bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of circulating cytokines in breast cancer: A prospective study in sixty breast cancer patients in Tunisia.
Authors: Ayari Jihene Braham , Haj Ammar Shourouk , Balti Mehdi , Ben Azaiz Mouna , Zribi Aref , Fendri Sana , Ben Nasr Sonia , Ghazouani Ezzedine , Agili Faida , Kullab Sharif Ahmed , Haddaoui Abderrazek 
Published: May 2019

e12592 Background: Breast cancer is the second most common cancer and the fifth most common cause of cancer mortality worldwide. The functional relationship between inflammation and cancer is an old concept of cancero- genesis, and it is now clear that inflammatory process certainly potentiates and/or promotes neoplastic risk. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. The aim of this study is to measure the level of circulating cytokines (IL17, IL6, IL22, IL23 and TNFα) in breast cancer patients in Tunisia, and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from sixty breast cancer patients in Tunisia. TNF-α and IL6 levels were determined using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, USA). Serum levels of IL17, IL22 and IL23 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 48 years, and fourth of them were metastatic. The mean level of cytokines IL6, IL17, TNFα, IL22 and IL23 were respectively 4.80 ± 7.26 pg/ ml (min 2, max 36.80 pg/ ml), 0.27 ± 0.69 pg/ ml (min 0, max 3.62 pg/ ml), 5.93 ± 2.27 pg/ ml (min 4, max 15.30 pg/ml), 50.82 ± 34.78 p/ml (min 26.48, max 199.48 pg/ ml) and 18.05 ± 30.91 pg/ ml (min 0, max 200.21 pg/ml). Serum IL6 level was significantly higher in advanced stages (p = 0.013), especially in metastatic cases (p = 0.001) and in patients who had recurrent disease (p = 0.010). High level of TNFα was also significantly associated with advanced stage (stage III and IV) (p = 0.019), and high level of IL22 was significantly associated with a high histopathological grade (Grade III of Bloom-Richardson grade (SBR)) (p = 0.028). IL23 was found to be significantly increased in lymph node metastatic cases (p = 0.042) and in young patients < 35 years (p = 0.034). Finally, the level of IL17 was significantly higher in patients who had recurrent disease (p = 0.018). Conclusions: Our results highlight the role of certain circulating cytokines as potential prognostic biomarkers in breast cancer patients. The serum analysis of these cytokines, which could contribute to tumor growth and progression, may help to identify groups of patients with poor prognosis and who may need more aggressive treatment. This correlation needs to be evaluated in large prospective validating trials and suggests a rational for the development and use of cytokine blockade in treatment of some groups of breast cancer patients.
Use of a granulocyte colony-stimulating factor for the prevention of febrile neutropenia in the era of value-based care.
Authors: Feinberg Bruce A. , Lord Kevin , Kish Jonathan , Laney Jalyna R. , Chopra Dhruv , Liassou Djibril 
Published: May 2019

