tbuckley/cabot-search huggingface dataset:
Evaluation of tumor- and stromal immune marker heterogeneity in lung adenocarcinoma.
Authors: David Casadevall, Lara Pijuan, Sergi Clave, Alvaro Taus, Ainhoa Hernandez, Marta Lorenzo, Blanca Espinet, Marta Salido, Joan Albanell, Edurne Arriola
Journal: Journal of Clinical Oncology (2016)

e20029 Background: In Lung Adenocarcinoma (LA), expression of several immune markers (IM) has been postulated to predict response to immunotherapy. LA is a histologically heterogeneous disease, in which diagnosis and biomarker assessment are usually based on small biopsies. Our aim was to evaluate the heterogeneity in the expression of IM in LA. Methods: Specimens from 78 surgically treated LA patients with clinical and molecular data were incorporated into five tissue microarrays (TMA). Two cores per patient were sampled, each from a morphologically distinct tumor area. IM evaluation was performed by immunohistochemistry. Expression of PD-1 and PD-L1 was assessed both in tumor cells (TC) and tumor stroma (TS) and scored using previously published criteria (0 if < 1%, 1 if ≥ 1% but < 5%, 2 if ≥ 5% but < 10%, and 3 if ≥ 10%). Stromal CD3 density (low < 25%, intermediate ≥ 25% but < 50%, and high ≥ 50%) and the presence of tumor-infiltrating lymphocytes (TIL) were also recorded. Heterogeneity of IM expression between cores was investigated, as well as the association of IM expression with clinical, pathological and molecular variables. Results:In our cohort,median age was 64 years, 67% were male and 45% were current smokers. KRAS and EGFR were mutated in 13 and 15 cases, respectively. PD-L1 expression in TC and TS was detected 23% and 56% of cases, respectively. PD-1 was only detected in the TS compartment (46% of cases). Fifty percent of cases showed high CD3 density and TILs were present in 41%. PD-L1 expression in TC and TS compartments among different cores was discordant in 10% and 20% of cases, respectively. PD-1 TS expression was discordant in 16% of cases. Up to 24% of patients could be misclassified regarding TIL presence. Agreement of CD3 density among different cores was poor (Kappa 0.294). Presence of TILs was more frequent in current smokers and was associated with solid growth pattern (p < 0.001 for both associations). Interestingly, TILs were present in 40% of KRAS-mutant samples, while no EGFR-mutant patient was TIL-positive. Conclusions: Intra-tumor heterogeneity must be taken into account in order to adequately assess IM status in lung adenocarcinoma. This could be relevant for the optimal selection of patients for cancer immunotherapy.
Abstract A007: Methyl jasmonate and finasteride synergistically reduce testosterone-induced benign prostatic hyperplasia through regulation of inflammatory and apoptotic processes in rats
Authors: Oluwatosin A. Adaramoye, Solomon E. Owumi, Olubukola Akanni, Oluwabunmi E. Olapade-Olaopa, Olusoji J. Abiola, Oluyemi Akinloye
Journal: Cancer Research (2018)

Abstract Background: Phytotherapy is becoming a treatment option in management of diseases, including benign prostatic hyperplasia (BPH). We have shown previously that methyl jasmonate (MeJA) ameliorated BPH; however, the underlying mechanism of action remains unknown. This study was designed to investigate in mechanistic terms the protective role of MeJA in BPH. Methods: BPH was induced by daily injections of testosterone propionate (TP) (3 mg/kg) for 28 days. Results: The weight and organo-somatic weight of prostate in BPH rats were 6.8 and 5.1 times higher than castrated-control group, respectively. Inflammatory markers, prostatic myeloperoxidase,and total nitric oxide were significantly increased in BPH group. The activity of aniline hydroxylase (Phase I drug metabolizing enzyme) was significantly increased in BPH rats by 22%. In BPH group, immunohistochemistry revealed strong expression of prostatic inducible nitric oxide synthase, cyclooxygenase-2 and Bcl2, while mild expression of p53 and Bax WAS seen. Serum triglyceride and total cholesterol were significantly increased, while HDL-c was decreased in BPH. Interestingly, MeJA and finasteride (singly or combination) attenuated inflammatory and apoptotic indices in BPH rats. Conclusion: MeJA and finasteride synergistically protect against TP-induced BPH via mechanisms that involve antiinflammation, induction of apoptosis, and inhibition of phase I drug metabolizing enzyme. Citation Format: Oluwatosin A. Adaramoye, Solomon E. Owumi, Olubukola Akanni, Oluwabunmi E. Olapade-Olaopa, Olusoji J. Abiola, Oluyemi Akinloye. Methyl jasmonate and finasteride synergistically reduce testosterone-induced benign prostatic hyperplasia through regulation of inflammatory and apoptotic processes in rats [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A007.
Abstract 16449: miR-195 Regulates Myocardial SIRT3 Expression and Mitochondrial Enzyme Acetylation
Authors: Xiaokan Zhang, Ruiping Ji, Xianghai Liao, Danielle Brunjes, Estibaliz Castillero, Isaac George, Michio Hirano, Peter Kennel, Paul Christian Schulze
Journal: Circulation (2015)

