tbuckley/cabot-search huggingface dataset:
Treatment of laryngeal cancer: The University of Michigan experience.
Authors: Francis P. Worden, Emily Light Bellile, Susan Urba, Carol Rossier Bradford, Avraham Eisbruch, Thomas E Carey, Jeremy MG Taylor, Ted Teknos, Douglas Chepeha, Gregory T. Wolf
Journal: Journal of Clinical Oncology (2016)

6073 Background: Previous success of Phase II trials from 1995- 2005, led us to develop personalized treatment selection based on tumor & patient (pt) characteristics using neoadjuvant bioselection—1 cycle of chemotherapy (NB) to select pts with stage III/IV cancer for laryngectomy (L) or chemoradiation (CRT). Methods: From 2002-2012, 247 previously untreated laryngeal cancer pts were treated. Treatment of 95 early disease (Stage I/II) pts included endoscopic resection (35%), RT alone (53%) or CRT for deeply invasive T2 lesions (12%). Of 152 pts with stage III/IV disease, NB was utilized in 71(47%) & CRT in 49 (32%) pts refusing NB. Primary L was recommended for severely compromised larynx in 26 (21%) or candidates for supraglottic L (n = 6). Propensity of treatment approach for advanced disease pts was modeled using logistic regression modeling & overall (OS) & disease specific survival (DSS) were analyzed with Cox proportional hazards models stratified by propensity score. Median follow up: 48 months.Results: Estimated 5 yr OS & DSS was 75% (95% C.I. 68-81%) & 83% (70-85%), respectively for the entire cohort. DSS was 91% (81-96%) for pts with Stage I/II & 78% (70-85%) for pts with stage III/IV disease. OS did not differ for stage I/II vs III/IV pts (p = 0.24). For 152 advanced disease pts, 5 year OS (& DSS) ranged from 78% (78%) for primary L to 76% (79%) for NB and 63% (68%) for primary CRT. Larynx preservation was 77% for primary CRT & 66% for the NB group. A propensity-stratified Cox proportional hazards model controlling for known prognostic factors showed NB was associated with a 0.33 hazard reduction [95% C.I., 0.13,0.89], (p = .03); current smoking & stage IV disease were associated with increased hazard in the multivariable model. Among non-NB pts, the multivariable propensity-stratified model showed surgical treatment was associated with significantly reduced hazard (0.09 [0.02, 0.51] p = 0.007)—trends for worse prognosis in older & stage IV pts. Conclusions: Our results confirm high long-term survival rates for an individualized treatment approach, particularly for Stage III/IV pts with NB. Future challenges include improving outcomes for pts with T2 cancers, decreasing rates of salvage L in pts with advanced disease & identifying predictive biomarkers.
Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1‐receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction
Authors: Adriaan A. Voors, Sanjiv J. Shah, Jeroen J. Bax, Javed Butler, Mihai Gheorghiade, Adrian F. Hernandez, Dalane W. Kitzman, John J.V. McMurray, Antonieta Bomfim Wirtz, Vivian Lanius, Michael van der Laan, Scott D. Solomon
Journal: European Journal of Heart Failure (2018)
LMTK3 to regulate the translation of oncogenic KIT in GIST regardless of imatinib sensitivity.
Authors: Lillian Rose Klug, Amber Bannon, Nathalie Javidi-Sharifi, Ajia Town, William H Fleming, Judy VanSlyke, Linda Musil, Jonathan A. Fletcher, Jeffrey Tyner, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2018)