e12601 Background: Value based care design is intended to encourage responsible use of medical resources to optimize cost effective delivery of quality patient care. Febrile neutropenia (FN) is a potentially life-threatening condition associated with myelosuppressive chemotherapy (chemo). Clinical guidelines and product label recommend granulocyte colony stimulating factors (G-csf) use for the primary prevention of FN in patients with clinically significant FN risk. This study evaluated the real-world use of primary prevention pegfilgrastim (PPP), a sustained release G-csf, in metastatic breast cancer (mBC) patients. Methods: Patients who had initiated systemic chemo from Jan-2013 to Dec-2017 were identified from a third-party, administrative claims database using medical and pharmacy claims (ICD-9/10 codes for both BC and metastases) were selected. Patients who received any HER2 and/or any oral or infused hormonal therapies, or had another malignant diagnosis, were excluded. FN risk: low < 10%, moderate 10-20% and high > 20%, was assigned to chemo drugs/regimens using multiple source data (e.g. Lexicomp). If patients received combination chemo, the assigned risk level was the highest risk of any individual agent. Patients administered a moderate or high FN risk (MHR) regimen were considered at “significant clinical risk”. The frequency of use of PPP in MHR and in low FN risk (LR) was calculated per line (L) of therapy. Results: 10,342 patients met the selection criteria. Mean age at initiation of treatment was 61.7 years (SD = 12.12). Total number of patients with exposure to MHR regimens were 4,601 (44%). By line of therapy, the proportion of patients prescribed PPP was: 1L MHR = 32%, 1L LR = 1%; 2L MHR = 12%, 2L LR = 1%; 3L MHR = 6%, 3L LR = 1%; 4L MHR = 6%, 4L LR = < 1%; 5L MHR = 5%, 5L LR = < 1%; and 6L MHR = 6, 6L LR = 1%. Conclusions: The observed rate of PPP use with LR chemo was exceptionally low and consistent with cost effective, high quality, evidence-based medicine. PPP use with MHR chemo was in the minority and declined with consecutive lines of treatment suggesting the need to study clinical outcome variances in mBC patients receiving MHR chemo with and without PPP.
SeqPlus sequencing methodology enables robust whole-genome sequencing, true variant detection, and novel genomic insights from archival esophageal carcinoma FFPE samples.
Authors: Bailey Shannon Terrell , Hicks Belynda , Zhu Bin , Hu Nan , Taylor Phil R. , Gulcher Jeffery R , Sun Hongye , Lund Jim , Oliner Kelly , Williams Richard T. , Chanock Stephen J. , Goldstein Alisa M. 
Published: May 2019

e13016 Background: Whole-genome sequencing (WGS) of formalin-fixed, paraffin-embedded (FFPE) samples could enable novel insights from archival sample collections, yet robust FFPE WGS is challenged by fragmented DNA, uneven genomic coverage & sequencing artifacts attributed to FFPE fixation. We report our proprietary extraction & library preparation methodology (SeqPlus) with high quality, uniform WGS sequencing performance comparable to that from fresh-frozen samples. Methods: We analyzed 20 paired esophageal carcinoma (EC) samples i.e., primary tumors & matched germline samples to assess SeqPlus performance on 10-15-year-old FFPE tissues, measure variant concordance between WGS and a high-depth sequencing panel (269 genes, 400x coverage) & identify novel genomic features. Results: At a targeted 70x WGS tumor sequencing depth, 93% of the genome was covered by ³ 20 reads, 99% of bases had 10x coverage & average duplicate reads were 31%. We noted similar transition/transversion ratios & mutational spectra as from fresh-frozen EC specimens, suggesting that extraction & library preparation contributes to prior FFPE artifacts. Concordance of tumor-specific SNVs & indels derived from WGS & targeted panel was high at 86%. All 76 targeted panel-detected variants above the WGS limit of detection (mutant allele frequency [MAF] > 10%) were detected by WGS, 2 variants (2 tumors) were detected only by WGS, and 12 variants at MAF ≤ 6% (9 tumors) were only detected by the targeted panel. Tumor WGS yielded SNV, indels & CNV findings beyond variants detected by targeted sequencing. WGS enabled detection of 10.4 putative cancer variants per tumor compared to 12 variants per patient from frozen specimens and a median of 7 (up to 16) cancer-associated variants in genes outside the targeted panel. WGS copy number analysis revealed CCND1, EGFR, TP63, and SOX2amplification, CDKN2A/B deletion and additional unrecognized genomic aberrations. Conclusions: Our study reinforces the utility of high-quality, uniform WGS sequencing of archival FFPE cancer samples with SeqPlus and unlocks the potential for massive-scale retrospective genomic analysis of archived pathology samples with associated clinical & outcomes data.
The targetable mutation landscape of Chinese patients with non-small cell lung cancer.
Authors: Li Jun , Zhang Cuiyun , Zhao Jiuzhou , Wang Zhizhong , Wei Bing , Sun Rui , Groen Harry J.M. , Ma Jie , Guo Yongjun 
Published: May 2019

