tbuckley/cabot-search huggingface dataset:
Role of radiotherapy to primary/metastatic sites in pediatric patients with metastatic rhabdomyosarcoma in the BERNIE study.
Authors: Alison Cameron, Julia Chisholm, Markus C. Elze, Michela Casanova, Birgit Geoerger, Mark Gaze, Odile Oberlin, Jeanette Bachir, Sabine Fürst-Recktenwald, Johannes H.M. Merks
Journal: Journal of Clinical Oncology (2017)

10541 Background: Local control is a key part of treatment of local/locoregional rhabdomyosarcoma (RMS) and often involves radiotherapy (RT) with/without surgery. The role of RT in metastatic RMS is uncertain, with little published evidence to guide clinicians. We analyzed data from the BERNIE trial to assess the benefit of RT for patients (pts) with metastatic RMS. Methods: In the BERNIE study (NCT00643565) pts aged ≥6 months to &lt;18yrs with metastatic RMS and non-RMS soft tissue sarcoma were randomized to receive chemotherapy (CT) with/without bevacizumab (BEV), surgery, and/or RT (at cycle 6–9) then maintenance CT. RT was recommended for all sites of metastases if feasible (investigator discretion allowed, resulting in variability in actual RT given). Pts were categorized into those receiving: RT all sites, partial RT, no RT. Event-free survival (EFS) and overall survival (OS) were calculated using Cox proportional hazards models and a landmark approach: only pts who were event free at day 221 (i.e. end of cycle 9 + 1 month) were included (EFS, n=85; OS, n=97). Variables adjusted were: treatment (as randomized), disease type (alveolar/embryonal/other), risk group, age &gt;10yrs, metastatic lesion count (1, 2–3, 4+). The analysis was non-randomized, exploratory and post hoc. Results: Of 102 pts with RMS, 22 received no RT, 49 partial RT, and 31 RT to all sites. Baseline characteristics were mostly balanced, and comparable proportions of pts received BEV. Better OS was observed in the RT group (Table) (comparable with unadjusted results). A non-significant EFS improvement was observed for the RT groups. Conclusions: Partial RT and RT to all sites of disease in metastatic RMS was associated with significant OS benefits, albeit in small pt numbers. This should be confirmed in a prospective randomized trial. Clinical trial information: NCT00643565. [Table: see text]
The prognostic and predictive value of AR-V7 quantification in mCRPC.
Authors: Adam Sharp, Jon Welti, Maryou B. Lambros, David Dolling, Caterina Aversa, Lorna Pope, Daniel Nava Rodrigues, Ines Figueiredo, Pasquale Rescigno, Michael Paul Kolinsky, Ruth Riisnaes, Penelope Flohr, Diletta Bianchini, Robert Chandler, Joaquin Mateo, Nina Tunariu, Stephen R Plymate, Jun Luo, Johann S. De Bono
Journal: Journal of Clinical Oncology (2018)

