tbuckley/cabot-search huggingface dataset:
Molecular profile of glioblastoma as perspective of targeted therapy.
Authors: Georgy M. Manikhas, Natalia P. Beliak, Svetlana I. Kutukova, Gregory Raskin, Daniil Korsenev
Journal: Journal of Clinical Oncology (2018)

e14037 Background: Glioblastoma is one of the most malignant forms of cancer, for which no effective therapy has been found. Although numerous genomic studies has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown Methods: We detected tumor samples of 31 patients with glioblastoma (15 men, 16 women; median age 55). We examined demographic data, tumor characteristics and EGFR, EGFR-VIII, HER2/neu, D2-40, IL-13R, EphA2, CD-133 by IHC (25 samples were acceptable). Results: We already know that overexpression of the EGFR gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism and can to predict time and patterns of recurrence in patients with glioblastoma. Rate of EGFR expression varied from 0.00 to 90.00%, M = 57.38±7.60 (95% CI 30.0-90.0), median of EGFR expression was 70.0%. Rate of EGFRvIII (presence of the mutant EGFR) varied from 0.00 to 90.00% with M = 40,52±8,92 (95% CI 0.00-80.0), median of EGFRvIII expression was 10.0%. In literature, it also has been shown that the EphA2 receptor tyrosine kinase has been linked to tumor PD, metastatic spread, and poor prognosis. Rate of EphA2 expression in our study varied from 0.00 to 80.00%, M = 50.48±5.55 (95% CI 30.0-74.40), median of EphA2 expression was 50.0%. D2-40 immunoreactivity was found in nestin-positive neural stem/progenitor cells and neuronal lineage cells. Rate of D2-40 expression varied from 0.00 to 90.00%, M = 48.81±6.67 (95% CI 34.89-62.73), median of D2-40 was 60.0%. IL-13Rα2 induces invasiveness of human GBM cells without affecting their proliferation. Rate of IL-13Rα2 expression varied from 0.00 to 80.00%, M = 26.67±7.12 (95% CI 11.82-41.51), median of IL-13Rα2 was 10.0%. Cluster of differentiation (CD-133) is an important cell surface marker of glioma stem cells. Overexpression of CD-133 were detected only in 3 samples: in 2 cases overexpression was 50.0% and in 1 case – 90%. Overexpression of HER2\neu was not detected in any cases. Conclusions: Thus, our goal was to study the frequency of occurrence in glioblastomas of key factors of initiation, invasiveness, proliferation and resistance of tumor cells to understand the possibilities of therapeutic targeted exposure.
Possible CDK4/6 inhibitor use in betel-nuts related head and neck squamous cell carcinoma(HNSCC).
Authors: Jo-Pai Chen, Jui-Ying Chang, Sung Hsin Kuo, Ruey-Long Hong
Journal: Journal of Clinical Oncology (2018)

