney toxicity with no problem Barriers of Turkish POC for LTFU of Pediatric Cancer Survivors were: Lack of enough care providers 66%, lack of time 57%, transportation problems 57 % ,lack of providing knowledge to patients 38 %. Although 80 % of the centers have fellows for HOF, not enough edication on survivorship 66%, due to lack of survivorship clinic ( 80%), busy working schedules. Conclusions: Questionnaire survey was able to reach 2/3 the pediatric oncology centers that were located in 8 cities and following most of the pediatric oncology patients in Turkey Mostly POCs do not provide enough LTFU. All centers agree on national guidelines for LTFU. [Table: see text]
Limb salvage surgery in pediatric and AYA patients with osteosarcoma: The incidence of venous thrombosis (VT).
Authors: McKillop Sarah Jane , Chu Quincy S. , Mulder Karen E. , Bauman Mary E , Crosty Ashley
Published: September 2018

e22505

Background: Pediatric, adolescent and young adult (AYA) patients with a diagnosis of osteosarcoma require surgical resection for local control in addition to adjuvant chemotherapy. Limb salvage surgery (LSS) has long been established as the standard of care. Pediatric and AYA patients with sarcoma are know to have an increased risk of VTE however thromboprophylaxis is not routinely used in the pediatric oncology patients. Here we review our experience over a 5 year period with patients up to 21 years diagnosed with osteosarcoma of the lower extremity treated with LSS, amputation or rotationplasty as local control and the development of VTE. Methods: A retrospective chart review was completed of patients up to 21 years of age treated for osteosarcoma of the lower extremity between January 2011 and December 2016 at our institutions. Those that underwent surgical resection of the tumor were included. Data regarding age, type of surgical procedure, the presence of a venous thrombosis, the time from diagnosis and surgery to detection of VTE and the use of anticoagulants was collected Results: 18 patients were identified: median age 14 year (6-21), 8 patients had LSS, 4 underwent rotationplasty and 6 had an amputation. Seven VTE were identified, 5 occurred in patients receiving LSS, 2 in a patient post rotationplasty and 0 in the amputation group. 6 of the 7 VTE occurred within the upper venous system, associated with the central venous line. Conclusions: In pediatric AYA patients being treated for lower limb osteosarcoma, the incidence of VTE was significantly increased for those undergoing LSS (63%) and rotationplasty (50%) compared to those receiving amputation (0%). While the population reviewed is small, based on these findings, prophylactic anticoagulation for patients with osteosarcoma, especially those patients undergoing LSS and rotationplasty should be considered beyond the immediate perioperative period. Larger prospective studies are needed to determine the risk of VTE and risks and benefits of prophylactic anticoagulation in this patient population.
Effect of MiR-137 and MiR-496 on Del-1 and triple negative breast cancer progression.
Authors: Jeong Jae-Hwan , Lee Soo Jung , Lee Jeeyeon , Jung Jin Hyang , Park Ho Yong , Park Ji-young , Kang Seung Hee , Chae Yee Soo , Kim Jong Gwang
Published: September 2018