12026 Background: Androgen receptor splice variant-7 (AR-V7) is associated with resistance to abiraterone/enzalutamide treatment in metastatic castration resistant prostate cancer (mCRPC). Methods: We determined CTC status and AR-V7 RNA quantification from mCRPC patient blood (Adnagen assay; AG). Reproducibility, clinical significance, and comparison to CellSearch CTC (CS_CTC) enumeration and biopsy AR-V7 protein quantification (Immunohistochemistry; IHC) was investigated. Results: To-date 218 blood samples from 130 patients have been analysed. AG reproducibility was determined from 84 samples run in triplicate with high concordance (70% of samples); poor concordance was seen in samples with low AR-V7 RNA expression supporting the identification of a cut-off for negative AR-V7 testing. CS_CTC enumeration was available for 109 samples; AG_CTCneg samples had lower CS_CTC counts (p = 0.0001). AG_CTCpos/AR-V7neg samples had lower CS_CTC counts than AG_CTCpos/AR-V7pos samples (p = 0.006). CS_CTC counts in AG_CTCpos/AR-V7pos samples positively correlated with AR-V7 RNA expression (p = 0.0002). Contemporaneous mCRPC biopsies were available for 56 samples. All 25 AG_CTCpos/AR-V7pos samples, 12/16 AG_CTCpos/AR-V7neg samples and 9/15 AG_CTCneg samples were AR-V7 IHC positive. Finally, AG_CTCpos/AR-V7pos patients had a worse prognosis than AG_CTCpos/AR-V7neg and AG_CTCneg patients (median OS 6.9 vs 14.4 vs 30.8 mo; p < 0.0001). In addition; only patients with AG_CTCpos/AR-V7neg (5/11) and AG_CTCneg (1/5) samples, not AG_CTCpos/AR-V7pos (0/5) samples, before either enzalutamide/abiraterone therapy had a 50% PSA response. Conclusions: We confirm that AG_AR-V7 RNA analyses can be conducted as a continuous variable, and determine a cut-off for negative tests and show that this is prognostic and predictive. Furthermore, we show that AG_AR-V7 RNA expression may be associated with higher CS_CTC counts and more advanced disease. Finally, we demonstrate that patients with AG_CTCneg and AG_CTCpos/AR-V7neg samples had mCRPC biopsies positive for AR-V7 protein expression; the clinical significance of this requires further interrogation to identify whether these patients derive less benefit from enzalutamide/abiraterone therapy.
Role of testosterone synthesized by skin melanocytes in preventing malignant transformation of nevi.
Authors: Elena Mikhaylovna Frantsiyants, Valeria Bandovkina, Yulia A. Pogorelova, Irina V. Kaplieva, Natalia D. Cheryarina, Natalia A. Maksimova, Maria I. Maksimova, Irina Valerevna Neskubina, Lidia K. Trepitaki, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e21066 Background: Melanocytes are involved into the synthesis and metabolism of steroid hormones in the skin. Cutaneous melanoma in 75% of cases occurs in congenital or acquired pigmented nevi. There are no studies comparing local hormonogenesis in nevi and melanomas. The purpose of the study was a comparative analysis of hormone levels in tissues of dysplastic nevi and cutaneous melanoma (pТ 1-2 N 0 M 0 ). Methods: Levels of prolactin (PRL), progesterone (P4), total and free testosterone (T and fT), estrone (E1) and estriol (E3) and sex steroid-binding globulin (SSBG) were studied by ELISA in 17 samples of рТ 1-2 N 0 M 0 melanoma and in 23 samples of dysplastic nevi. Intact tissues (n = 15) obtained from non-cancer patients during surgical treatment was used as the control. Results: Levels of T in nevi, compared to intact tissues, were 1.4 times higher, fT – 8.7 times higher, while SSBG content was 1.9 times lower; E3 was 1.6 times higher, PRL – 1.4 times lower, and levels of E1 in nevi were similar to the values in intact tissues. рТ 1-2 N 0 M 0 melanomas, compared to intact tissues, demonstrated local androgen imbalance: T levels were decreased by 1.8 times, while fT exceeded the norm by 1.8 times, and SSBG – by 6 times. E1 content increased by 1.6 times, E3 decreased by 2.8 times. The E1/E3 ratio in nevi was reduced by 1.6 times, while in melanoma it was increased by 4.4 times. The T/E1 ratio in nevi was increased by 1.4 times, and in melanoma it was decreased by 2.8 times. Levels of PRL and P4 in melanomas, nevi and in intact tissues did not differ significantly. Conclusions: Melanoma was characterized by hyperestrogenia due to increased levels of E1 and low E3 concentrations which caused malignant transformation of melanocytes. Most likely, in melanoma spent SVT estrone synthesis, as evidenced by increase in the E1 / E3 and decrease T / E1.Apparently, fT in melanoma is used for estrogen synthesis, as indicated by the E1/E3 increase and decrease in the T/E1 ratio. Increased E1 synthesis can contribute to the realization of estrogen genotoxic effects. These mechanisms are absent in tissues of nevi. Hyperandrogenism in nevi probably prevents malignant transformation due to low aromatase activity.
Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications
Authors: Hitesh Deshmukh, Sing Sing Way
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Pregnancy stimulates an elaborate assortment of dynamic changes, allowing intimate approximation of genetically discordant maternal and fetal tissues. Although the cellular and molecular details about how this works remain largely undefined, important clues arise from evaluating how a prior pregnancy influences the outcome of a future pregnancy. The risk of complications is consistently increased when complications occurred in a prior pregnancy. Reciprocally, a prior successful pregnancy protects against complications in a future pregnancy. Here, we summarize immunological perturbations associated with fetal loss, with particular focus on how both harmful and protective adaptations may persist in mothers. Immunological aberrancy as a root cause of pregnancy complications is also considered, given their shared overlapping risk factors and the sustained requirement for averting maternal-fetal conflict throughout pregnancy. Understanding pregnancy-induced immunological changes may expose not only new therapeutic strategies for improving pregnancy outcomes but also new facets of how immune tolerance works that may be applicable to other physiological and pathological contexts.
Surveillance for Cancer Incidence and Mortality — United States, 2012
Authors: Simple D. Singh, S. Jane Henley, A. Blythe Ryerson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

