tbuckley/cabot-search huggingface dataset:
Analysis of ALK-status of tumor tissue in patients with non-small cell lung cancer (NSCLC) using immunohistochemistry (IHC).
Authors: Inna Arnoldovna Novikova, Oleg Ivanovich Kit, Elena Petrovna Ulianova, Evgeniya M. Nepomnyashchaya, Elena Bondarenko, Yury N. Lazutin, Tamara G. Ayrapetova, Anna V. Chubaryan, Pavel A. Anistratov, Sergey P. Pyltsin, Rukiyat Isaeva
Journal: Journal of Clinical Oncology (2016)

e20071 Background: The purpose of the study was to assess the rate of ALK-positive NSCLC patients in dependence on their age, gender, smoking status and localization of metastases. Methods: ALK expression was studied by the molecular-genetic method in 326 patients aged 21-78 years with stage IV NSCLC living in the South of Russia after EGFR-negative status of tumors was confirmed. Staining was performed using VENTANA BenchMark GX immunostainer, OptiView DAB IHC Detection Kit and OptiView Amplification Kit. VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibodies were used. Results: IHC showed ALK-positive status in 8% of cases (26 of 326 patients), with a marked even granular cytoplasmic staining of cells observed in tumor tissue. Positive tumor status was confirmed by FISH in 100% of the cases. ALK-positive patients were: under 40 years of age – 11.5%, 40-50 and 50-60 y.o. – 26.9% each, older than 60 y.o. – 34.6%. Number of ALK-positive men and women was equal (13 of 26 patients, 50%). In dependence on the smoking status: smokers – 26.9% (7 patients, including 0 W and 7 (26.9%) M); non-smokers – 57.8% (15 patients, including 11 (42.3%) W and 4 (15.4%) M); former smokers – 11.5% (3 patients, including 1 (3.8%) W and 2 (7.7%) M); N/A – 3.8% (1 W). ALK-positive status was found in 18 (69.2%) patients with lymph node metastases, 6 (23.1%) – with metastases to the other lung, 1 (3.8%) – brain metastases and 1 (3.8%) – liver and bone metastases. Conclusions: The rate of ALK protein detection by IHC in MSCLC patients in the South of Russia was 8%. Gender-dependent differences were not found; ALK-positive status was most frequent in non-smoking women and smoking men, in patients with lymph node metastases and in patients older than 50 years of age.
Impact of cancer therapy on oral care utilization.
Authors: Derek Smith, Emily Castellanos, Barbara A. Murphy
Journal: Journal of Clinical Oncology (2017)

e18010 Background: Cancer therapy can result in lifelong detrimental changes to oral function. These changes often result in negative effects on patients' quality of life. The primary objective of this study is to evaluate attendance at dental visits among patients receiving a cancer diagnosis, and how attendance may change as patients move through pre-diagnosis, diagnosis and into survivorship. Methods: The Health and Retirement Study is a publically available dataset containing longitudinal survey data detailing financial and health information on 4195 patients, over 51 years old who received a new cancer diagnosis during the study. The odds of reporting a dental visit were examined as patients proceed through various phases of cancer therapy using a mixed-effects logistic regression model. A propensity score weighted analysis of the association between dental attendance in the survey wave in which the cancer was diagnosed and survival was also undertaken. Results: The odds of attending a dental visit were substantially lower in the diagnosis wave OR = 0.784 (0.700, 0.876) and the post-diagnosis waves OR = 0.734 (0.655, 0.823) compared to pre-diagnosis waves. This effect persisted in patients who survived for at least two years indicating that the decline in oral health visits was not due to extremely low expected survival. The decrease in oral health visits was not affected by age, race, gender, income, insurance coverage or education. After propensity score weighting, patients who attended a dental visit in their diagnosis wave demonstrated a reduced hazard of all-cause mortality HR = 0.825 (0.681, 0.979) compared with those with no attendance. Conclusions: Dental attendance decreases by a statistically and clinically significant amount both during and after cancer therapy despite indications for dental referral existing for many types of cancer therapy. Attendance at dental appointments during cancer therapy is associated with improved survival, which is likely due to a combination of direct and indirect effects. The fact that the decreases in care were not modified by socioeconomic factors suggests that it is not driven by strictly financial concerns and more research is necessary to identify barriers to adequate care.
Inception of early-life allergen–induced airway hyperresponsiveness is reliant on IL-13 <sup>+</sup> CD4 <sup>+</sup> T cells
Authors: Sejal Saglani, Lisa G. Gregory, Avneet K. Manghera, William J. Branchett, Faith Uwadiae, Lewis J. Entwistle, R. A. Oliver, Jessica E. Vasiliou, Rebekah Sherburn, Stephen Lui, F. Puttur, David Vöhringer, Simone A. Walker, James Buckley, Ruth Grychtol, Valentina Fainardi, Laura Denney, Adam Byrne, Erika von Mutius, Andrew Bush, Clare M. Lloyd
Journal: Science Immunology (2018)

Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinnegCD45+CD90+IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4creIL-13 KO mice (lacking IL-13+CD4+ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13+ ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13+CD4+ T cells, whereas IL-13+ ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13+CD4+ T cells, rather than IL-13+ ILCs or IL-33, are critical for inception of allergic AHR in early life.
First analysis of the National Lung Cancer Register in Spain (RTT).
Authors: Ramon De Las Penas, Enric Carcereny, Delvys Rodriguez Abreu, Joaquim Bosch, Carlos Camps, María Guirado-Risueño, Jose-Luis Gonzalez-Larriba, Bartomeu Massuti, Joaquin Casal, Rosario Garcia Campelo, Elvira Del Barco Morillo, Manuel Domine, Esther Noguerón, María Ángeles Sala, Julia Calzas, Remei Blanco, Miriam Dorta, Miguel Angel Munoz, Pilar Lianes, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2018)

e13608 Background: The Spanish Lung Cancer Group (GECP) initiated a Tumor Thoracic Register (RTT) in September 2016 with the aim of evaluating accurate, basic data concerning this oncological pathology in Spain. Methods: The RTT data base collects demographic, diagnostic and treatment data from all the hospitals participating in the project. Results: From September 2016 to October 2017, the register has included 2200 patients from 53 different hospitals. Patients have been included at a rate of 160 per month. The majority of cases are male (73.6%), with females already presenting one in four cases of lung cancer (26.3%). Concerning those affected, 39.5% are habitual smokers while the other 44.6% are ex-smokers. The majority present non-small-cell lung cancer (87%) followed by small-cell lung cancer (9.7%). With respect to age, 63% of lung cancers occur in patients younger than 70 years of age. The main symptoms at presentation are cough, pain, dyspnea and occasionally weight loss. Differential characteristics according to place of residence A study comparing Spanish regions revealed that there are some differentiating characteristics between patients with respect to their smoking habits and age at diagnosis. Access to innovation In the majority of cases, the time between diagnosis and initiating treatment is from 1 to 3 months and, in terms of access to innovation in diagnostic techniques, there are no significant differences between the regions, with 70% of cases in stage IV having undergone at least 1 molecular determination.(92% EGFR, 73% ALK, and 25% ROS1) Conclusions: The RTT is a valuable tool for analyzing the current situation of lung cancer in Spain. The database provides medical information that can also assist the orientation of healthcare policies.
P02.13 Before requiring a cure: towards preventing the outgrowth of brain metastases
Authors: M A Karreman, A S Berghoff, K Gunkel, M Piechutta, M Feinauer, W Wick, F Winkler
Journal: Neuro-Oncology (2018)