Background: Unique cardiac and systemic miRNAs play an important role in cardiac remodeling and the associated response to injury by modulating key signaling elements. Through deep-sequencing of cardiac and circulating non-coding miRNAs, we identified miR-195 as the only miRNA up-regulated in plasma, serum and myocardium of patients with advanced heart failure (HF). Further, binding elements for miR-195 were found in the 3’UTR region of sirtuin3 (SIRT3), the major mitochondrial deacetylase. We hypothesized that miR-195 regulates myocardial SIRT3 expression and mitochondrial protein acetylation levels with subsequent changes in cardiac metabolism. Methods: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells and acetylation levels in a rodent model of transgenic miR-195 overexpression were compared to WT. Luciferase assays, Western blotting and immunoprecipitation (Co-IP) assays were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. Results: We observed suppression of SIRT3 and increased total protein acetylation in failing human myocardium. Luciferase assays confirmed that miR-195 directly targets the SIRT3 mRNA 3’UTR and negatively regulates SIRT3 expression. Transfection of miR-195 into AC16 cells resulted in a pronounced decrease in SIRT3 expression levels and induction of total protein acetylation levels. Myocardium of miR-195 transgenic animals was showed a global increase in total protein acetylation compared to WT. Co-IP assays revealed increased acetylation of 3 subunits of PDH (2.1-, 1.6-, 2.2-fold) and ATP synthase α subunit (2.3-fold), two key regulators of mitochondrial energy metabolism. Enhanced acetylation of these proteins correlated with a 24% decrease in PDH activity and a 30% decrease in ATP synthase activity. Conclusions: Altogether, these data demonstrate a crucial role of miR-195 in HF and identified SIRT3 as a direct target of miR-195. Our findings suggest a new pathway of abnormal cardiac energy metabolism in the failing myocardium through miR-195-mediated SIRT3 suppression and increased protein acetylation. These changes result in specific inhibition of PDH and ATP synthase activity leading to impaired energy metabolism and ATP deprivation.
Time trends in the use of surgery for stage I non-small cell lung cancer (NSCLC) and the impact on population survival: Analysis from the Surveillance, Epidemiology, and End Results (SEER) Program.
Authors: Krystel Tran, John Benjamin, Katrina Woodford, Louise Nardone, Catherine Martin, Sashendra Senthi
Journal: Journal of Clinical Oncology (2017)

e18013 Background: Surgery is the standard of care treatment for stage I NSCLC. Improvements in surgical techiques and perioperative care over time are developed to facilitate surgery for more patients. We assessed the factors influencing the use of surgery, the interaction of these with time and the impact on population survival. Methods: Patients enrolled into SEER between 2004 and 2012, aged at least 18 years with a first malignant primary stage I NSCLC were retrospectively assessed. Patients diagnosed on the basis of autopsy or death certificate only were excluded.Time was catergorized into three periods; 2004-6, 2007-9 and 2010-12. Age, gender, marital status, race, geographic location and time were all considered exposure variables influencing surgical use and were adjusted for using logistic regression. Impact of variables with time was assessed using interaction terms between them. The impact of time on population survival was assessed using cox regression. Results: Sex, age, marital status, race, location and time all significantly influenced whether surgery was performed (all p &lt; 0.001). The proportion undergoing sugery declined from 68.0% during 2004-6 to 62.7% during 2010-12 (adjusted HR 0.88, p &lt; 0.001 between subsequent periods). Patients were less likely to have surgery with increasing age (adjusted HR 0.94 per year, p &lt; 0.001) and if they were Black or Hispanic (adjusted HR 0.58, p &lt; 0.001 and 0.87, p = 0.008 repectively) relative to Non-Hispanic Whites. There were significant differences with location. Relative to San-Fransisco-Oakland, the greatest adjusted differences were between Louisiana (HR 0.51, p &lt; 0.001) and New Jersey (HR 1.57, p &lt; 0.001). Age significantly interacted with time (p = 0.007). Surgical use declined from 75.5% during 2004-6 to 71.5% during 2010-12 when less than 75 years. For those older, the decline was greater, 55.3% to 46.5%. The risk of death declined with time (adjusted HR 0.94, p &lt; 0.001 between periods). Conclusions: Since 2004, the use of surgery for stage I NSCLC has declined and done more so with increasing age. Despite this overall population survival has improved.
High prevalence of anemia in newly diagnosed lung cancer patients undergoing chemotherapy: Associations and prognostic value.
Authors: Navneet Singh, Satyam Bhatt, Valliappan Muthu, Kuruswamy Thurai Prasad, Digambar Behera, Prashant Sharma
Journal: Journal of Clinical Oncology (2018)

