tbuckley/cabot-search huggingface dataset:
A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with <i>RET</i>-altered cancers.
Authors: Alexander E. Drilon, Vivek Subbiah, Geoffrey R. Oxnard, Todd Michael Bauer, Vamsidhar Velcheti, Nehal J. Lakhani, Benjamin Besse, Keunchil Park, Jyoti D. Patel, Maria E. Cabanillas, Melissa Lynne Johnson, Karen L. Reckamp, Valentina Boni, Herbert H. F. Loong, Martin Schlumberger, Ben Solomon, Scott Cruickshank, Stephen M. Rothenberg, Manisha H. Shah, Lori J. Wirth
Journal: Journal of Clinical Oncology (2018)

102 Background: Multikinase inhibitors (MKIs) have limited activity in RET fusion-positive (+) and RET-mutant cancers, questioning the therapeutic potential of these targets. LOXO-292 selectively targets RET and has preclinical activity against activating RET fusions/mutations, potential resistance mutations, and brain metastases. Methods: This global phase 1 study for patients (pts) w/ advanced solid tumors included RET fusion+ NSCLC and papillary thyroid cancer (PTC), RET-mutant medullary thyroid cancer (MTC), and any other cancer w/ these alterations. Pts were dosed orally in 28-day cycles. Dose escalation followed a 3+3 design. The primary endpoint was MTD determination. Secondary endpoints included safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Results: As of 05-Jan-18, 57 pts were treated at 7 doses (20 mg QD→160 mg BID), including 35 RET fusion+ tumors (27 NSCLC, 7 PTC, 1 pancreatic) and 20 RET-mutant MTCs. 67% were MKI pre-treated (median 1, range 1-4; included pts w/ acquired MKI resistance). No DLTs were observed. The MTD was not reached. AEs (≥10% of pts) were fatigue (16%), diarrhea (16%) and dyspnea (12%); most were grade 1-2. No AEs ≥ grade 3 were attributed to LOXO-292. The ORR in evaluable RET fusion+ pts was 69% (95% CI 50%-84%, n = 22/32, 11 pending confirmation, 9/13 MKI-naïve,13/19 MKI pretreated): 65% (n = 17/26) in NSCLC and 83% (n = 5/6) in PTC. 84% (27/32) had radiographic tumor reduction (range -19% to -67%). NSCLC responses occurred independent of upstream partner when known (9/13 KIF5B vs 7/9 non-KIF5B) and included 3 pts w/ baseline brain metastases. Tumor reduction was achieved in 79% of MTC pts (n = 11/14 evaluable, range -9% to -45%), including 2 PRs, 1 in a patient w/ a hereditary RET V804M gatekeeper mutation treated w/ 3 prior MKIs. 79% (n = 11/14) of MTCs had a ≥50% decrease in serum calcitonin (for ≥4 weeks). Most pts (n = 52/57) remained on treatment. The median DoR was not reached (all responses ongoing, longest > 6 months). Conclusions: LOXO-292 was well-tolerated and had marked antitumor activity in pts w/ RET-altered cancers, including those w/ resistance to prior MKIs and brain metastases. Rapid development w/ registrational intent is planned. Clinical trial information: NCT03157128.
Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer
Authors: Kirsten K. Ness, James L. Kirkland, Maria Monica Gramatges, Zhaoming Wang, Mondira Kundu, Kelly McCastlain, Xiujie Li-Harms, Jinghui Zhang, Tamar Tchkonia, Saskia Martine Francesca Pluijm, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2018)

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.
Material and behavioral financial hardship as predictors of health-related quality of life in a diverse cohort of cancer survivors.
Authors: Theresa A. Hastert, Felicity W. K. Harper, Jennifer Lynn Beebe-Dimmer, Tara Baird, Ann G. Schwartz
Journal: Journal of Clinical Oncology (2018)