e23058

Background: Although Del-1 was recently proposed as a new biomarker for early breast cancer in our previous studies, the mechanisms of Del-1 expression are barely understood. In the current study, we selected two microRNAs (miR-137 and - 496), potentially affecting Del-1 expression in breast cancer and examined their impact on Del-1 expression in a variety of breast cancer cell lines to identify their potential role in Del-1 expression and thereby breast cancer development or progression. . Methods: Del-1 mRNA and miR-137/– 496 levels were measured by qRT-PCR among breast epithelial (MCF10A) and cancer cells (MDA-MB-231, MCF7, SK-BR3 and T-47D). The effects of miR-137/– 496 on cell proliferation and invasion were detected using MTT, wound healing and Transwell assays. Furthermore, luciferase reporter assay was used to identify the direct regulation of Del-1 by miR-137 or – 496 in MDA-MB-231 cells. Plus, we analyzed the expressions of miR-137 or – 496 and Del-1 mRNA from 20 patients with triple negative early breast cancer. Results: miR-137 and – 496 levels were low in all breast cancer cell lines. As Del-1 mRNA expression was remarkably higher in MDA-MB-231 compared to the other breast cancer cell lines, further functional analyses were done with MDA-MB-231 representing triple negative breast cancer subtype. Both miR-137 and miR-496 were revealed to directly bind at the 3’-UTR of Del-1. Del-1 by Luciferase reporter assay and Del-1 expression was upregulated by inhibitors and reversed by both mimics of both miR-137 and miR-496. Furthermore, both miR-137 and miR-496 were also demonstrated to inhibit cell proliferation, migration and invasion of MDA-MB-231, suggesting that these miRNAs affect cancer progression via Del-1. MiR-137 and miR-496 were remarkably down-regulated in 7 out of 12 triple negative breast cancer tissues, in particular with high Ki67 and high histologic grade. Conclusions: Although Del-1 was recently introduced as a new biomarker for triple negative breast cancer, the mechanisms of Del-1 expression were barely identified. The current study firstly demonstrated that microRNA 137 and 496 are involved in Del-1 regulation by binding at Del-1 gene, affecting cancer progression by altering Del-1 expression.
Accuracy of profiling of circulating tumor DNA for CRC MRD and monitoring using NGS technology equipped with concatemer-based error correction.
Authors: Zhao Grace Q. , Weng Li , Li Xin-Xing , Li Min , Tang Paul , Lu Yontao , Wang Yingyu , Huang Yi , Wang Hongyan , Guo Lingchen , Yeo Dana , Sun Zhaohui Johnny , Xiao WeiWei , Hu Zhi-Qian , Li Ming , Ying Kang , Faham Malek , Lin Shengrong
Published: September 2018

e23067

Background: Circulating tumor DNA (ctDNA) is a promising biomarker for the detection of minimal residual disease and monitoring treatment in patients with CRC. The performance demands of any technology used for this purpose, however, are tremendous. Here we aim to develop a high-performance multiplex NGS platform suitable for cancer MRD using ctDNA. Methods: We have developed Firefly, a NGS method capable of detecting low-frequency variants with high precision in plasma cfDNA. In our protocol, denatured double-stranded cfDNA is circularized and converted into long tandem repeats using rolling-circle amplification enabling consensus-based concatemer error correction. We demonstrated Firefly’s performance sensitivity and specificity by testing our technology on cfDNA samples with known variant frequencies and cfDNA collected from healthy individuals (n = 82). Further analysis of Firefly as a tool for MRD and treatment monitoring was performed by tracking ctDNA mutation profile concordance between 81 CRC tumor samples and their corresponding plasma samples collected from patients before and after treatment. Results: Performance sensitivity of Firefly NGS was 0.1% with an error-rate was 1 in 1 Million for 20ng of input ctDNA. Concordance analysis was performed on CRC tumor/plasma pairings derived from patients with CRC using, Accu-Act, a 61-gene assay. The number of tumor-matching mutations detected in plasma varied greatly on a per-patient basis (range, 0-28). Pre and post-treatment ctDNA profiling was performed on all 81 patients included in our study (surgery, n = 56; chemotherapy/radiotherapy, n = 30). Among patients who underwent surgery, 46% had detectable tumor-matching mutations in their plasma. Among patients who received neoadjuvant therapy, 70% ctDNA fluctuations consistent with tumor reduction based on surgical tumor regression grades evaluation(TRG1-3). Conclusions: We report a novel ultra-accurate NGS-based ctDNA assay suitable for MRD and monitoring in CRC patients. Firefly should ultimately make a significant contribution in the development of personalized cancer treatment.
A novel CDA liquid biopsy technology for effective non-small cell lung cancer diagnosis.
Authors: Wu Junjie , Jiang Gengxi , Li Yutao , Du Xuedong , Tao Hongmei , Tang Xing , Lou Da , Lin Yue , Bai Chong , Yu Chris Chang
Published: September 2018