e21169 Background: Anemia is frequent in lung cancer (LC) but data from South Asia is sparse. This prospective study aimed to assess prevalence of anemia, its incidence during first line chemotherapy (CTx), its associations with baseline variables & treatment related characteristics and prognostic role. Methods: Consecutive newly-diagnosed LC patients (pts) were enrolled at a tertiary care centre in North India over 15 months. Pts with renal dysfunction and those who had received blood transfusion(s) or hematinics in the preceding two weeks were excluded. Prevalence of anemia (Hb < 12gm/dL) was assessed at baseline, before third cycle (C3) and at end of first-line CTx (EOCTx). All pts received histology-guided platinum doublet chemotherapy. Anemic pts underwent evaluation with RBC indices, serum iron, Total Iron Binding Capacity, transferrin saturation and ferritin to classify anemia as Iron Deficiency Anemia (IDA) and/or Anemia of Chronic Disease (ACD). Results: Of 138 pts enrolled, majority were males (84.4%), current/ex-smokers (76.8%), had stages IIIB/IV disease (82.6%) with mean age of 58.8 years. Adenocarcinoma (45.7%) was commonest histological type. Mean Hb at baseline, at C3 & EOCTx was 12.3, 10.6 & 10.1 gm/dL respectively (p < 0.001). Prevalence of any grade [& clinically significant (≥ grade 2)] anemia was 38.4% [& 15.9%] at baseline, 76.5% [& 40.9%] at C3 and 87.0% [& 43.0%] at EOCTx respectively. Incidence of new-onset anemia was 64.7% at C3 & 82.1% at EOCTx. Anemia was more common in females (66.7%) and in squamous histology (54.8%). Following CTx, worsening severity of anemia was seen in 56.5% (40.0% by 1 grade & 16.5% by ≥2 grades) at C3 & 64.0% (46.0% by 1 grade & 18.0% by ≥2 grades). Most cases of anemia were multifactorial: ACD alone or in combination in 79.1%, IDA in 59.1% and both ACD + IDA in 54.5%. Pts with anemia at C3 were older, received significantly lower %predicted CTx doses, lesser CTx cycles, experienced greater inter-cycle delays, had worse performance status and lower radiological responses as compared to those without. Conclusions: Anemia is frequent at LC diagnosis and worsens after CTx. ACD & IDA are frequent and coexist. Presence of anemia during LC CTx is a/w poor prognosis.
A longitudinal brain fMRI study of chemotherapy-induced peripheral neuropathy in 50 breast cancer patients.
Authors: Ian Kleckner, Richard Aslin, Charles E. Heckler, Michelle Christine Janelsins, Nimish Mohile, Matthew Asare, Calvin Cole, Po-Ju Lin, Karen Michelle Mustian, Vikram Rao, Shelli Kesler
Journal: Journal of Clinical Oncology (2017)