e13018 Background: In recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has been substantially improved by targeted therapies against specific molecular aberrations, i.e. tyrosine kinase inhibitors (TKIs) for Epidermal Growth Factor Receptor ( EGFR) etc. Several genes have been suggested by NCCN guideline (v7.2017) to test for NSCLC patients, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS. The aim of this study is to profile the landscape of actionable mutations in Chinese NSCLC patients. Methods: From 2015 to 2017 621 treatment naïve NSCLC patients enrolled in the affiliated cancer hospital of Zhengzhou University were included in this analysis. DNA was extracted from the FFPE biopsies of these patients and processed for target capture sequencing covering the exons and flanking splicing regions of the 8 genes suggested by NCCN guideline, as well as introns of ROS, ALK and RET. Results: In total, 593 out of the 621 NSCLC patients harbor one or more mutations in these 8 genes, accounting for 95.5% of all the cases. EGFR, ALK and HER2 are the top 3 mutants, with a frequency of 52%, 32% and 26% respectively. Genetic aberrations in BRAF, MET, ROS1, KRAS and RET occur in 22%, 18%, 16% and 14% of the patients. The most common variation is missense; T > G, C > T and C > A changes are more often observed than T > C, T > A and C > G; the median number of variants per sample is 2, ranging from 1 to 13. There are 418 mutations detected on EGFR, of which 206 (49.28%) are clinically relevant. EGFR L858R, Exon19 deletion, Exon20 insertion, G719, A750P were observed in 123 (29.43%), 43 (10.29%), 8 (1.91%), 6 (1.44%) and 6 (1.44%) cases respectively. Gene fusions were identified in 78 cases, and the EML4- ALK is the most common one occurred in 54 patients, other fusion genes include KIF5B- ALK (11) ， CCDC6- RET (4), CD74- ROS1 (4), EZR- ROS1 (2), ERC1- RET (1), , SDC4- ROS1 (1) and TCOF1- ROS1 (1). Conclusions: Target sequencing of the 8 genes suggested by NCCN guideline for NSCLC patients reveals essential information for designing personalized therapeutic regimen. Chinese patients, maybe other Asian countries also, may benefit more from this molecular testing, because of the high occurrence of actionable mutations.
Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in Chinese population.
Authors: Hong Ruoxi , Qinglian Zhai , Yuan Zhongyu , Xia Wen , Xu Fei , Wang Shusen 
Published: May 2019

e13031 Background: Triple negative breast cancer (TNBC) represents about 19% of all breast cancers in Chinese population. Compared with other breast cancer subtypes, TNBC tend to be more aggressive and is associated with early relapse and worse survival. In this study, we performed comprehensive genomic profiling to explore the clinical relevant genomic alterations (CRGAs) and potential therapeutic targets in very early relapsed TNBCs, regarding as tumor recurrences within 24 months. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from 23 very early relapsed TNBC patients were tested by FoundationOne CDx (F1CDx), a next generation sequencing based diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB). Results: In total, 137 CRGAs were detected in all the 23 TNBC patients, averaging 6 alterations per sample. The mean TMB was 4 Muts/Mb, and only one patient was MSI-Intermediate. The top ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%), BRCA1 (22%), NOTCH1 (13%), MYC (13%) and CCND1 (13%). Notable co-segregating amplifications included KAS-KDM5A and FGF3-FGF4-FGF19. Importantly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of them were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion and EGFRvIVa in the first time, which has not been reported in breast cancer before. Furthermore, we also found EGFR amplification with copy number equal to 126 in one TNBC patient. In addition, 61%, 52%, 43%, 22% and 17% TNBC patients have at least one CRGA in pathways involving PI3K/mTOR, Cell cycle, DNA repair, Growth factor receptors (GFRs) and RAS/MAPK signaling pathways, respectively. Importantly, alterations in RAS/MAP tended to occur in very early-stage, such as IA-IIB tumors, and GFRs tended to occurr in IIIA-IIIC tumors. Furthermore, 100% of these patients have at least one CRGA and 87% patients have at least one actionable alteration. Conclusions: This study demonstrated that most of TNBCs have at least one actionable alteration. In conclusion, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very early relapsed TNBC patients.
Germline mutation PTCH2 1172-1173delCT in Chinese population with early-onset breast cancer.
Authors: Li Lixi , Li Chunxiao , Ma Fei , Qian Haili , Guan Xiuwen , Yi Zongbi , Liu Binliang , Zhai Jingtong , Li Yanchen , Suo Ying , Mo Hongnan , Xu Binghe 
Published: May 2019