Brain metastases (BM) are a devastating and frequent complication in patient with metastatic cancer. Survival is severely limited as the current treatment strategies have to conquer several obstacles in symptomatic BM including the heterogenous composition of the blood-brain barrier and the altered microenvironment characteristics. “Prevent_BM” is a collaborative effort of five research groups, both clinical and pre-clinical, to identify a treatment concept targeting the formation of early BM and preventing the outgrowth to macro-metastases. In Prevent_BM, the preclinical studies focus on tumor cell-astrocyte gap junction connections, the PI3K/mTor pathway, improving brain-tropism of T-cells and the role of the pro-metastatic perivascular niche. These targets will be validated in a clinical setting, and state-of-the-art bioinformatics platform allows integration and analysis of the results. To monitor the early steps of brain colonization in real time, we employ intravital multiphoton laser-scanning microscopy (MPLSM) through a chronic cranial window in mice. Following intracardiac injection of fluorescent tumor cells, we can study the effect of different treatments on BM growth over the period of weeks. Intravital imaging allows us to investigate the effects of PI3K/mTor inhibitors on BM growth over time, as a potential target strategy for BM prevention. While studying the role of tumor cell-astrocytes in BM formation, we observed tumor-microtube formation in a subset of tumor cells, analogue to the connections formed by glioblastoma cells. To visualize tumor cell-astrocyte connections, we can measure the transfer of gap-junction permeable dye in vivo. Here, we find that the microtube-forming metastatic cells indeed take up the SR101 dye, with similar dynamics as astrocyte cells. The intravital MPLSM approach uniquely enables studying how the tumor microenvironment and therapeutic agents affect the development of BM, and allows revealing the BM immune-surveillance and the structural organization of the blood-tumor-barrier. Importantly, the remodeling of the brain vasculature during metastatic seeding can monitored during the early steps of colonization and metastatic outgrowth. Hereto, we can correlate in vivo imaging to 3D electron microscopy to reveal the dynamic interactions between tumor cells and the neurovascular unit at high resolution. Upon completion of Prevent_BM, we expect to have generated a unique database, allowing deciding how to move forward with a first-of-its-kind, randomized clinical trial to prevent the symptomatic occurrence of BM. Preventing future metastasis outgrowth with a well-tolerated, low-dose targeted systemic treatment, would fundamentally change the course of many patients suffering from metastatic cancer.
Genomic landscape of micropapillary nonmuscle-invasive bladder cancer.
Authors: Brendan Reardon, Stephanie A. Mullane, Jaegil Kim, Gad Getz, Anna Orsola, David J. Kwiatkowski, Eliezer Mendel Van Allen, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2016)

e16028 Background: High grade T1 (HGT1) nonmuscle-invasive bladder cancer (NMIBC) represents a challenging and clinically heterogeneous subset of bladder cancer. Micropapillary carcinomas (MC), a rare variant of HGT1, are aggressive and associated with progression to muscle-invasive disease. Targeted panel testing of MC identified recurrent ERBB2 alterations, although the genomic landscape of this rare subtype is incompletely characterized. Methods: Primary HGT1 NMIBC samples underwent pathology review to identify MC variant histology. Whole exome sequencing (WES) of tumor and available normal samples was performed to identify somatic alterations. ExAC and COSMIC databases were used to filter likely germline variants in unmatched tumor samples. Two-tailed fisher’s exact tests were performed for statistical comparisons across groups. Results: 16 primary MC tumor samples, underwent WES, with 134-fold mean read depth. Many genes characterizing muscle-invasive bladder cancer by TCGA harbored point mutations in this cohort, including TP53 (50%), KMT2D (25%), KDM6A (18.8%), RB1 (18.8%), ARID1A (12.5%), and PIK3CA (12.5%). Recurrent amplification of 1q21-23 (including MCL1 and PVRL4) and deletions in 9p21 (including CDKN2A/B) were seen in 43.75% and 25% of MC cases, respectively. Consistent with prior reports, ERBB2 point mutations or amplifications were also observed (6/16; 37.75%); notably, we also observed 6 patients harboring point mutations in ERBB3 (2/6 intersect with ERBB2). Comparison of genomic features enriched in MC tumors with a cohort of non-MC HGT1 tumors (n = 30) implicated recurrent MCL1amplification as enriched in MC (p = 0.02; Fisher's Exact). Conclusions: MC harbor multiple somatic genetic lesions previously described in both HGT1 and MIBC. Comprehensive profiling nominated additional mutated genes relevant to this rare subtype, such as ERBB3 and MCL1; however, these require clinical validation in larger clinical cohorts and experimental exploration to determine their relative contribution to the MC phenotype. Broadly, these results highlight the need for large scale genomic profiling of rare cancers to inform their genetic basis.
Adverse health outcomes (AHO) after modern cisplatin-based chemotherapy (CHEM) compared to surgery-only: A study of 503 testicular cancer survivors (TCS).
Authors: Nabil Adra, Clint Cary, Sandra K. Althouse, Patrick O. Monahan, Kelli Norton, Ryan Cook, Lawrence Einhorn, Lois B. Travis
Journal: Journal of Clinical Oncology (2018)