e23131

Background: Cancer Differentiation Analysis liquid biopsy (CDA) has been investigated as a viable clinical utility in NSCLC diagnosis, as well as a new candidate for part of an overall post-CT scan clinical diagnostic and treatment decision tool kit. It has been also evaluated in NSCLC diagnosis, combined with imaging technologies. Methods: This was a retrospective investigation in which 160 individuals were recruited at Changhai Hospital of Shanghai from July to Dec. in 2014. CDA and CT scan tests were performed on all samples before final confirmation by biopsy. For CDA tests, peripheral blood was drawn in EDTA tubes before operation. A performance predication model of CDA and CT scan test results was built using pROC package in R Language for the data of Area Under the Curve (AUC) and CDA threshold values. Further analysis was carried out based on the CDA threshold values. Results: Out of the 160 individuals, 40 were diagnosed as benign lung diseases selected as control group, 120 were confirmed as NSCLC by pathology. CDA and CT test data along with epidemiological information were collected and complied. Details of other statistical results were given in the Table below. Conclusions: CDA liquid biopsy is a novel, multi-level, multi-parameter based disease diagnosis technology with improvements in multiple areas including but not limited to higher sensitivity and specificity, ability to diagnose cancer early, no side effects, and covering a wide range of cancer sites. Results showed that AUC values of CDA were higher than those of CT scan for all NSCLC stage groups. CDA plus CT scan combination has the highest average AUC value for all stages. CDA test can provide more accurate and reliable diagnostic information and data for oncologists in making crucial clinical decisions. It is expected that CDA liquid biopsy technology will play an important and critical role in NSCLC diagnosis. [Table: see text]
Antitumor effect of the combination of proteasome inhibitor (Pi) and histone deacytelase inhibitor (HDACi) in breast cancer (BC).
Authors: Kannarkatt Joseph , Alkharabsheh Omar Abed , Madhukar Burra V , Leece Cheryl , Tamkus Deimante
Published: September 2018

e23156

Background: Previous studies demonstrated the efficacy of HDACi and Pi as single agents in BC. The synergistic combination of HDACi and Pi has been shown to be effective in clinical studies in other tumor types, including multiple myeloma, non-small cell lung cancer, and pancreatic cancer. In this in vitro study, we explored the hypothesis that combination of these two agents may improve overall antitumor effect in BC. Methods: In the experiment, we used 3 BC cell lines: MCF7 (ER+), MDA-MB-231 (ER-), and BCSV (isolated from metastatic ER+ tumor which lost ER expression with disease progression). The cells were treated with carfilzomib (Pi) and scriptaid (HDACi) as single agents and in combination. Cell viability was determined using MTT assay, and combination indexes were determined using CalcuSyn software. Additionally, cells were cultured in 3D tumor spheroid model, and response to treatment was assessed on day 5, 10, 15 and 20. Results: In comparison with control, single agent HDACi, single agent Pi and combination HDACi/Pi increased cell viability by 6%, decreased cell viability by 60% and by 69% respectively (p < 0.0001) in MCF7 cells; and decreased cell viability by 25%, 59% and 66% respectively (p = 0.0061) in BCSV cells. The combination indexes for most HDACi and Pi combinations were lower than 1.0, indicating synergistic effects in MCF-7 and BCSV cells but not in MDA-MB-231 cells. In 3D cultures, the combination of carfilzomib 1µM and scriptaid 10µM led to significant reduction of tumor spheroid size as compared to single agent. By day 20, BCSV tumor spheroid size increased by 258% in control group and by 50% in Pi, decreased by 17% in HDACi and by 30% in HDACi/Pi combination group (p < 0.0001). Conclusions: Combination of HDACi and Pi exhibited synergistic activity in both MCF7 and BCSV monolayer cultures. Additionally, combination HDACi and Pi significantly decreased 3D tumor spheroid size as compared to either single agent alone. Further study is needed to evaluate the mechanisms of Pi/HDACi combination in estrogen-mediated BC tumorigenesis.
Molecular profiling of 502 patient cohort with NSCLC using a 27 somatic gene panel.
Authors: Tsoulos Nikolaos , Papadopoulou Eirini , Metaxa-Mariatou Vasiliki , Tsaousis Georgios , Efstathiadou Chrisoula , Tounta Georgia , Skapeti Katerina , Bourkoula Jenny , Zarogoulidis Paul , Pentheroudakis George E. , Kakolyris Stylianos , Boukovinas Ioannis , Papakotoulas Pavlos , Athanasiadis Ilias , Floros Theofanis , Koumarianou Anna , Vassilios Barbounis , Nasioulas George
Published: September 2018