145 Background: Financial hardship is common among cancer survivors, but its association with health-related quality of life (HRQOL) unknown. Methods: We utilized data from 570 black participants the Detroit Research on Cancer Survivors (ROCS) cohort study diagnosed with breast, colorectal, lung or prostate cancer since 1/1/13 and diagnosed or treated at the Karmanos Cancer Institute, and 402 white survivors meeting the same criteria. HRQOL was measured using the functional assessment of cancer therapy-general (FACT-G) and its subscales of physical, social, emotional and functional wellbeing, and site-specific measures. We fit linear regressions to estimate associations between material (debt, borrowing, selling assets, reduced income) and behavioral (skipping medication, not seeing a doctor, refusing treatment due to cost) financial hardship (MFH and BFH, respectively) and HRQOL. Adjusted models include demographic, socioeconomic, and treatment-related factors. Results: Overall, 50.3% of participants experienced material and 17.6% experienced behavioral financial hardship. In unadjusted models, HRQOL scores were 0.39 (95% CI 0.27, 0.51) standard deviations (SD) lower in those reporting any MFH. MFH was associated with significantly lower physical, emotional, and functional wellbeing scores, and with lower scores on breast-, colorectal-, and prostate-specific HRQOL measures. Total HRQOL was 0.68 SD (95% CI 0.52, 0.84) lower for participants who reported BFH than those who did not, and BFH was inversely associated with each subscale and each cancer-specific measure. In adjusted models, HRQOL scores were 0.15 (95% CI 0.03, 0.27) SD lower among participants reporting MFH and remained inversely associated with physical and functional wellbeing. BFH was associated with 0.42 (95% CI 0.27, 0.57) SD lower HRQOL scores and remained inversely associated with physical, social, emotional, and functional wellbeing; and with breast- and prostate-specific measures. Conclusions: MFH and BFH are associated with lower HRQOL among diverse cancer survivors. Addressing BFH in particular may improve HRQOL among survivors, particularly those with breast and prostate cancer.
Should we consider changing traditional physiotherapy treatment of patellofemoral pain based on recent insights from the literature?
Authors: Christian J Barton, Kay M Crossley, Erin M Macri
Journal: British Journal of Sports Medicine (2018)

The 2016 international patellofemoral pain (PFP) consensus statement1 suggested exercise therapy targeting the hip and knee, combined interventions and prefabricated foot orthoses can be used to improve pain and function in people with PFP. These recommendations are based on strong foundations including synthesis of multiple high-quality systematic reviews combined with voting from the International Patellofemoral Research Network group.

A recent prognostic paper indicated that nearly 50% of people with PFP are likely to benefit from traditional physiotherapy in the longer term.2 However, 57% report unfavourable outcomes 5–8 years after being enrolled in a traditional physiotherapy clinical trial, indicating a need for alternative approaches in these individuals.2 

Importantly, patient outcomes may be improved by providing interventions tailored to their needs. Efforts are under way to optimise subgrouping of patients in order to target traditional physiotherapy interventions. The purpose of this Editorial is a ‘call to action’ for researchers and clinicians (see box 1) to also consider exploring, incorporating and tailoring non-traditional physiotherapy interventions to optimise patient outcomes. Based on recent insights contained within two systematic reviews and one randomised clinical trial published in the British Journal of Sports Medicine , this may include weight management, addressing psychological factors …
Protein‐coding genes combined with long noncoding RNA as a novel transcriptome molecular staging model to predict the survival of patients with esophageal squamous cell carcinoma
Authors: Jin‐Cheng Guo, Yang Wu, Yang Chen, Feng Pan, Zhi‐Yong Wu, Jia‐Sheng Zhang, Jian‐Yi Wu, Xiu‐E Xu, Jian‐Mei Zhao, En‐Min Li, Yi Zhao, Li‐Yan Xu
Journal: Cancer Communications (2018)

Abstract Background Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal carcinoma in China. This study was to develop a staging model to predict outcomes of patients with ESCC. Methods Using Cox regression analysis, principal component analysis (PCA), partitioning clustering, Kaplan–Meier analysis, receiver operating characteristic (ROC) curve analysis, and classification and regression tree (CART) analysis, we mined the Gene Expression Omnibus database to determine the expression profiles of genes in 179 patients with ESCC from GSE63624 and GSE63622 dataset. Results Univariate cox regression analysis of the GSE63624 dataset revealed that 2404 protein‐coding genes (PCGs) and 635 long non‐coding RNAs (lncRNAs) were associated with the survival of patients with ESCC. PCA categorized these PCGs and lncRNAs into three principal components (PCs), which were used to cluster the patients into three groups. ROC analysis demonstrated that the predictive ability of PCG‐lncRNA PCs when applied to new patients was better than that of the tumor‐node‐metastasis staging (area under ROC curve [AUC]: 0.69 vs. 0.65, P &lt; 0.05). Accordingly, we constructed a molecular disaggregated model comprising one lncRNA and two PCGs, which we designated as the LSB staging model using CART analysis in the GSE63624 dataset. This LSB staging model classified the GSE63622 dataset of patients into three different groups, and its effectiveness was validated by analysis of another cohort of 105 patients. Conclusions The LSB staging model has clinical significance for the prognosis prediction of patients with ESCC and may serve as a three‐gene staging microarray.
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
Authors: Daniela S. Thommen, Viktor H. Koelzer, Petra Herzig, Andreas Roller, Marcel Trefny, Sarah Dimeloe, Anna Kiialainen, Jonathan Hanhart, Catherine Schill, Christoph Hess, Spasenija Savic Prince, Mark Wiese, Didier Lardinois, Ping-Chih Ho, Christian Klein, Vaios Karanikas, Kirsten D. Mertz, Ton N. Schumacher, Alfred Zippelius
Journal: Nature Medicine (2018)
Abstract 19359: Inhibition of miR-146a Attenuates Neointima Formation
Authors: Daniel Sedding, Laura Korte, Rebecca Teske, Katrin Donde, Johann Bauersachs
Journal: Circulation (2016)