e18030 Background: The treatment of betel-nuts related HNSCC in Taiwan is challenging due to (1)strong inflammation, invasion, and angiogenesis; (2)poor response to chemotherapy , radiation, and epidermal growth factor receptor inhibitors. In our previous studies, betel-nuts related TW2.6(p53 defective mutation, p16 loss, BCL2+) was very resistant. In addition to PI3K/mTOR dual inhibition, polo-like kinase inhibitor with radiation, CDK4/6 inhibitor, WEE1 inhibitor, ALK/IGF-1R inhibitor, Bcl2 inhibitor, and eribulin, FGFR inhibitor & VEGFR2/FGFR/PDGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse its refractoriness. Activated CCND1 are often found in HNSCC. A phase I trial of cetuximab with palbociclib in refractory R/M HNSCC had brought clinical benefits in patients with negative HPV status and positive phospho-Rb staining. CDK4/6 inhibitor can also (1) increase intracellular double-stranded RNA inducing type III interferon response & tumor antigen presentations by epigenetic modulations; (2) suppress Treg; (3) overcome hyper-progressive disease from CCND1 amplification. Purpose: We try to find out whether palbociclib could also reverse betel-nuts related HNSCC refractoriness. Methods: Palbociclib was tested on TW2.6 to evaluate (1)the in vitro drug sensitivity; (2)synergistic effect with some target therapies with MTT assay, colon formation assay, flow cytometry, and western blot assay. Results: Palbociclib could resensitize TW2.6 to docetaxel, afatinib, & radiation and enhance further response to PI3Kalpha inhibitor & VEGFR2/c-MET/Axl triple inhibitor. Western blotting showed (1)mesenchymal differentiation markers(Slug, Snail, N-cadherin, Twist, Vimentin, Claudin-1, Axl) and PI3K/Akt/mTOR signaling(p-Akt and p70S6K) decrease; (2)BMI-1 and PDL1 drop. Conclusions: Palbociclib was effective on TW2.6 and reverse its treatment refractoriness, maybe through the inhibition of mesenchymal transformation & PI3K/Akt/mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. The ability to inhibit EMT and modulate PDL1 might overcome immune escape to enhance immunotherapy effects, too.
NTRK and ALK rearrangements in mesothelioma and lung carcinoid.
Authors: Geoffrey David Peters, Marcin Szaumkessel, Trishe Leong, Marzena Walkiewicz, Hongdo Do, Alexander Dobrovic, Gareth Rivalland, Bibhusal Thapa, Thomas John
Journal: Journal of Clinical Oncology (2018)

e20558 Background: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK result in oncogenic fusion proteins that have been identified in many tumor types, including lung, colorectal, salivary gland, sarcoma, papillary thyroid, glioblastoma, melanoma. Identification of these rare rearrangements enables potential therapeutic targeting with specific inhibitors. Given the limited data available in rare tumor types, we investigated a panel of fusion genes in mesothelioma, small cell lung cancer and carcinoid tumors. Methods: Tumor tissue samples from 335 patients with mesothelioma, 154 with carcinoid and 105 with small cell lung cancer were arrayed in triplicate onto tissue microarrays (TMAs). TMA slides were stained by immunohistochemistry(IHC) with antibodies against NTRK1,2,3 ROS1 and ALK. Positive samples by IHC underwent RNA sequencing using the ArcherDX FusionPlex CTL (Comprehensive Thyroid and Lung) diagnostic assay. Target-enriched libraries were sequenced on the Illumina Miseq NGS platform and analysed using the cloud-based Archer Analysis tool to call NTRK1,2,3, ROS1 or ALK fusion transcripts. Results: There were 15 positive cases via IHC, eight mesothelioma and 7 carcinoid. Of these, 1 mesothelioma patient with an NTRK ex10-TMP3 ex8 fusion, 1 mesothelioma patient with an ALK ex20-EML4ex13 and 1 atypical carcinoid patient with an ALK ex20-EML4 ex6/intron6 was found. Clinicopathological features of the NTRK positive mesothelioma patient demonstrated biphasic histology subtype, with documented asbestosis exposure. The ALK positive mesothelioma patient had sarcomatoid histology, whilst the carcinoid patient had resected stage 3A disease, but died after relapsing after 6 months with metastatic disease. Conclusions: This is the first study to demonstrate the existence of NTRK gene fusions in mesothelioma. ALK rearrangements were also detected in carcinoid and mesothelioma. In spite of the low incidence, IHC would be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilised.
Advice to athletes with back pain—get active! Seriously?
Authors: Kieran O’Sullivan, Peter B O’Sullivan, Tim J Gabbett, Mary O’Keeffe
Journal: British Journal of Sports Medicine (2018)

The recent Lancet low back pain (LBP) series1–3 recommended exercise and physical activity, particularly for persistent and debilitating pain. Given a dearth of clinical trials for LBP among athletes, is encouraging activity justifiable for athletes with LBP when they are often already highly active? This editorial teases out the role of exercise and activity for LBP among athletes.