e23193

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a tumor with broad spectrum of targeted therapies already available or in clinical trials. Thus, molecular characterization of the tumor using the Next Generation Sequencing (NGS) technology, has become a key tool for NSCLC patients’ treatment decision and clinical management. Methods: The performance of a custom 23 gene multiplex amplification hot spot panel, based on Ion AmpliSeq Technology, was evaluated for the analysis of tumor DNA extracted from FFPE (Formalin Fixed Parraffin Embedded) tissue. Furthermore the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel was used for fusion RNA transcript analysis. Tumors’ mutation spectrum was determined in a cohort of 502 patients with NSCLC using the aforementioned targeted gene panels. Results: The panel used for tumor DNA analysis in this study exhibit high rates (100%) of sensitivity, specificity and reproducibility at a mutation frequency of 3%. At least one DNA mutation was detected in 374 patients (74.5%) and an RNA fusion was identified in 16 patients, (3.2%). In total, alterations in a cancer driver gene were identified (including point mutations, gene rearrangements and MET amplifications) in 77.6% of the tumors tested. Among the NSCLC patients, 13.5% (68/502) presented a mutation in a gene with approved targeted therapy (EGFR, ALK ROS1) and 9.4% had an alteration in a gene related to emerging targeted therapies according the NCCN guidelines. These alterations include ERBB2, BRAF and MET mutations, MET amplification and RET rearrangements. The remaining 51.6% of the patients had a mutation in a gene that could be related to an off label therapy or give them access to a clinical trial. Conclusions: Thus the NGS panel validated is a reliable approach of clinical applicability for tumor molecular profile detection in NSCLC patients.
A pilot RCT of sarcopenia-focused prehabilitation in pancreas cancer.
Authors: Hile Elizabeth , Hoffman Leah , Postier Russell , Ding Kai , Yang Jingxuan , Li Min
Published: September 2018

TPS10127

Background: Now the 3rd leading cause of US cancer deaths, pancreatic cancer (PanC) incidence is rising. Surgery is the only chance at cure, but sarcopenia (low muscle mass, strength, function) can eliminate surgical and chemotherapy options, and independently predicts poor outcomes. Strengthening (Str) with protein combats sarcopenia of aging, and pre-op exercise (prehab) benefits other cancer survivors. But the impact of Str in a brief pre-Whipple window, and a host with PanC-mediated catabolism, is unknown. We aim to quantify the post-op QoL impact of adding Str to our standard clinical aerobic instruction before Whipple for pancreatic head and related cancers. Methods: Pilot RCT of 130 PanC survivors age 30+ randomized (stratified by neo-chemo) to 2 home-based prehab arms: Standard/NPRE = aerobic + protein, or Sarcopenia/SPRE = Standard + Str. To explore PanC-sarcopenia as moderating Str's impact, a 3rd pre-malignancy Whipple group (p-mal, n=50) also receives SPRE. All participants get protein and exercise instruction personalized to baseline status, adherence diaries, actigraphy, and phone follow-up in pre-op period only. Endpoints are QoL (primary) as Functional Assessment of Cancer Therapy (FACT), performance as 6 Minute Walk (6MW) & Short Physical Performance Battery (SPPB); and self-reported symptoms & activities of daily living (ADL). Assessments at baseline, 1-3 days pre-op, and post-op week 4 & month 4 (primary) are blind. Sarcopenia measures are clinical (dynamometry, bioimpedance, CT body composition) and preclinical (ZIP4/ catabolic mediators in blood, muscle, tumor & duodenum). Analyses: QoL change at post-op month 4 will be compared across PanC arms (SPRE & NPRE) with mixed-models before Baron-Kenny and Preacher/Hayes' mediator analyses. To explore impact of PanC catabolic host environment on Str, outcomes will be compared by SPRE group (PanC & p-mal). To our knowledge, this is the first PanC prehab RCT with sarcopenia focus, comprehensive mechanistic approach, and high dose (60 min daily)/short duration (2-3 week) intervention. With local feasibility established, we continue to accrue (n=30), and seek multicenter collaboration to target NCI funding. Clinical trial information: pending - in submission.
An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY.
Authors: Patsouris Anne , Vicier Cecile , Campion Loic , Gouraud Wilfried , Jimenez Marta , Pezzella Veronica , Loehr Andrea , Raponi Mitch , Bieche Ivan , Callens Celine , Andre Fabrice
Published: September 2018