Introduction:  Drug-eluting stents are used to prevent in-stent-restenosis. However, anti-proliferative agents delivered lack cell specificity and also impair reendothelialization. Micro RNAs are promising therapeutical targets as they exhibit diverse and distinct cell specific functions and can be effectively attacked  in vivo .   Hypothesis:  Here, we propose miR-146a as a putative target beneficial for the treatment of noontima formation following vascular injury.   Methods and Results:  Micoarray analysis revealed a significant upregulation of miR-146a upon wire-induced injury in C57BL6/N mice. The inhibition of miR-146a  in vitro  led to opposing effects in endothelial (EC) and vascular smooth muscle cells (VSMC). EC proliferation and migration was induced, whereas VSMC proliferation and migration were reduced significantly. Vasorin, a transmembrane protein, mainly expressed in VSMC, was verified as a direct target mRNA of miR-146a as shown by qRT-PCR, Western Blot analysis and luciferase assays. Continually,  vasorin  mRNA was shown to be downregulated upon wire-induced injury  in vivo . In a subsequent  in vivo  study, a miR-146a inhibitor was applied locally in a self-degrading pluronic gel after wire-induced injury. Ablation of miR-146a led to the reduction of neointimal hyperplasia in mice 21 days after injury (Neointima/Media Ratio 2.84 in control vs 1.72 in treated animals p   Conclusions:  This study reports an essential role of miR-146a during vascular remodeling. Inhibition of miR-146a is sufficient to improve the outcome upon wire-induced injury by preventing SMC proliferation while supporting EC regeneration. Thus, miR-146a represents a novel promising target to treat and prevent post-angioplasty restenosis.
TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial.
Authors: Shaveta Vinayak, Sara M. Tolaney, Lee Steven Schwartzberg, Monica M. Mita, Georgia Anne-Lee McCann, Antoinette R. Tan, Andrea Elisabeth Wahner Hendrickson, Andres Forero-Torres, Carey K. Anders, Gerburg M. Wulf, Patrick M Dillon, Filipa Lynce, Corrine Zarwan, John Kalil Erban, Bruce Jeffrey Dezube, Yinghui Zhou, Nathan Buerstatte, Sujata Arora, Haroun Achour, Melinda L. Telli
Journal: Journal of Clinical Oncology (2018)