10095 Background: Over half of patients receiving taxane, platinum, and vinca alkaloid chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which involves numbness and neuropathic pain in the hands and feet. CIPN has no effective treatments partly because its etiology is poorly understood. We theorize that CIPN symptoms are partly caused by impairment of interoceptive brain circuitry, which processes bodily sensations via the posterior insula and anterior cingulate cortex (ACC). We investigated whether CIPN is associated with altered connectivity in interoceptive brain circuitry. Methods: Fifty women with breast cancer (50±9 years) reported CIPN symptoms (CIPN-20) and underwent resting fMRI one or more times: before surgery, one month after completion of chemotherapy, and one year after chemotherapy. We used an a priori seed-based investigation of connectivity between the posterior insula and ACC. We compared connectivity between 31 patients without CIPN symptoms (≤10 CIPN-20-Sensory), 19 patients with CIPN symptoms ( &gt; 10 CIPN-20-Sensory), and 280 healthy adults (174 women, 19.3 years) from another study. Results: Patients with CIPN symptoms had significantly reduced connectivity between the posterior insula and the ACC compared to patients without CIPN symptoms (p = 0.01, d = 0.73). Connectivity between the posterior insula and the ACC was negative in patients with CIPN symptoms but positive in both healthy adults and patients without CIPN symptoms. Conclusions: CIPN is characterized by reduced connectivity in interoceptive brain circuitry. Interoceptive networks may be a target for the development of therapies directed to prevent or treat CIPN. Future work will assess causal relationships between CIPN symptoms and reduced connectivity.
Combined hepatocellular carcinoma and cholangiocarcinoma: Debate for the ideal surgical option.
Authors: Hardik Satish Chhatrala, Chintan Shah, Karthik Kailasam, Lokesh Yadav, Sreenivasa Rao Chandana
Journal: Journal of Clinical Oncology (2017)

e15644 Background: Current limited evidence from observational studies suggest lack of survival benefit from liver transplantation (LT) for combined hepatocellular carcinoma with cholangiocarcinoma (cHCC-CC) when compared to surgical resection. This is in contrast to hepatocellular carcinoma (HCC) which has clear survival benefit with LT. We hypothesized that cHCC–CC patients have similar overall survival (OS) after LT compared to resection. Methods: Localized HCC and cHCC–CC patients treated with surgical resection versus transplant were identified in SEER Database (1973–2013). Kaplan-Meier method was used to examine survival with LT versus resection. Results: In the total period between 1973-2013, we identified 9,306 (5496 [59.06%] resection, 3810 [40.94%] transplant) patients with HCC, and 175 (107 [61.14%] resection, 68 [38.85%] transplant) patients with cHCC–CC. 3-year OS of patients undergoing LT remains significantly greater for HCC than for cHCC–CC (80.5% vs 59.9%, P &lt; 0.01). Interesting, for period 2008-13, 3-yr OS for cHCC-CC patients undergoing LT was better than resection, although the difference was not statistically significant (66.4% vs 46.27%, p &gt; 0.10). While there has been improved 3-year and 5-year OS from period 2002-07 to 2008-13 after LT for localized HCC patients (83.6% vs 79.4%, p &lt; 0.002 and 76.4% vs 73.6, p &lt; 0.01, respectively), there has been no significant improvement in 3-year or 5-year survival after for HCC-CC (66.4% vs 65.2%, p &lt; 0.4 and 58.3% vs 55.3%, p &gt; 0.4 respectively). Conclusions: Over the past decade, 3-yr OS of cHCC-CC with LT remains dismal and has not improved. However, LT in patients with localized cHCC–CC may have a potential survival benefit over liver resection, although clearly lower than the survival benefit of LT for HCC. Our results argue for a randomized trial for LT versus resection for localized cHCC-CC patients to obtain better understanding of survival benefit from the two surgical options.
HIV Preexposure Prophylaxis “Smart Pill” in Early Testing
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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BRAF (V600E) mutant metastatic colorectal cancer: What is the role of the antiangiogenic therapy in a real-world setting?
Authors: Nieves Martinez Lago, Ana Fernandez Fernandez Montes, Marta Covela Rúa, Elena Brozos Vazquez, Juan Cruz De La Camara, Mónica Jorge Fernández, Antia Cousillas, Jose Carlos Méndez Méndez, Marta Carmona Campos, Carlos Romero Reinoso, Paula Gonzalez Villarroel, Yolanda Vidal Insua, Elena Gallardo Martin, Begoña Graña, Francisca Vazquez Rivera, Maria Luz Pellon Augusto, Guillermo Alfonso Quintero Aldana, Margarita Reboredo Lopez, Sonia Candamio Folgar, Mercedes Salgado Fernandez
Journal: Journal of Clinical Oncology (2018)