The evidence that athletes get LBP because they are excessively active is limited. For example, there are data that LBP intensity among rowers is higher during intense training periods,4 and that highly active teenagers develop more future LBP.5 However, these studies either did not always examine how meaningful or disabling the LBP was4 5 or several other factors were also implicated. What is clear is that being consistently active is associated with less pain and injury. In other words, being active might be a good thing to reduce pain, including LBP, as long as the rate of increase in activity is managed appropriately and other relevant factors (eg, sleep, mood, relationships) are also addressed.

It is worth remembering that many factors linked with …
Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials
Authors: Glenn J. Jaffe, Gui-Shuang Ying, Cynthia A. Toth, Ebenezer Daniel, Juan E. Grunwald, Daniel F. Martin, Maureen G. Maguire
Journal: Ophthalmology (2018)
Prospective evaluation of the cardiovascular safety profile of abiraterone acetate (AA) in mCRPC patients (pts).
Authors: Veronica Prati, Fiorella Ruatta, Angela Gernone, Caterina Aversa, Danilo Galizia, Sofia Torino, Laura Marandino, Imperia Nuzzolese, Alessandro Bonzano, Massimo Aglietta, Cinzia Ortega
Journal: Journal of Clinical Oncology (2016)

e16534 Background: AA is a potent inhibitor of CYP17; common adverse events include fluid retention and hypertension. In COU-AA-301 study a 13.3% of cardiovascular (CV) toxicity was reported. The aim of this studyis to evaluate the CV toxicity of AA in mCRPC ptswith CV comorbidities or CAD (coronary artery disease) risk factors. Methods: We prospectively analyzed pts receiving AA for mCRPC. At baseline we recorded CAD risk factors (hypertension-heart disease(HD), dyslipidemia, diabetes, tobacco smoke, obesity) and CVcomorbidities (HD, rhythm disturbances, valvular disease and heart failure); we performed electrocardiogram (ECG) and echocardiography with evaluation of LVEF (Left ventricular ejection fraction) and diastolic function at baseline and every 6 months. Cardiotoxicity was defined as median ≥ 10% LVEF reduction compared to baseline or absolute LVEF value < 50%. Clinical and instrumental variables and toxicity data were analyzed by descriptive statistics. We searched correlations between cardiotoxicity onset and CAD risk factors or cardiovascular comorbidities; results were assessed with paired Student’s t-test and Chi-square test. Results: Between November 2011 and December 2015, 87 consecutive pts, median age 66 yrs (range: 50-81) were treated with AA 1000 mg orally once daily and prednisone 5 mg twice daily. Median treatment duration was 9 mos (1-44). 58 pts (66.7%) had received previous chemotherapy. At baseline, 84 pts (96%) had one or more CAD risk factor: 70 pts (80,5%) hypertension, 13 (15%) diabetes, 37 (42,5%) obesity, 31 (35,5%) dyslipidemia, 34 (39,1) tobacco smoke. Preexisting CV comorbidities included heart failure (9,2%), rhythm disturbances (16%) and valvular disease (13%). On AA therapy 26 pts (30%) worsened the preexisting HD and 4 pts (4,6%) developed HD, which was controlled with medical treatment according to American Heart Association guidelines. 2 pts (2,3%) developed atrial fibrillation. Median LVEF at baseline was 64%, and 63% after AA. LVEF reduction and diastolic function changes were not statistically significant (p < .005). Conclusions: In our study AA was safe and well tolerated even in pts with CV comorbidities or CAD risk factors.
Immunoprofiling in intrahepatic cholangiocarcinoma (IHCC).
Authors: Roberto Carmagnani Pestana, Luisa Maren Solis, Xuemei Wang, Reham Abdel-Wahab, Hsiang-Chun Chen, Wai Chin Foo, Lawrence Kwong, Milind M. Javle, Ignacio Ivan Wistuba, Rachna T. Shroff
Journal: Journal of Clinical Oncology (2018)