11535 Background: The majority of gastrointestinal stromal tumors (GIST) have been shown to be caused by somatic activating mutations in the receptor tyrosine kinase KIT. The major cause of death in patients with advanced KIT-mutant GIST is due to the development of KIT tyrosine kinase inhibitor-resistant (TKI-resistant) metastatic disease. Drug resistance arises almost exclusively from secondary mutations within KIT, highlighting the importance of KIT in the proliferation and survival of these tumors. Methods: We performed a human kinase siRNA screen in multiple KIT-mutant cancer cell lines, using viability as a read out. We defined candidate targets as those whose knockdown decreased viability in all cell lines. Validation and mechanistic studies were done using a library of KIT-mutant GIST cells. Results: We identified lemur tyrosine kinase 3 (LMTK3) as candidate target in three KIT-mutant cell lines. LMTK3 silencing reduced the viability of all KIT-mutant GIST cells tested to date, including cell lines with KIT TKI-resistance mutations. Importantly, LMTK3 silencing decreased the viability of KIT-mutant cells specifically, but not that of KIT-independent cells. LMTK3 knockdown also reduced tumor growth in vivo in a GIST xenograft model. Further, we found that decreased cell viability after LMTK3 silencing was due to induction of apoptosis. Because these cells depend so heavily on KIT and the loss of KIT signaling results in cell death, we hypothesized that LMTK3 silencing may affect this pathway. Indeed, LMTK3 silencing decreased total KIT protein across all cell lines. The reduction in KIT protein was not the result of changes in KIT transcript or KIT protein stability, but translation rate of KIT was significantly reduced after LMTK3 knockdown. Conclusions: The protein kinase LMTK3 is an important translational regulator of oncogenic KIT expression in KIT-mutant GIST regardless of drug sensitivity and represents a novel, tractable target, particularly in drug-resistant tumors.
A case series of sarcoma brain metastases (SBM): A single-institution experience.
Authors: Melissa Amber Burgess, Michael Nathenson, Pashtoon Murtaza Kasi, Lana Khalil, Mitchell Ross, Hussein Abdul-Hassan Tawbi
Journal: Journal of Clinical Oncology (2016)

e22536 Background: Brain metastasis, although a common and severe complication in patients with systemic cancer, is considered a rare manifestation in sarcoma (3% of all brain metastases). Due to newer chemo- and radiotherapeutic treatments that prolong survival through systemic disease control without effective intracranial control, there is increasing evidence that the incidence of SBMs will increase. To date, literature regarding SBMs is limited to case reports and case series reporting 1.9% incidence in adults with sarcoma and 4% in pediatric patients. In this review, we seek to characterize the incidence, treatments, and prognosis of bone and soft tissue SBMs. Methods: From 2008-2014, sarcoma patients with brain metastases treated at the University of Pittsburgh Medical Center (UPMC) were identified. Results: Of 905 new sarcoma patients evaluated at UPMC, a total of 20 patients were identified with brain metastases, 2.2% (10 women and 10 men; aged 20 to 66). Among them, 4 were leiomyosarcoma, 4 undifferentiated pleomorphic sarcoma, 2 liposarcoma, 2 Ewing’s sarcoma, 2 osteosarcoma, 1 alveolar soft part sarcoma, and 5 other. Stereotactic radiosurgery (SRS) alone was the most common treatment modality (45%) and 35% of patients were treated with combination modalities (whole brain radiation, SRS, and/or surgery). 80% of patients had concurrent pulmonary metastases (16/20) and the majority were treated by stereotactic radiosurgery (12/20) (60%). Median overall survival was 20 months. Median survival from the time of SBM was 5 months. One patient is still alive. Conclusions: Brain metastasis is a rare outcome of sarcoma accompanied by very poor prognosis. The increased incidence at UPMC may be related to higher prevalence, or perhaps could portend a more aggressive biological behavior in certain sarcoma subtypes. Similarly to reported literature, patients with SBM at UPMC lived longer and presented with SBM late in their disease course. Routine screening is not an implemented procedure for these patients, yet the increasing incidence of SBM mandates special attention since earlier detection may affect treatment strategies and ultimately prolonged survival, as well as, potential impact on management of brain metastasis in the future.
Pediatric Computed Tomography Scans and Cancer Risk
Authors: Mohan Doss
Journal: JAMA Pediatrics (2018)

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Abstract 15137: Association of Congenital Heart Defects With Childhood Cancer in Privately Insured US Children: A Rapid Claims Analysis
Authors: Matthew Oster, April Dawson, Cynthia Wetmore, Scott Grosse
Journal: Circulation (2016)

Background: As treatment for congenital heart defects (CHDs) has improved, understanding the long-term outcomes of survivors has become important. Recent studies have focused on the risk of adult-onset cancer in CHD survivors, but little is known about the incidence of childhood cancer in this population. Our objective was to determine the association of CHDs with childhood cancer using a nationwide administrative healthcare database of more than 100 million Americans. Methods: Using the Treatment Pathways online analytic interface to access the Truven Health MarketScan® research databases, we examined the presence of ICD-9 diagnosis codes for neoplasm during 2009-2015 among 6.1 million children <18 years of age not coded for Down syndrome, continuously enrolled in employer-sponsored plans during 2014. To avoid overestimating the risk of cancer in CHD survivors, only those children with ≥1 CHD code during 2009-2014 ≥30 days prior to the first neoplasm code were considered to be CHD survivors with cancer. ...
Clinical outcomes of advanced small cell lung cancer patients (SCLC pts) on phase I (Ph I) trials in the Drug Development Unit (DDU) at the Royal Marsden Hospital (RMH).
Authors: Samuel John Harris, Brent O'Carrigan, Juanita Suzanne Lopez, Jaishree Bhosle, Udai Banerji, Sanjay Popat, Johann S. De Bono, Mary E.R. O'Brien, Timothy Anthony Yap
Journal: Journal of Clinical Oncology (2016)