e13049 Background: Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The peak age of breast cancer in China is about 40 years old, 10 years ahead of that in Europe and the United States. PTCH2 was characterized as susceptibility gene in early-onset breast cancer by whole exons sequencing in preliminary work. PTCH2 performs as a tumor suppressor in the Hedgehog signaling pathway, but it has never been reported in breast cancer. Methods: 259 women with early-onset breast cancer and 571 women with non-early-onset breast cancer with peripheral blood samples were included for genetic testing. According to the ACMG guidlines, PTCH2 1172-1173delCT was defined as likely pathogenic mutation. To make an in-depth exploration of the function and molecular mechanism of PTCH2 gene, we performed experiments at molcular, cellular and animal level. Results: The frequency 2.3%(6/259)of PTCH2 germline mutation in early-onset breast cancer was significantly higher than that(2/571) in non-early-onset breast cancer( P ＜ 0.05), and increased with the age at diagnosis younger. Bioinformatics analysis showed that the patients with lower expression of PTCH2 had worse prognosis. PTCH2 knockout cells lines promoted the cell proliferation and enhanced the ability of colony formation and tumorigenic ability of nude mice. Furthermore, the expression level of pten in the PTCH2 knockout cell lines was significantly downregulated. Conclusions: Patients with PTCH2 1172-1173delCT mutation had aggressive clinicopathological characteristics and worse prognosis. As a tumor suppressor gene, PTCH2 may promote the incidence of early-onset breast cancer by downregulating the expression of pten and cross-regulating Hedgehog and PI3K/AKT signaling pathways. PTCH2 could be acted as a diagnostic and prognostic biomarker for early-onset breast cancer.
Lung cancer: Improving screening in rural clinic.
Authors: Le Thuy Thanh Thi , Johnson-wall Helen , Hu Katherine 
Published: May 2019

e13060 Background: Lung cancer is the leading cause of overall cancer-related deaths in both men and women in the United States. In 2009, cancer surpassed cardiovascular disease as the leading cause of death in North Carolina. Between 2010-2014, the age-adjusted incidence rate for lung and bronchus cancers in North Carolina was 70 per 100000 persons per year. Between 2010-2014, the age-adjusted mortality rate for lung and bronchus cancers in North Carolina was 50.6 per 100000 persons per year. It is documented that about half of lung and bronchus cancer cases were diagnosed at the distant stage and about 60 percent of deaths occurred in adults ages 65-84. In 2011, 32 percent of cancer death was from lung/bronchus cancer in Robeson County. A chart review in a rural primary care clinic identified patients not being appropriately screened for targeted intervention. Methods: Our retrospective chart review at Lumberton Medical Clinic, a rural outpatient Internal Medicine Clinic, reviewed 91 records from adults aged 55 to 80 years old during the timeframe of September 2017 through August 2018. Patients with a known history of lung cancer were excluded from this study. Patient records were assessed for compliance with USPTF lung cancer screening guidelines. USPTF recommends adults aged 55 to 80 who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years to have an annual low-dose computed tomography of the chest to screen for lung cancer. Results: The review showed that during the timeframe studied, 42% of patients who qualified received appropriate screening, while 58% of those qualified were found to have no documentation of screening. Following data analysis, intervention to increase screening rates has been initiated. This involves provider education, posters, and individualized letters mailed to patients found deficient during the study. The success of this direct patient outreach effort will be measured over six months. Conclusions: It is the responsibility of providers to emphasize the importance of proper lung cancer screening. This retrospective review found that a large percentage (58%) of adults were not being adequately screened in our rural clinic. Direct outreach is underway to increase compliance rates in this high-risk population served by our rural clinic.
Breast Cancer Cases in a Surveillance Program: Report from the Hereditary Department at South General Hospital, Sweden.
Authors: Karumo Anna-Maria , Thorén Linda , Von Wachenfeldt Väppling Anna 
Published: May 2019