12049 Background: Molecular profiling has become important in directing therapy for IHCC, while not much has been described about the immune environment of this disease. Understanding the immune milieu could highlight potential options for immunotherapy (IT). Methods: We performed a retrospective institutional review of 99 surgically resected IHCC from February 2007 to November 2016. Immunohistochemistry was performed using 13 immune antibodies including CD3, CD4, TIM-3, PD-1, and ICOS. Overall survival (OS) was defined as the time from surgery to death date or last follow-up (f/u). OS was estimated by Kaplan-Meier method, and differences were assessed by two-sided log-rank tests. Cox proportional hazards regression models were used to assess association between pt characteristics and OS. Results: Median age: 62 yrs (range, 24-83), females (61%), T stage (T1/T2; 75%), w/o metastasis (90%), and w/o neoadjuvant chemotherapy (NACT) (73%). Median f/u among survivors :3.0 yrs (range 0.04 to 9.1). Median OS was 6.3 yrs (95% CI: 3.6 – NE). Among B- and T-lymphoid cells, CD3+ T-cells represented the dominant population and were predominantly located in the invasive margin (IM). Positivity for PD-1 was seen in 4.7 centrally located, tumor infiltrative lymphocytes (CL-TI)/mm2 and 14.2 CL-TI/mm2 were positive for TIM-3. Univariate Cox analysis revealed that longer OS was significantly associated w/ a high number of CL-TI CD3+ (HR 0.78; p=.044) and CD4+ (HR 0.76; p=.05) immune cells, and lower CL-TI TIM-3+ cells (HR 0.87; p=.01). Multivariate Cox analysis demonstrated that lower number of CL-TI TIM-3+ cells (HR 0.87; p=.01) was an independent predictor of improved OS. Expression of CL-TI TIM-3+ cell was significantly associated with higher CL-TI CD3+ (p<.001), CD4+(p=.003), and PD1+ (p<.001) immune cells. Expression of a membrane-bound form of B7-H4 was significantly increased in pt that received NACT (p=.013). Conclusions: Our findings identify CL-TI CD3+/CD4+ and TIM-3 expression as independent prognostic factors following surgical resection in IHCC and shed light on changes in immune markers with NACT. This study represents one of the largest analyses of the immune environment of IHCC and suggests potential targets for drug development with IT in this disease.
Influence of race and socioeconomic status on genetic risk assessment for breast cancer.
Authors: Mahvish Muzaffar, Jessica R. Hildebrand, Nicole Lawing, Suzanne Hudson, Jan H. Wong, Allyson Meyer, Elizabeth Gottsch, Debra Mascarenhas, Nasreen A. Vohra
Journal: Journal of Clinical Oncology (2016)

e18079 Background: National guidelines recommend genetic risk assessment for breast cancer patients meeting established criteria.We sought to assess the use of genetic risk assessment for breast cancer at Leo Jenkins Cancer Center (LJCC). Methods: We conducted an IRB approved retrospective study at LJCC.Institutional cancer registry database was used to identify all patients diagnosed with breast cancer between 2007 and 2014. Charts were reviewed to collect demographics, family history and data about referral for genetics risk assessment, counseling, and testing. JMP 12.1.0 and SPSS was used for analysis.Chi-square and Fisher’s exact test, as well as multivariate analysis was performed. Results: 968 patients with breast cancer were treated at out center between 2007 and 2014, 49.0% were AA and 47% were non-Hispanic white. Based on personal and family history 446(46.2%) met NCCN criteria for genetic risk assessment. Of those who met criteria, only 59.6% were referred for assessment and only 45.7% of the referred patients met with a counselor. Of the patients who were recommended to undergo testing, 81% received testing. 55% of African American patients met genetic risk assessment criteria based on personal history of triple negative breast cancer at age ≤ 60 yrs. (p < 0.0001). Reasons for not undergoing counseling after referral were largely undocumented due to a lack of follow up and communication (66.7%, p < 0.0001). Financial barrier (81.8%) was the most common reason for not undergoing testing (p < 0.0001). However, there was no significant difference in undergoing genetic counseling or testing based on race or ethnicity. Patients living in counties with a higher median household income were more likely to undergo genetic counseling compared to those in the lower income counties.(p = 0.0209) Conclusions: African American patients with breast cancer have high likelihood of meeting genetic risk assessment criteria, based on personal history alone. Lack of provider recognition for genetic risk assessment need and financial barrier were the primary reason for low referral and testing. We will utilize the electronic health record, provider education and nurse navigators to improve genetic risk assessment at our center.
Impact of chemotherapy on survival in locally advanced and metastatic soft tissue sarcoma.
Authors: Mark Ashamalla, Theodore Yanagihara, Adel Guirguis, Hani Ashamalla
Journal: Journal of Clinical Oncology (2018)