e14048 Background: SCLC has a poor median survival of 2-5 months in pts with relapsed or refractory disease. Such pts are often referred to Ph I trial units for consideration of novel antitumor therapies. However, outcomes of advanced SCLC pts treated with such experimental agents are unknown. Methods: Retrospective study of SCLC pts referred for Ph I trials at DDU in (2002-15). Endpoints included enrolment and response rates, time to progression (TTP) and overall survival (OS). Baseline pt factors included the RMH score (albumin < 35 g/L, lactate dehydrogenase > upper limit of normal and > 2 metastatic sites) which predicts 90-day mortality to identify suitable pts for ph I trials. Results: 62 pts (M/F 36/26; median age 61y) were identified. 35/62 (57%) pts were allocated to a ph I trial, with 20/35 (57%) entering study. Pts with ECOG PS 2-3 were less likely to be allocated to study (p = 0.002). Clinical deterioration was the most common reason for failure to enter a trial after allocation. All pts had ≥ 1 prior lines of therapy, with 41 pts ≥ 2 and 18 pts ≥ 3. Females (p = 0.02), RMH score 0,1 (p = 0.02), ECOG 0,1 (p = 0.01) pts were more likely to enter trial. Pts were treated with inhibitors against PARP (n = 9), PI3K-AKT pathway (n = 4), BCL (n = 2), PIM, IGF and PD-1 (all n = 1), and dolastatin analogues (n = 2). Grade 1 nausea was the most common toxicity (7/19 pts). No DLTs were observed, with only one grade 3 toxicity (vomiting). Median OS was higher for pts entering a ph I trial versus pts who did not, 20.5weeks (w) vs 10.6w (p = 0.002, HR 0.43, 95%CI 0.25-0.74). Pts on trial had a median TTP of 6.4w. First line platinum (plt) sensitivity (progressive disease ≥ 6m after treatment) and RMH score were predictive for TTP on trial: plt sensitive 17w vs plt resistant 3.5w, p = 0.004; RMH score 0-1 = 10.9w vs RMH score 2-3 = 3.1w (p = 0.04). 2/19 (10.5%) evaluable pts had RECIST partial response (PARP inhibitor and PD-1 inhibitor), 5/19 (26%) pts had best response of RECIST stable disease, for clinical benefit rate of 37%. Conclusions: Ph I trials are well tolerated with antitumour activity in selected SCLC pts. Ph I trials should be considered for advanced SCLC pts, using the RMH score and plt sensitivity as selection tools.
Response to induction or hypomethylating agent therapy among patients with myeloproliferative neoplasms progressing to accelerated or leukemic phase.
Authors: Gabriela Hobbs, Jennifer Lombardi Story, Maura A. Blaney, Philip C. Amrein, Amir Tahmasb Fathi, Andrew Mark Brunner
Journal: Journal of Clinical Oncology (2017)