This report provides, in tabular and graphic form, official federal statistics on the occurrence of cancer for 2012 and trends for 1999-2012 as reported by CDC and the National Cancer Institute (NCI) (1). Cancer incidence data are from population-based cancer registries that participate in CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results (SEER) program reported as of November 2014. Cancer mortality data are from death certificate information reported to state vital statistics offices through 2012 and compiled into a national file for the entire United States by CDC's National Center for Health Statistics' (NCHS) National Vital Statistics System (NVSS). This report is a part of the Summary of Notifiable Noninfectious Conditions and Disease Outbreaks - United States, which encompasses various surveillance years but is being published in 2016 (2). The Summary of Notifiable Noninfectious Conditions and Disease Outbreaks appears in the same volume of MMWR as the annual Summary of Notifiable Infectious Diseases (3).
Immunological differences between primary and metastatic breast cancer
Authors: B. Szekely, V. Bossuyt, X. Li, V.B. Wali, G.A. Patwardhan, C. Frederick, A. Silber, T. Park, M. Harigopal, V. Pelekanou, M. Zhang, Q. Yan, D.L. Rimm, G. Bianchini, C. Hatzis, L. Pusztai
Journal: Annals of Oncology (2018)

Little is known about how the immune microenvironment of breast cancer evolves during disease progression.We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples.TIL counts and PD-L1 positivity were significantly lower in metastases. Immune cell metagenes corresponding to CD8, T-helper, T-reg, Cytotoxic T, Dendritic and Mastoid cells, and expression of 13 of 29 immuno-oncology therapeutic targets in clinical development including PD1, PD-L1, and CTLA4 were significantly lower in metastases. There was also coordinated down regulation of chemoattractant ligand/receptor pairs (CCL19/CCR7, CXCL9/CXCR3, IL15/IL15R), interferon regulated genes (STAT1, IRF-1,-4,-7, IFI-27,-35), granzyme/granulysin, MHC class I and immune proteasome (PSMB-8,-9,-10) expression in metastases. Immunotherapy response predictive signatures were also lower. The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets.Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.
Transarterial chemoembolization treatment in the management of BCLC c stage hepatocellular carcinoma: A large real-world observational study of 885 cases.
Authors: Xin Yin, Bei Tang, Jia Yuan, Miao Li, Boheng Zhang, Yu-Hong Gan, Yan-hong Wang, Ning-lin Ge, Yi Chen, Rong-xin Chen, Li-Xin Li, Bi-Wei Yang, Lan Zhang, Tong-chun Xue, Zhenggang Ren
Journal: Journal of Clinical Oncology (2018)

e16115 Background: Patients with advanced stage hepatocellular carcinoma (HCC) have a dismal prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging system does not recommend transarterial chemoembolization (TACE) for treating BCLC C HCC. However, numerous Asian-Pacific institutes still perform TACE for this patient group. There remains a paucity of large real-world data characterizing treatment outcomes of these patients.We aimed to share experiences of 885 cases of BCLC C stage HCC patients treated by TACE in real-world practice. Methods: 885 patients were included in this real-world study who received TACE based monotherapy or combination therapy in liver cancer institute, Fudan University between January 2008 and December 2015. We investigated the clinical outcomes of TACE-based treatment in BCLC C stage HCC. Results: In this cohort of 885 BCLC C HCC patients, vascular invasion was present in 582 patients (65.8%), lymph node involvement was present in 108 patients(12.2%), extrahepatic metastases was present in 232 patients (26.2%).The mean number of TACE per patient was 3.0±1.9 sessions. Median overall survival was 8.0 months (range 3-37) for the entire study population. Of all the patients, 600 patients received TACE-alone treatment, 137 patients received TACE combined Sorafenib treatment, 41 patients received TACE combined local regional treatment, 59 patients received TACE with chemotherapy, 123 patients received TACE with radiotherapy. The median survival time was 6.0 months for TACE-alone group, 11.5 months for TACE+Sorafenib group, 19.8 months for TACE+local regional treatment group, 12.0 month for TACE+chemotherapy group and 12.0 months for TACE+radiotherapy group respectively.These data showed that TACE-based combination therapy can improve overall survival in BCLC C stage HCC, in comparison with TACE alone treatment.After propensity score matching and adjusting for potential confounders, there were still significant survival differences between TACE-alone group and TACE-based combination treatments mentioned above. Conclusions: TACE-based combination therapy can improve overall survival in BCLC C stage HCC patients.
SM-88 efficacy and safety in metastatic breast cancers.
Authors: Xinhua Zhu, Marcus Smith Noel, Patricia Zawisny, Zachary Gostout, Douglas Decorato, Gerald H. Sokol, Maria Loushin, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