e23536 Background: Soft tissue sarcomas (STS) are challenging to treat given their various primary sites, grades, histologies and distinct behaviors which have driven clinicians to identify subgroups that might benefit most from treatment. This study presents an analysis of the impact of chemotherapy (CT) and radiotherapy (RT) on overall survival (OS) in patients with locally advanced (N1) and metastatic (M1) STS. Methods: Adult STS patients identified in the 2004–2014 NCDB were stratified by demographics and tumor characteristics including primary site, histology, size, grade, margin status, N1, M1, AJCC 8 stage and treatment received. Primary RP-STS, “other/unusual” histologies and those with delays in therapy were excluded. Chi-square tests were used to compare demographics, tumor characteristics and therapy received, while Kaplan-Meier estimates, Cox proportion hazard ratios and log rank tests were used for survival analyses. Results: 55,417 STS patients met inclusion criteria. On MVA, factors independently associated with worse OS were N1 and M1 disease, CARE histologies, intermediate/high grade, tumor size, close/positive margin and stage. RT was independently associated with improved OS on MVA (HR = 0.78; p < 0.0001) with the largest improvements in median survival (MS) in patients with tumors > 5-10cm (94.3mos vs. 76.9mos) and > 10cm (66.5mos vs. 54.5mos); p < 0.0001. In patients with M1 disease, the use of CT was associated with an improvement in MS from 6 to 14.3mos (p < 0.0001), however, this benefit was not observed in N1M0 patients, where MS was 25.2mos with CT relative to 34.1mos without it (p = 0.12). Conclusions: We identify several prognostic factors for OS in adults with STS and present these in the context of AJCC 8th edition. MVA found CARE histologies, intermediate/high grade, size > 5cm, close/positive margins, N1 disease, M1 disease and stage as variables most significantly associated with a worse OS. On MVA, CT and RT demonstrated protective effects (HR = 0.74 and HR = 0.78, respectively), with improvements in OS for those treated. The survival benefit with RT is most pronounced in patients with tumors > 5cm, while the benefit of CT is clear in M1, but not N1 disease.
Suppressive Regulation by MFG‐E8 of Latent Transforming Growth Factor β–Induced Fibrosis via Binding to αv Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis
Authors: Chisako Fujiwara, Akihito Uehara, Akiko Sekiguchi, Akihiko Uchiyama, Sahori Yamazaki, Sachiko Ogino, Yoko Yokoyama, Ryoko Torii, Mari Hosoi, Chiaki Suto, Katsuhiko Tsunekawa, Masami Murakami, Osamu Ishikawa, Sei‐ichiro Motegi
Journal: Arthritis & Rheumatology (2018)