e22068 Background: Few studies comprehensively examine AHO in uniformly treated TCS after modern cisplatin-based CHEM compared to surgery-only (SURG). We evaluated AHO in an ongoing North American study of TCS given CHEM (NCI R01 CA157823) compared to TCS managed with SURG. Methods: 401 TCS > 1 year (yr) post CHEM and 102 TCS > 1 yr post SURG underwent physical examination and completed a questionnaire. Wilcoxon rank sum test compared median values of outcomes and chi-square tests compared categorical variables between the 2 groups. Results: Median age at diagnosis was 30 (range, 16-55) in CHEM and 34 (15-56) in SURG. Median time since CHEM was 4 yrs (1-35) and since SURG 4 yrs (1-31). Median number of AHO after CHEM was 2 (0-9), and after SURG 1 (0-11). After CHEM, 46% of TCS had ≥3 AHO compared with 12% after SURG. No AHO were observed in 14% and 36%, respectively. 11% and 8% TCS, respectively, had hypogonadism and were on testosterone therapy (P = 0.34). ED occurred in 16% and 8%, respectively (P= 0.05). For other AHO, the prevalence was significantly greater in the CHEM group. Conclusions: Although potentially curative, treatment with CHEM is associated with increased prevalence and number of AHO compared to SURG. Characteristic/AHO Treatment Regimen Chemotherapy (N = 401) Surgery-only (N = 102) P CHEM regimen, N (%) . N/A -Bleomycin, etoposide, cisplatin (BEP) 338 (84%) -Etoposide, cisplatin (EP) 23 (6%) -Etoposide, ifosfamide, cisplatin (VIP) 13 (3%) -Other 27 (7%) Cumulative cisplatin dose: median (range), mg/m2 300 (198-700) N/A No. AHO (%) . . . Median (range) 2 (0-9) 1 (0-11) < 0.001 0 57 (14%) 37 (36%) 1 82 (20%) 40 (39%) 2 80 (20%) 13 (13%) 3 58 (15%) 8 (8%) 4 47 (12%) 0 ≥5 77 (19%) 4 (4%) Tinnitus 169 (42%) 17 (17%) < 0.001 Hearing impairment 147 (37%) 12 ( 12%) < 0.001 Peripheral neuropathy 130 (32%) 4 (4%) < 0.001 Hypertension on prescription medication 58 (15%) 0 < 0.001 Cardiovascular disease 26 (7%) 1 (1%) 0.03 Raynaud phenomenon 88 (22%) 2 (2%) < 0.001 Problems with balance vertigo dizziness 50 (13%) 6 (6%) 0.04 Hypogonadism on testosterone therapy 44 (11%) 8 (8%) 0.34 Erectile dysfunction (ED) 62 (16%) 8 (8%) 0.05 Prescription medication for anxiety and or depression 39 (10%) 3 (3%) 0.03
OS4.6 Does radiation target volume affect health-related quality of life in patients with low grade glioma on the short-term? - a secondary analysis of the EORTC 22033–26033 trial
Authors: C Seidel, L Dirven, J C Rejneveld, C Coens, M J B Taphoorn, T Gorlia, T Tzuk-Shina, M Back, R Stupp, B Baumert
Journal: Neuro-Oncology (2018)

It is currently unknown whether increasing radiotherapy volumes have a negative impact on the health-related quality of life (HRQoL) of low-grade glioma (LGG) patients on the short-term. The aim of this study was to examine if the size of the target volume is independently associated with HRQoL. Patients treated with radiotherapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033–26033 study, and who completed a baseline HRQoL form, were included. This phase 3 trial of radiotherapy vs. temozolomide chemotherapy in high-risk LGG requiring treatment did not show a progression free survival difference. HRQoL was measured at baseline and every 3 months thereafter until progression, using the EORTC QLQ-C30 core questionnaire and QLQ-BN20 brain module. Associations between radiation volumes and (changes in) four preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue) were determined. Also, it was determined if radiation volumes were independently associated with a change in HRQoL over time. A total of 195 out of the 240 patients randomized to radiotherapy (81.3%) were included in this analysis. The brain volume receiving radiotherapy was not associated with (changes in) HRQoL during the first 24 months after radiotherapy. Over time, radiation volumes were also not independently associated with HRQoL. Although treatment with radiotherapy resulted in worse functioning, and more fatigue three months after treatment, pre-treatment levels were reached thereafter and maintained during further follow-up. Particularly the occurrence of tumour progression was found to be associated with clinically relevant worse social functioning (Beta: -13.7, 95% CI:-19.5 to -7.9), and more fatigue (Beta: 13.2, 95% CI:7.8–18.5) during 24 months follow-up. The volume of brain receiving focal radiotherapy does not seem to be an important determinant for the level of HRQoL in high-risk LGG patients on the short-term. From this point of view, safety margins do not need to be reconsidered. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.
Association of immune biomarkers with overall and disease-free survival in hepatocellular carcinoma.
Authors: Qiyun Ou, Yunfang Yu, Xiaolin Xu, Wenda Zhang, Taige Wu, Tuping Fu, Quanlong Gao, Baoming Luo
Journal: Journal of Clinical Oncology (2018)