e13100 Background: SM-88 is a relatively non-toxic novel combination therapy (dysfunctional tyrosine, CYP3a4 inducer, mTOR inhibitor and oxidative stress catalyst) that has demonstrated efficacy in breast and other metastatic cancers. Early testing of SM-88 therapy with over 100 subjects has shown a potential efficacy signal, including RECIST responses in 13 different cancer types (JCO 2013, e22095), while maintaining a manageable toxicity profile (no grade 3-5 drug-related AEs). We assessed its effect in an updated cohort of breast cancer subjects. Methods: Retrospective chart review of metastatic breast cancer (mBC) subjects treated with SM-88 (aka SMK) under Phase I or compassionate use programs. All subjects received po SM-88 5 days/week. Combination therapy with other anti-neoplastics including parenteral SM-88, was used in 5 compassionate use cases. Results: A total of 25 mBC cases with 21 evaluable were identified from 107 charts of subjects treated with SM-88 between 2012–7. Mean age 51 (35 – 70); 95% white; median prior systemic therapies: 3 (1–8); and baseline ECOG: 1 (0 – 4). All subjects had previously treated progressing mBC and were considered incurable with 33% (7/21) refractory, 67% (14/21) recurrent. Overall response rate (ORR) was 43% (9/21) with responses seen across all receptor profiles (see table). Outcomes included improvement of ECOG PS in 81% and 67% of EORTC QLQ-C30 “overall health
A phase I study of LXH254 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.
Authors: Filip Janku, Gopa Iyer, Anna Spreafico, Noboru Yamamoto, Yung-Jue Bang, Elena Elez, Maja J. De Jonge, Harry J.M. Groen, Frederik Marmé, Kathrin Gollmer, Annie St-Pierre, Maritza Melendez, Anna Mais, Heidi Nauwelaerts, Uz M. Stammberger, Reinhard Dummer
Journal: Journal of Clinical Oncology (2018)

2586 Background: CRAF is a key mediator of oncogenic mitogen-activated protein kinase (MAPK) pathway reactivation following MEK or BRAF inhibition. LXH254 is a BRAF and CRAF inhibitor with antitumor activity in MAPK-driven tumor models. This Phase I dose-finding study of LXH254 in pts with advanced solid tumors harboring MAPK pathway alterations is evaluating safety/tolerability and preliminary antitumor activity (NCT02607813). Methods: Primary objective: characterize the safety/tolerability of single-agent LXH254 and identify a recommended dose (RD)/schedule for future study. Secondary objectives: characterize antitumor activity (per RECIST 1.1) and PK. Dose escalation was guided by a Bayesian model-based approach. Eligible pts had advanced, pretreated solid tumors with MAPK pathway alterations. Results: At data cut-off 4 Dec 2017, 75 pts were enrolled in 9 dose cohorts: 100 (n = 4), 200 (n = 4), 300 (n = 5), 400 (n = 6), 800 (n = 12), 1200 mg QD (n = 12), and 200 (n = 7), 400 (n = 12), 600 mg BID (n = 13). Pts (ECOG PS 0/1, 41% male, median age 57 yrs) had lung (n = 16), colorectal (n = 14), ovarian (n = 12), melanoma (n = 12), or other (n = 21) cancers. Median duration of exposure was 7.7 wks; 59/75 (79%) pts discontinued treatment, due to disease progression (49 pts [65%]), physician/pt decision (5 pts [7%]), death (3 pts [4%]), or AE (2 pts [3%]). Three DLTs were reported: platelet count decrease (Gr 4, 1 pt 1200 mg QD), pruritus and maculopapular rash (both Gr 3, 1 pt 600 mg BID). The most common ( > 15%) drug-related, any-Gr AEs were rash (dermatitis acneiform/rash/maculopapular rash, 53%), fatigue (20%), and nausea (20%). Gr ≥3 drug-related AEs occurred in 16% of pts, most frequently rash, myalgia, and increased lipase (2 [3%] pts each). Plasma peak drug concentration (Cmax) and exposure (AUC) after QD/BID oral doses increased approximately dose-proportionally. There were two confirmed partial responses (with > 50% tumor size reduction) in pts with KRAS-mut and BRAF-mut cancers; stable disease was reported in 25/75 (33%) pts. Conclusions: Oral LXH254 was well tolerated, all AEs were manageable, and preliminary antitumor activity was observed. The study is ongoing to establish a RD/schedule, and further establish antitumor activity. Clinical trial information: NCT02607813.
Abstract 20274: The Ratio of Coronary Arterial Lumen Volume to Left Ventricle Mass on Coronary Computed Tomography Angiography Identifies Patients Prone to Vessel-Specific Ischemia Measured by Fractional Flow Reserve
Authors: Charles A Taylor, Sara Gaur, Kristian A Øvrehus, Damini Dey, Amir Ahmadi, Sophie Khem, Hyun J Kim, Alan Wilk, Christopher K Zarins, Jesper Jensen, Stephan Achenbach, Daniel S Berman, Hiram Bezerra, Hans E Bøtker, Jonathon Leipsic, John Lesser, Jagat Narula, Jens Lassen, Bernard De Bruyne, Bjarne Norgaard
Journal: Circulation (2016)