1011 Background: Chemotherapy is a standard of care for TNBC despite its suboptimal efficacy. ≈15–20% of TNBC have BRCA1/2 mutations (mut); ≈75% of BRCA1 mut BCs are TN. Single agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical activity in pts with BRCA1/2 mutations (BRCAmut) BC and provide median PFS of 6 mos in pts with BRCAmut TNBC vs 3.5 mos for chemotherapy. Single-agent pembrolizumab (pembro), a programmed death 1(PD–1) inhibitor, has shown objective response rates (ORR) of 5–18% in previously treated TNBC. TOPACIO (NCT02657889) is a fully enrolled study evaluating the safety and efficacy of combination treatment with selective PARP1/2 inhibitor niraparib + pembro in pts with met TNBC. Methods: Pts received niraparib 200 mg orally once daily + pembro 200 mg IV on day 1 of each 21-day cycle. Primary efficacy endpoint was ORR and secondary endpoints included disease control rate (DCR = CR+PR+SD [stable disease]). Results: As of Jan 2018, 12 of 54 enrolled TNBC pts (22%) had deleterious BRCAmut; 9 (17%) not tested/indeterminate results. Median age was 54 yrs, with median of 1 prior line of therapy in the met setting (range 0–3); 22 (41%) had received prior platinum in the met setting; 39 (72%) had received prior (neo)adjuvant therapy. Forty-five pts were evaluable, with ≥1 on-study scan. To date, ORR is 29% and DCR is 49%, including 3 CR (7%), 10 PR (22%), 9 SD (20%), and 23 progressive disease (PD) (51%). Ten of 13 responders have ongoing responses; 13 pts have received > 6 mos of treatment (6 BRCAmut, 5 BRCAwt, 2 BRCAunk); 11 pts remain on treatment. The 12 BRCAmut pts were 1 CR, 7 PR, 1 SD and 3 PD. Median PFS in BRCAmut group is 8.1 mos (95% CI 0.2–NE). ORR (any BRCA status) was 33% in PD-L1-pos (combined proportion score ≥1%) vs 15% in PD-L1-neg pts. Treatment-related grade ≥3 AEs occurred in 27 pts (50%); most common were thrombocytopenia (13%) & anemia (11%). Follow-up is ongoing. Conclusions: Preliminary activity is encouraging with durable responses observed irrespective of BRCA1/2 or PD-L1 status or prior platinum exposure with the highest ORR in BRCAmut pts. No new safety signals were identified with the combination. Clinical trial information: NCT02657889. ORR DCR TNBC overall, n = 45 29% 49% TNBC BRCAmut, n = 12 67% 75%
MiCEE is a ncRNA-protein complex that mediates epigenetic silencing and nucleolar organization
Authors: Indrabahadur Singh, Adriana Contreras, Julio Cordero, Karla Rubio, Stephanie Dobersch, Stefan Günther, Sylvia Jeratsch, Aditi Mehta, Marcus Krüger, Johannes Graumann, Werner Seeger, Gergana Dobreva, Thomas Braun, Guillermo Barreto
Journal: Nature Genetics (2018)
Lung cancer and benign lung diseases in patients with serious vitamin D deficiency in eastern China.
Authors: Rong Li, Jing Wu, Liwen Xiong, Baohui Han
Journal: Journal of Clinical Oncology (2012)

e12010 Background: Vitamin D deficiency is a global problem. Methods: We estimated the 25-hydroxyvitamin D (25(OH)D) concentrations to confirm whether patients with lung diseases in eastern China showed vitamin D deficiency and whether this deficiency was related to the risk of lung cancer.We used chemiluminescence to estimate the 25(OH)D concentrations in 250 patients from eastern China, of whom 197 had untreated stage III/IV lung cancer and 53 had benign lung diseases. Results: The mean serum 25(OH)D concentration of patients with lung cancer was 10.63 ± 7.04 ng/mL and that of patients with benign lung disease was 9.62 ± 6.37 ng/mL. Although there was no significant difference between the values, the mean serum concentrations of 25(OH)D obtained in patients with lung cancer and benign lung diseases were lower than the normal value (&gt;20 ng/mL); p values in both cases were less than 0.0001. Among the 250 patients, 90 showed low serum 25(OH)D levels of ≤ 4 ng/mL. Conclusions: Patients with lung diseases in eastern China show low serum levels of 25(OH)D, and the average serum 25(OH)D level is much below the normal vitamin D level. Presently it cannot be concluded whether the low levels of 25(OH)D is a risk factor for lung cancer, because the average serum 25(OH)D levels in patients with lung cancer or benign lung diseases are very low.
Predicting neo-adjuvant chemotherapy response from pre-treatment breast MRI using machine learning and HER2 status.
Authors: Nathaniel Braman, Kavya Ravichandran, Andrew Janowczyk, Jame Abraham, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