e13068 Background: Women with a doubled, or greater, lifetime risk of developing breast cancer are according to Swedish guidelines offered intensified surveillance with one or more of the following modalities; mammography (MG), ultrasound (US) and magnetic resonance imaging (MRI). MRI is primarily recommended for mutation carriers < 55 years of age. From 2014 mutation carriers undergo annual surveillance, alternating MRI and MG/US every 6 months. Aim: To evaluate which modality was able to detect the tumor, tumor stage and characteristics in women who developed breast cancer under surveillance at the Hereditary Department, South General Hospital, Stockholm. Methods: Data on women in the surveillance program diagnosed with breast cancer 2003 - 2018 was collected from patient notes. Results: Fifty-five women were diagnosed with breast cancer. Twenty-five women underwent MRI, in 22 cases the tumor was visible. Forty percent of the women aged 55 or older had tumors only visible on MRI. Fifty-three women underwent US, in 38 cases the tumor was visible. Thirty two of 49 tumors were detected by MG. In 35 cases the tumor was not palpable. Fourteen women were diagnosed with DCIS. These cases, combined with patients with T1 N0 tumors, constituted 69% of the 55 women. Eleven women were node positive. Twelve women were diagnosed in between screening rounds, ie interval cancers. Three of these were small tumors found only at the pathology examination after prophylactic mastectomy. The proportion of interval cancers decreased from 31% to 14% after 2014. Twenty-four women were identified as mutation carriers in BRCA1, BRCA2 or PALB2. Seven of these mutations were detected after the patient´s cancer diagnosis. Nine mutation carriers were diagnosed with interval cancers, four were node positive. Conclusions: All women were diagnosed at a potentially curable stage and most were node negative. Mutation carriers constituted the largest portion of women with interval cancers. This study indicates that MRI may be of benefit in the surveillance of mutation carriers after 55 years of age. The transition from annual to biannual examinations with MG/US and MRI appears to decrease the incidence of interval cancers.
Complex multimorbidity, perceived life expectancy, and routine cancer screening receipt: Differences between older women and men.
Authors: Koroukian Siran M. , Warner David F 
Published: May 2019

e13071 Background: Complex multimorbidity (MM) predicts poor health outcomes. How MM predicts preventive health services receipt, such as cancer screening, is less clear. Yet cancer screening decision making involves not only clinical presentation (MM) and age, but also patients’ perceptions about need. We hypothesize that patients’ perceived life expectancy (PLE) moderates the effect of MM and age on cancer screening receipt (mammography for women and prostate screening for men). Methods: Data came from 20,705 women and men, ages 52-90, from the 2002-2012 waves of the U.S. Health and Retirement Study. Receipt of screening mammogram (women) or “examination of [the] prostate to screen for cancer” (men) in the last two years were binary (0/1) measures. MM was an ordinal count (0-3) of the co-occurrence of any chronic conditions, functional limitations, and geriatric syndromes. Age was measured in years. PLE was the chance respondents’ thought they would live 10-15 more years (0 = 0% - 10 = > 90%). Additional control variables included self-rated health, race/ethnicity, socioeconomic status, marital status, smoking, BMI, and other preventive services (e.g., flu shot) receipt. We used survey-adjusted repeated measures logistic regression to predict screening receipt separately by gender. Results: Women reported higher MM and PLE than men. Greater MM reduced the likelihood of mammography receipt. However, women with MM who had greater PLE had an increased likelihood of mammography receipt. Furthermore, mammography receipt decreased more slowly with age for women with high PLE. For men, greater MM did not lead to reduced prostate screening. Men’s PLE was not associated with screening nor did it modify the effects of MM or age. Conclusions: Greater PLE increases likelihood of cancer screening for women even when MM and advanced age would recommend against. Men’s clinical presentation and subjective perceptions of longevity are not associated with prostate screening receipt. We speculate that the differences in the nature of the screening tests combined with greater public awareness of breast cancer create conditions where subjective perceptions are more likely to affect mammography decision-making.