Background: We hypothesize that in patients with suspected coronary artery disease (CAD), the ratio of coronary arterial lumen volume to myocardial mass (V/M) varies among subjects and that patients with low values of V/M are predisposed to ischemia. The purpose of this study was to quantify the relationship between V/M, plaque volume and FFR. Methods and Results: V/M was computed in 254 patients with suspected CAD from the NXT trial (NCT01757678). All patients underwent clinically indicated coronary CTA, invasive angiography, and FFR studies. Nitroglycerin was administered in all patients prior to CT and angiography/FFR. The total arterial lumen volume was calculated as the sum of volumes of the patient-specific anatomical model derived from coronary CTA and, downstream of the image-based model, a morphometric model of the smaller arteries generated using branching laws. The total arterial lumen volume was divided by left ventricular mass. Calcified and noncalcified plaque volumes were quantified using s...
Financial toxicity in patients with colorectal cancer and neuroendocrine tumors.
Authors: Leonidas Apostolidis, Katja Mehlis, Julian Witte, Bastian Surmann, Matthias Kudlich, Juergen Walther, Wolfgang Greiner, Eva Caroline Winkler
Journal: Journal of Clinical Oncology (2018)

6533 Background: Financial toxicity of cancer has so far been discussed primarily in the US health care system and has been shown to be associated with higher morbidity and mortality. In Germany with its third-party paid health care system the socio-economic impact of cancer is poorly understood. This study aims to provide data on financial consequences of a colorectal cancer (CRC) or neuroendocrine tumor (NET) diagnosis on patients' economic situation and psychosocial outcomes. Methods: This prospective study recruited 247 patients (n = 125 CRC / n = 122 NET) from November 2016 to March 2017 at the National Center for Tumor Diseases, Heidelberg University Hospital. They completed a survey on income, cancer-related out-of-pocket costs, distress (DT) and quality of life (EORTC-LQ). Results: Overall, 80.6 % (n = 199) stated to have higher out-of-pocket costs, and 37.2 % (n = 92) reported income loss as a sequel to their disease. While monthly out-of-pocket costs did not exceed 200 € in 76.9 % of affected patients, 44.6 % of those with income losses report losing more than 800 € per month. A multiple regression analysis showed effects of economic deteriorations on patient's quality of life and distress depending on the type of health insurance: high financial loss relative to income was significantly associated with a lower estimation of patient's quality of life (p = 0.0009) and more distress (p = 0.0037). Patients with private health insurance indicate better quality of life (p = 0.0134) and less distress (p = 0.0005) compared to those with statutory health insurance. Conclusions: Distress and reduced quality of life due to financial problems intensify the burden that already results from a cancer diagnosis. As many patients have to face financial loss and most are insured under the statutory health insurance scheme, there is a need for targeted support measures at the individual and system level in Germany.