e18561 Background: Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) and accelerated phase disease (AP) are associated with poor outcomes; the optimal management of these patients at transformation is uncertain in the era of widely available molecular testing. Methods: We performed a retrospective analysis of adult patients with MPN that had transformed into AML (greater than 20% blasts) or AP (10-19% blasts and dysplastic features) from 2006-2016. Patients were 18 or older at AML/AP diagnosis. Outcomes were described by Kaplan and Meier and the Log rank test. Results: We identified 30 patients, with transformed MPN into AML (n = 23) or AP (n = 7), including one patient in AP at presentation. Most were male (73%). Disease evolved from polycythemia vera (n = 6), essential thrombocythemia (n = 11), primary myelofibrosis (n = 9) and other MPN diagnoses (MPN/MDS overlap, n = 3; MPN NOS, n = 1). The median age at MPN diagnosis was 67.5 yrs, and at transformation 72 yrs. The median time from MPN diagnosis to transformation was 5.6 yrs (range 0.3-36.0). 12 patients had JAK2 V617F testing both at MPN diagnosis and AML diagnosis; 6 had JAK2 mutations at both time points and 2 lost JAK2 at transformation. At AML/AP transformation, 11 patients had NGS mutation testing; the most common somatic mutations were NRAS (5/11), RUNX1 (2/11), and SRSF2 (2/11). 20 patients received treatment outside of supportive care. Of these, 8 achieved a CR or CRi (40%; 7/10 with induction and 1/8 with HMA). The only HMA response was on a trial of HMA+SGN33a. The median survival from AML/AP transformation was 5.8 mo. Of treated patients, median survival was 7.4 mo; 37% of treated patients were alive at 1 yr. Nine patients (31%; 7 with AML and 2 with AP) underwent allogeneic transplantation; 2 relapsed during follow-up. 74% of patients treated with allo-HCT were alive at 1 yr after AML/AP transformation. Conclusions: AML or accelerated phase disease arising out of MPN carries a dismal prognosis. HMA monotherapy had little efficacy in this group (0/7 achieved remission). Allogeneic transplantation offered the best chance of survival at one year, but fewer than a third of patients were able to proceed to transplant.
Prognosis after local recurrence in vulvar cancer: A subset analysis of the AGO-CaRE-1 study.
Authors: Linn Lena Woelber, Christine Eulenburg, Jens Kosse, Petra Neuser, Christoph Heiss, Peer Hantschmann, Peter Mallmann, Berno Tanner, Jacobus Pfisterer, Barbara Richter, Julia Kathrin Jueckstock, Felix Hilpert, Nikolaus de Gregorio, Severine Iborra, Jalid Sehouli, Anika Habermann, Peter Hillemanns, Sophie Fuerst, Hans-Georg Strauss, Sven Mahner
Journal: Journal of Clinical Oncology (2016)

5595 Background: Dependent on nodal involvement 15-40% of patients with vulvar cancer develop recurrence at the vulva. Isolated local recurrence is deemed to be of minor relevance for survival. Methods: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Pts with primary squamous-cell vulvar cancer FIGO stage ≥ 1B (UICC-TNM version 6) treated at 29 gynecologic cancer centers in Germany 1998-2008 were included in a centralized database. This subgroup analysis focuses on patients with isolated vulvar recurrence. Results: 1249 documented pts had surgical groin staging and known lymph-node status. Most had locally restricted tumors [1124/1249 (90.0%) pT1b/pT2] and received an R0 resection [1022/1249 (81.8%)]. 447/1249 pts (35.8%) were node-positive (N+). 324 (25.9%) received adjuvant treatment. Median follow-up was 39.4 months. 360 pts (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only after a median of 17.1 months; of those 38 (19.7%) had initially received adjuvant radiotherapy to the vulva. Prognostic factors for vulvar recurrence were nodal involvement [N+ vs. N-: HR 2.47, 95%CI (1.52-4.03)] and complete tumor resection [R1 vs R0: HR 0.33, 95%CI (0.17-0.63)].Treatment of vulvar recurrence comprised surgery only in 104 (53.9%) cases, surgery and radiotherapy in 40 (20.7%) and radio(chemo)therapy only in 14 (7.3%) pts, 19 (9.8%) did not receive any treatment and in 16 (8.3%) cases the treatment was unknown. Median follow-up after diagnosis of local recurrence was 11.5 months. 58 (30.1%) of the patients with local recurrence developed second recurrence at the following locations: 40 (20.7%) vulva, 15 (7.8%) groin, 7 (3.6%) pelvis, 12 (6.2%) distant, 2 (1.0%) unknown (multiple locations possible). 1-year disease-free survival rate after local recurrence was 58.5%. 3-year and 5-year overall survival rate of patients with local recurrence was 76.7% and 66.9% compared to 85.9% and 80.6% in patients without recurrence. Conclusions: Opposite to the common believe patients with isolated vulvar recurrence seem to have an impaired prognosis. A high percentage of the patients with local recurrence develop second recurrences.
Should ASCO re-examine the febrile neutropenia threshold for primary G-CSF prophylaxis in breast cancer?
Authors: Tallal Younis, Daniel Rayson, Sanja Jovanovic, Chris Skedgel
Journal: Journal of Clinical Oncology (2016)