582 Background: Many breast cancer patients receiving neo-adjuvant chemotherapy (NAC) will ultimately fail to achieve pathological complete response (pCR). A pre-treatment clinical marker of pCR could guide NAC without requiring potentially ineffective initial treatment periods. Advances in medical image analysis, such as deep learning (pattern recognition using neural networks) and radiomics (computer-extracted quantitative image features), demonstrate significant potential for non-invasive assessment of NAC outcome. We present a machine learning (ML) approach for pre-NAC response prediction fusing deep learning, radiomics, and clinical variables. Methods: 166 patients with pre-treatment contrast-enhanced MRI from the ISPY1-TRIAL and surgically-confirmed NAC response outcome (ypT0N0, 49 pCR, 117 non-pCR) following anthracycline-cyclophosphamide chemotherapy with or without taxane were retrospectively analyzed. Patients were divided randomly into training (n = 133) and testing (n = 33) cohorts, with proportionate distribution of pCR between cohorts. Multinomial logistic regression integrated DL, radiomics, and HER2 status was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, and specificity within the testing set. Deep learning: A six-layer convolutional neural network was trained to predict response using 65 pixel square patches centered within a tumor. Radiomics: From a pool of 215 radiomic intra-tumoral heterogeneity features, the 8 best-performing features were identified algorithmically and used to train a linear discriminant analysis classifier within the training set. Results: A ML only approach strongly predicted response (AUC = .84) in the testing set. Integrating clinical HER2 status into the combined imaging model yielded optimal pre-treatment response prediction (AUC = .93), with 75% sensitivity and 92% specificity. Conclusions: Further validation of an approach fusing deep learning, radiomic analysis, and clinical information could potentially provide a means of pre-NAC response prediction from MRI. AUC Sensitivity Specificity HER2 Status .69 63% 76% ML only .84 63% 84% ML+HER2 Status .93 75% 92%
Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial.
Authors: Aleksei Manikhas, Eduardo J. Pennella, Igor Bondarenko, Guzel Mukhametshina, Maria Luisa T. Abesamis-Tiambeng, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Sirshendu Ray, Cornelius F. Waller, Miguel Hernandez Bronchud, Jay Herson, Subramanian Loganathan, Abhijit Barve, Hope S. Rugo
Journal: Journal of Clinical Oncology (2018)

110 Background: The Heritage trial is a multicenter, double-blind, randomized, parallel-group, phase 3 study (NCT02472964) evaluating efficacy and safety of trastuzumab-dkst (Ogivri), a trastuzumab biosimilar, vs trastuzumab, in combination with taxane as first-line therapy for patients with HER2+ metastatic breast cancer. The primary endpoint, overall response rate on combination therapy at week 24, was previously reported (Rugo et al, JAMA 2017). Methods: Eligible patients were randomized 1:1 to trastuzumab-dkst or trastuzumab, combined with taxane. After 24 weeks, patients with responding or stable disease received monotherapy as per randomization. Here, we describe secondary endpoints of safety and immunogenicity during monotherapy and cumulative through 48 weeks; progression-free survival (PFS) and event-based overall survival (OS) will be presented in the future. Results: 500 patients were randomized, 342 continued treatment after 24 weeks, and 214 continued through 48 weeks. Treatment-emergent adverse event (TEAE) rates during monotherapy were similar (trastuzumab-dkst, 54.7%; trastuzumab, 60.1%); most were low grade. Grade ≥3 TEAEs were more frequent with trastuzumab (11.7%) vs trastuzumab-dkst (6.7%); serious TEAE rates were similar (trastuzumab-dkst, 2.8%; trastuzumab, 2.5%). When assessed over 48 weeks of combination and monotherapy, cumulative rates of TEAEs of special interest were similar for pulmonary events, significant cardiac disorders, and infusion-related events (trastuzumab-dkst, 13.0%, 4.9%, and 9.3%; trastuzumab, 12.2%, 4.1%, and 8.1%, respectively). Immunogenicity and incidence of left ventricular ejection fraction < 50% ≥1 time postbaseline and ≥10% reduction at week 48 were similar between groups (trastuzumab-dkst, 3.9% and 3.6%; trastuzumab, 4.4% and 2.8%, respectively). No new safety signals were detected. At week 48, median PFS was 11.1 months in both groups and OS curves were similar. Conclusions: Maintenance monotherapy with FDA-approved trastuzumab-dkst after combination with taxane was well tolerated, with safety and efficacy profiles similar to originator trastuzumab. Clinical trial information: NCT02472964.
GP is struck off for wrongly charging patients and lying to colleagues
Authors: Clare Dyer
Journal: BMJ (2018)

A medical practitioners tribunal has struck off a GP who it found had told a litany of lies to colleagues, employers, and appraisers and had improperly charged patients for treatment, pocketing the money.

Sri Subramaniam was referred to the General Medical Council by NHS England after an Australian patient who had attended an out-of-hours clinic in Oxford complained that the doctor had failed to examine him properly. The patient produced a handwritten receipt and said that Subramaniam had charged him £80 (€90; $105) cash, the money he had on him, after telling him he was not eligible for free NHS treatment. The patient had not intended to complain about the payment, not having realised it was improper.

NHS England began investigating Subramaniam and notified the …