e16129 Background: The role of immune biomarkers in predicting benefits of hepatocellular carcinoma (HCC) was still controversial. We was aimed to investigate the prognostic value of immune biomarkers in patients with HCC. Methods: We identify relevant studies that investigated the association of immune biomarkers with survival in HCC until February 2018. Overall survival (OS) and disease-free survival (DFS) were calculated hazard ratios (HRs) using random-effects model. The PROSPERO registry number is CRD42018083994. Results: 27 studies comprising 5,408 patients were entitled. Pooled analysis shows that high levels of CD8+ tumor-infiltrating lymphocytes (TILs) had a good prognostic effect on DFS (HR 0.33, 95% confidence interval [CI] 0.17 to 0.67) and OS (HR 0.34, 95% CI 0.20 to 0.58). By contrast, high levels of FoxP3+ regulatory TILs had a worse prognostic effect for DFS (HR 1.67, 95% CI 1.28 to 2.18) and OS (HR 2.07, 95% CI 1.41 to 3.03). High levels of tumor-infiltrating neutrophils (TINs) had a worse prognostic effect, with HRs of 2.33 (95% CI 1.46 to 3.71) and 3.04 (95% CI 1.75 to 5.26) for DFS and OS, respectively. There was no significant predictive association of survival in tumor-infiltrating macrophages (TAMs) (DFS, HR 1.25, 95% CI, 0.82 to 1.89; OS, HR 1.11, 95% CI, 0.76 to 1.62), programmed death-ligand 1 (DFS, HR 1.16, 95% CI 0.54 to 2.49; OS, HR 0.99, 95% CI, 0.55 to 1.80), and programmed death-ligand 2 (DFS, HR 1.14, 95% CI 0.78 to 1.65; OS, HR 1.42, 95% CI 0.81 to 2.48). Conclusions: The present results provided an evidence that reveal CD8+, FoxP3+ regulatory TILs and TINs as predictors of survival in HCC patients, which may represent a novel mechanism that links the response to immune therapy in the tumor milieu.
Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: A cost-effective analysis compared with conventional chemotherapy.
Authors: Bin Wu, Te Li, Yuejuan Xu, Gang Zhao
Journal: Journal of Clinical Oncology (2017)

e15531 Background: Apatinib can improve survival in patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy. Apatinib Patient Assistance Program (PAP) is implemented for Chinese patients. A cost-effective analysis is needed for apatinib with PAP. Methods: A Markov model was developed to simulate the clinical course of typical patients with chemotherapy-refractory mGC. We estimated 10-year quality-adjusted life-years (QALY), costs, and incremental cost-effectiveness ratios (ICER). The Clinical efficacy and safety were derived from the pivotal phase II and III trials of apatinib. Direct costs were estimated from the perspective of Chinese health care system. One-way and probabilistic sensitivity analyses were conducted. Scenario analysis for Patient Assistance Program (PAP) was checked. Results: Baseline analysis showed that the apatinib increased the cost and QALYs by $7,859 and 0.191, respectively, relative to conventional chemotherapy, resulting in an ICER of $40,997/QALY gained. The ICER was $21,132/QALY when 3+X PAP (paying for 3 months following free donation until disease progressed) was available. Probabilistic sensitivity analyses confirmed that apatinib with 3+X PAP achieved nearly two 2/3 likelihood of cost-effectiveness under the Chinese willingness-to-pay threshold of $ 22,200 per QALY gained. One-way sensitivity analyses found that the utility of progression-free survival was the most influential factor with respect to the robustness of the model. Budget impact analysis estimated that the annual increase in fiscal expenditures would be approximately 0.45 million dollars. Conclusions: Our analysis suggests that apatinib is likely to be cost-effective in patients with chemotherapy-refractory mGC when 3+X PAP is available.