e21671 Background: Adjuvant chemotherapy (AC) for breast cancer (BC), with TAC, FEC-D and TC, is associated with high a ≥ 20% risk of febrile neutropenia (FN). ASCO recommends primary prophylaxis (PP) with granulocyte-colony stimulating factors (G-CSF), as opposed to secondary prophylaxis (SP), for AC regimens associated with FN risk ≥ 20%. The adoption of PP G-CSF for FN prevention in various health care jurisdictions however could be affected by its value for money (i.e. cost-effectiveness). We conducted a systematic review of all cost-effectiveness / cost-utility analyses (CEA / CUA) involving AC in BC to examine i) the value for money associated with PP vs. SP; ii) the FN threshold at which PP is a cost-effective strategy relative to SP and iii) the potential impact of G-CSF efficacy assumptions on PP cost-effectiveness. Methods: A literature search of PubMed / Cochrane Databases was performed on December 1st 2015 to identify all CEA / CUA associated with PP G-CSF for AC in BC. All relevant data, including study characteristics, modeling parameters (e.g. costing, FN impact, G-CSF benefits) and outcomes were extracted by two authors with discrepancies resolved by consensus. Results: Of 114 publications identified through initial search, 5 CEA / CUA from various health care jurisdictions (USA = 1, UK = 1, Canada = 3) met the predefined inclusion / exclusion criteria. These CEA / CUA examined various AC regimens (TAC = 2; FEC-D = 1; TC = 2), different G-CSF formulations (filgrastim “F” = 4; peg-filgrastim “P” = 4) and varying baseline FN’ risks (range 24 ¯ 32%), mortalities (range 1.4 ¯ 5.0%) and utilities (range 0.33 ¯ 0.47). The potential G-CSF benefits (i.e. ↓ FN risk, ↓ FN mortality, ↑ AC dose intensity, and ↑ BC survival) including FN risk reduction with P vs. F (range 0.53 ¯ 0.60) varied among models. Overall, PP G-CSF was not associated with good value for money, as per commonly-utilized CE thresholds, relative to SP at the baseline FN rates examined in most of these studies (n = 4) including the ASCO 20% FN threshold. The value for money associated with PP was dependent on G-CSF benefits assumptions. Conclusions: PP with G-CSF for FN prevention in BC patients undergoing AC may not be a cost-effective strategy at the ASCO 20% FN threshold.
Abstract 12216: Age-Related Macular Degeneration as a Predictor of Incidence and Progression of Subclinical Cardiovascular Disease and Cardiovascular Outcomes: The Multi-Ethnic Study of Atherosclerosis
Authors: Antonio B Fernandez, Kevin D Ballard, Mengye Guo, Tien Y Wong, Ronald Klein, Paul D Thompson, Mary Frances Cotch, Robyn L McClelland, Barbara Klein, Matthew A Allison, Gregory L Burke
Journal: Circulation (2015)

Introduction: Age-related macular degeneration (AMD) is a leading cause of vision loss in US adults and shares many similarities with CVD pathophysiology. Hypothesis: We assessed the hypothesis that the presence of AMD would independently predict the incidence and progression of subclinical CVD and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: Our cohort consisted of 5,803 adults free of known CVD who had retinal photographs taken during the first follow-up examination of the MESA (Exam 2; Aug 2002-Jan 2004). Photographs were evaluated for AMD using the Wisconsin age-related maculopathy grading system. Coronary artery calcium (CAC), carotid intima-media thickness (cIMT), ankle brachial index (ABI), and brachial artery flow-mediated dilation (FMD) were assessed at baseline (Exam 1; July 2000-Aug 2002). Changes in CAC and cIMT from Exam 1 were determined at follow-up Exam 5 (April 2010-Dec 2011). Incident CVD events were ascertained from 2002 through 2012. Results: Participants were categorized as AMD+ (n = 244) or AMD- (n = 5,559). Groups did not differ at baseline for cIMT, ABI, or FMD (P&gt;0.19). At Exam 5, 92 AMD+ and 2684 AMD- participants had CAC scores. In those with CAC = 0 at baseline, CAC incidence did not differ between AMD+ (n = 21) and AMD- groups (n = 761). In those with CAC&gt;0, CAC progression was greater in the 46 AMD+ vs. the 1170 AMD- participants after a mean follow-up of 10.4 ± 2.4 years using multivariable-adjusted models (530 ± 537 vs. 339 ± 426 Agatston units, P = 0.004). Ten year cIMT progression (P = 0.85) and incident CVD events (multivariable-adjusted HR (95% CI) = 1.3 (0.9, 1.8); P = 0.20) did not differ between groups. Conclusions: In conclusion, the presence of AMD in a diverse population without known CVD was independently associated with higher 10-year CAC progression in participants with baseline CAC&gt;0. AMD was not associated with CAC incidence, other subclinical CVD markers or CVD events. The association between AMD and CAC progression suggests that AMD is associated with a greater degree of atherosclerosis. Longer follow up of individuals with AMD is warranted to clarify whether greater CAC progression increases risk of CVD events.