TPS1117

Background: BRCA1 and/or BRCA2 mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition to BRCA1/2, alterations of other genes (PALB2, RAD51C….) implicated in homologous recombination repair (HRR) pathways leads to a BRCAness phenotype that is also associated with PARPi sensitivity. Rucaparib, a potent oral PARP-1, -2 and -3 inhibitor, has shown activity in a phase 1 study of patients (pts) with homologous recombination deficient (HRD) breast cancer (Kristeleit, RS. J Clin Oncol 32:5s, 2014 [suppl; abstr 2573]). This single arm, open-label, multicenter phase II study (NCT02505048) is evaluating the efficacy and safety of rucaparib in pts with HER2- metastatic breast cancer (MBC) associated with a BRCAness phenotype determined by “high tumor genomic LOH” score and/or a somatic BRCAmutation. Methods: Pts with HER2- MBC exhibiting a BRCAness phenotype will receive oral rucaparib 600 mg BID continuously in 21-day cycles until disease progression. The primary endpoint is clinical benefit rate (CBR), defined by complete and partial response and stable disease lasting for at least 16 weeks and, if CBR is significant, the objective response rate (ORR). Secondary endpoints include progression-free survival, overall survival, safety, and the prognostic value of the BRCAness signature. Targeted enrollment is 41 pts using a Simon two-stage design. Eligibility: Women with HER2- MBC with a BRCAness phenotype who received 1-4 prior chemotherapy regimens are eligible. ECOG PS 0-1 and adequate organ function is required. The BRCAness phenotype is defined by high tumor genomic LOH (LOH cutoff of 18%) that can identify HRD tumors, including both known BRCA1 methylation and unknown genetic/epigenetic mechanisms and somatic BRCA1/2 mutations. Pts with a known BRCA1 and/or BRCA2 germline mutation are excluded. “high tumor genomic LOH” score will be generated from the CytoScan HD SNP array, which is available from the SAFIR02 protocol or other molecular programs. To date, 13 pts have been enrolled, with enrollment ongoing. This trial design is intended to establish proof-of-concept that rucaparib can improve ORR in HER2- MBC with HRD. Clinical trial information: NCT02505048.
A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.
Authors: Ingles Garces Alvaro Henrique , Chenard-Poirier Maxime , Jones Robert Hugh , Quinton Amy , Plummer Elizabeth R. , Drew Yvette , Kowalski Mark Marion , Klencke Barbara J. , Banerji Udai
Published: September 2018

TPS2613

Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells. Chk1 is also believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage and the combination of SRA737 with these standards-of-care may provide synergistic antitumor activity. SRA737 is being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation study of SRA737 in combination with gemcitabine/cisplatin (GC) or gemcitabine (G) alone (NCT02797977). Methods: Up to 70 patients will receive escalating doses of SRA737+GC in Stage 1 or SRA737+G in Stage 2 until a recommended Phase 2 dose (RP2D) is established, followed by expansion cohorts. Patients will receive a single SRA737 PK run-in dose followed by Gem on D1 and 8, Cis on D1, SRA737 on D2, 3, 9 and 10 of each 21-d cycle or Gem on D1, 8 and 15, SRA737 on D2, 3, 9, 10, 16, 17 of each 28-d cycle. Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of SRA737 combination therapy and to establish a RP2D. The PK profile and PD biomarkers (eg, phosphorylation of Chk1 at Ser296, Ser345 and γH2AX foci in PBMCs and tumor tissue) will be explored. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of an indication specific expansion cohort of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations (eg, gene mutations and amplifications/deletions), has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. Clinical trial information: NCT02797977.