e15561 Background: BRAF mutations, mostly missense V600E, occur in approximately 8% to 12% of patients with metastatic colorectal cancer (mCRC). BRAF (V600E) mt is a strong predictor of a poor prognosis, with distinct clinical and pathological features. However, it is unknown the predictive impact in a real world setting. Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university hospitals in NW Spain, belong the GITuD. Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively collected and analyzed. Results: Data from 57 pts. treated between November 2010 to December 2017 were recorded in the study. Patients´characteristics are summarized in table 1. Median OS was 13.0 months (95% CI, 9.8-16.2 months). Primary tumor surgery (p = 0.001), metastasectomy (p = 0.005), T3 tumor invasion (p = 0.011), ECOG PS < 2 (p = 0.002) and NLR < 3 (p = 0.042) were associated with prolonged OS. Median first line PFS was 4.1 months (95% CI, 2.1-6.2 months). Anti-angiogenic based chemotherapy was associated with a prolonged first line PFS (median 5.2 vs. 2.1 months, HR, 0.39; 95% CI, 0.19-0.79; p = 0.006). Conclusions: Our study confirms BRAF V600E-mt worse prognosis and encourage the use of anti-angiogenic based chemotherapy in this subgroup of patients. Table 1. Characteristics N (%) Age Median (Range) 61.2 (30 -83 years). Sex Male 24 (42.1) Female 33 (57.9) ECOG PS 0-1 44 (77.2) 2-3 13 (22.8) Primary Tumor Location Right sided 29 (50.9) Left sided 18 (31.6) Rectum 10 (17.5) Differentiation Grade Low Grade 30 (52.6) High Grade 17 (29.8) Unknown 10 (17.5) Tumor presentation Synchronous 41 (71.9) Metachronous 16 (28.1) MMR deficiency protein expression No 24 (42.1) Yes 2 (3.5) Unknown 31 (54.4) N. Metastatic Locations Median (Range) 2 (1-5) Metastatic Locations Liver 28 (51.9) Lung 21 (36.2) Peritoneum 16 (29.6) Distant Lymph Nodes 16 (29.6) Others 16 (29.6) Primary Tumor Resection Yes 38 (66.7) No 19 (33.3) First Line Treatment Triplet CT Bevacizumab 7 (12.3) Doublet CT Bevacizumab 28 (49.1) Doublet CT antiEGFR 8 (14.0) Doublet CT 10 (17.5) Others 4 (7.0)
P01.069 Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter retrospective study by the Brain-Study-Group of the Radiation Oncology Italian Association (AIRO)
Authors: P Navarria, G Minniti, V Pinzi, L Draghini, V Borzillo, P Ciammella, S Scoccianti, D Amelio, M Krengli, M Buglione di Monale
Journal: Neuro-Oncology (2018)

The role of re-irradiation is still under investigation, particularly regarding to the appropriate patients selection, the time interval between the first and second irradiation, and the optimal RT schedule. The aim of the present study was to evaluate clinical outcome of patients with recurrent glioma underwent re-irradiation in 13 Italian Centers. Data of 321 recurrent glioma patients underwent re-irradiation were reviewed. The data collection focused on patients, tumor, and treatments characteristics at diagnosis and at recurrence, interval time between diagnosis and local relapse, features of re-irradiation concerning target volume, total doses and fractionations used, acute and late toxicity. Overall survival (OS) was calculated from the date of re-irradiation to the time of death or to the last follow-up examination. Among 321 patients evaluated, 223 had primary diagnosis of glioblastoma, 81 grade III gliomas, 17 low grade glioma. At recurrent time the median age was 53 years (range 20–82 years) and the majority (92%) of patients had a KPS ≥70. Re-irradiation was performed in all 321 patients at a median time of 15 months (range 3–340 months). The median total dose prescribed was 25 Gy in 5 fractions (range 10–52.5Gy in 1–15 fractions). A combined treatment, including surgery and/or chemotherapy was carried out in 102 patients while 219 received radiation therapy only. The median follow up time was 8.2 months (range 2–73 months) for the whole cohort and 17.6 months (range 3–67.7 months) for the alive patients. The median OS time, and the 6,12,24 months OS rate were 9.5 months (95%CI 8.2–10.4), 84% (95%CI 80–88), 47% (95%CI41-52), and 22% (95%CI17-27), respectively. At the last observation time 54 are alive and 267 dead. Acute grade 1–2 toxicity was recorded in 43 (13.4%) patients. Grade 1 radionecrosis occurred in 16 patients, grade 2 in 12, and grade 3 in 1. Univariate analysis showed the statistical significance of the extent of surgical resection, histology of primary tumors, IDH and MGMT status at diagnosis; at relapse time age, KPS, the interval between first and second radiation therapy, and the combined treatment performed were recorded as influencing survival. Age, KPS, histology, IDH and MGMT status were confirmed as influencing survival also on multivariate analysis. According to our results, re-irradiation could be considered a safe and feasible therapeutic option for recurrent high grade glioma. Multidisciplinary evaluation is mandatory to assure the best treatment where local therapy is part of multimodal management.