Objective Several studies have demonstrated that the secreted glycoprotein and integrin ligand milk fat globule–associated protein with epidermal growth factor– and factor VIII–like domains (MFG‐E8) negatively regulates fibrosis in the liver, lungs, and respiratory tract. However, the mechanisms and roles of MFG‐E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. We undertook this study to elucidate the role of MFG‐E8 in skin fibrosis in SSc. Methods We assessed expression of MFG‐E8 in the skin and serum in SSc patients. We examined the effect of recombinant MFG‐E8 (rMFG‐E8) on latent transforming growth factor β (TGFβ)–induced gene/protein expression in SSc fibroblasts. We examined the effects of deficiency or administration of MFG‐E8 on fibrosis mouse models. Results We demonstrated that MFG‐E8 expression around dermal blood vessels and the serum MFG‐E8 level in SSc patients (n = 7 and n = 44, respectively) were lower than those in healthy individuals (n = 6 and n = 28, respectively). Treatment with rMFG‐E8 significantly inhibited latent TGFβ–induced expression of type I collagen, α‐smooth muscle actin, and CCN2 in SSc fibroblasts (n = 3–8), which suggested that MFG‐E8 inhibited activation of latent TGFβ as well as TGFβ signaling via binding to αv integrin. In a mouse model of bleomycin‐induced fibrosis (n = 5–8) and in a TSK mouse model (a genetic model of SSc) (n = 5–10), deficient expression of MFG‐E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG‐E8 significantly inhibited bleomycin‐induced dermal fibrosis. Conclusion These results suggest that vasculopathy‐induced dysfunction of pericytes and endothelial cells, the main cells secreting MFG‐E8, may be associated with the decreased expression of MFG‐E8 in SSc and that the deficient inhibitory regulation of latent TGFβ–induced skin fibrosis by MFG‐E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients.
Impact of aging on immune response and survival in melanoma.
Authors: Sarah Ann Weiss, Jeremy Tchack, Joseph Han, Farbod Darvishian, Richard L. Shapiro, Michelle Krogsgaard, Judy Zhong, Iman Osman
Journal: Journal of Clinical Oncology (2016)

e21079 Background: Age is an independent predictor of worse survival in melanoma. Multiple factors may contribute to this observation including decline in host anti-tumor immune response with aging. However, the underlying immunologic pathways in which age impacts the anti-tumor immune response are unclear. Methods: We queried the U.S. Surveillance, Epidemiology, and End Results Program (SEER), NYU’s prospective melanoma biorepository database, and the Cancer Genome Atlas (TCGA) to examine the association of patient age at time of diagnosis (young: < 45, middle: 46-65, and old: > 65) with clinicopathologic features and melanoma-specific survival (MSS). The prognostic value of tumor infiltrating lymphocytes (TIL) was evaluated in each age group. Differential expression of 579 immunoregulatory genes was assessed in a subset of the NYU cohort using an integrative pathway analysis. A mediation analysis tested whether gene expression levels transmitted an aging effect on decreased overall survival (OS). TCGA primary melanoma gene expression data served as independent validation. Results: We analyzed 304,476 (SEER), 1,241 (NYU), and 292 (TCGA) patients. Old age associated with shorter MSS in all cohorts (p < 0.001) independent of gender and stage and positively correlated with thickness, ulceration, stage, and mortality in the SEER and NYU cohorts (p < 0.001). Brisk TIL grade in old NYU patients and lymphocyte score 3-6 in middle age TCGA patients associated with prolonged MSS (p < 0.01). The NYU subset (n = 84) showed decreased lymphocyte migration, chemotaxis, and iCOS and CD28 signaling, which associated with decreased OS in the mediation analysis. IL-1B and IFN-g were predicted as inhibitory upstream regulators with aging, leading to downregulation of genes involved in dendritic cell function. The TCGA cohort (n = 41) pathway analysis validated IL-1B as an inhibitory upstream regulator with aging. Conclusions: Age’s association with worse clinicopathologic features is dependent upon the specific study cohort. TIL as a read-out of the host immune response may have greater prognostic value in patients > age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.