tbuckley/cabot-search huggingface dataset:
Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance
Authors: Jinye Xu, Qiqi Shi, Wenxia Xu, Qiyin Zhou, Rongkai Shi, Yanning Ma, Dingwei Chen, Liyuan Zhu, Lifeng Feng, Alfred Sze-Lok Cheng, Helen Morrison, Xian Wang, Hongchuan Jin
Journal: Theranostics (2019)

Background & Aims: Dysregulation of metabolism plays an important role in the development and progression of cancers, while the underlying mechanisms remain largely unknown.This study aims to explore the regulation and relevance of glycolysis in chemoresistance of gastric cancer.Methods: Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by metabolism profiling, microarray gene expression, PCR or western blotting.Cancer cell growth in vitro or in vivo were analyzed by viability, apoptosis and nude mice assay.Immunoprecipation was used to explore the interaction of proteins with other proteins or DNAs.Results: By metabolic and gene expression profiling, we found that pyruvate dehydrogenase kinase 3 (PDK3) was highly expressed to promote glycolysis in chemoresistant cancer cells.Its genetic or chemical inhibition reverted chemoresistance in vitro and in vivo.It was transcriptionally regulated by transcription factor HSF1 (Heat shock factor 1). Interestingly, PDK3 can localize in the nucleus and interact with HSF1 to disrupt its phosphorylation by GSK3β.Since HSF1 was subjected to FBXW7-catalyzed polyubiquitination in a phosphorylation-dependent manner, PDK3 prevented HSF1 from proteasomal degradation.Thus, metabolic enzyme PDK3 and transcription factor HSF1 forms a positive feedback loop to promote glycolysis.As a result, inhibition of HSF1 impaired enhanced glycolysis and reverted chemoresistance both in vitro and in vivo.Conclusions: PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance.Targeting this mitonuclear communication may represent a novel approach to overcome chemoresistance.
A phase III, multicenter study to assess the diagnostic performance and clinical impact of <sup>18</sup>F-DCFPyL PET/CT in men with suspected recurrence of prostate cancer (CONDOR).
Authors: Michael J. Morris, Frederic Pouliot, Lawrence Saperstein, Steven P. Rowe, Michael A. Gorin, David Y. Josephson, Jeffrey Y.C. Wong, Peter Carroll, Tess Lin, Nancy Stambler, Vivien Wong, Jessica Donato Jensen, Barry A. Siegel
Journal: Journal of Clinical Oncology (2019)

TPS5093 Background: Early and accurate detection of recurrent or metastatic prostate cancer remains an unmet diagnostic need for patient management. While agents for positron emission tomography (PET), such as 11 C-choline and 18 F-fluciclovine, have emerged as options for imaging recurrent prostate cancer, these agents are not specific for the disease. 18 F-DCFPyL is a novel, low-molecular weight, PET radiopharmaceutical that binds selectively to prostate-specific membrane antigen with high affinity. In prior studies, 18 F-DCFPyL PET/CT has shown reliable diagnostic performance in detecting metastatic or recurrent prostate cancer (Rowe Mol Imaging Biol 2016 18:411-19; Gorin J Urol 2018 1999:126-32). Methods: CONDOR is a phase 3, multicenter, open-label study designed to assess the diagnostic performance and clinical impact of 18 F-DCFPyL PET/CT in men with suspected recurrent or metastatic prostate cancer. Approximately 200 patients are planned to be enrolled across 15 centers in the United States and Canada. Eligible patients ≥18 years of age must have histologically confirmed prostate adenocarcinoma, have rising PSA after definitive therapy, and negative or equivocal conventional imaging. A single 9 mCi (333 MBq) dose of 18 F-DCFPyL is administered, followed by whole body PET/CT scan 1 hour later. The primary objective is to assess the correct localization rate (percentage of patients with a one-to-one correspondence between localization of at least one lesion identified on 18 F-DCFPyL PET/CT and the composite truth standard, defined as either evaluable histopathology, informative correlative imaging, or PSA response after radiation therapy). Additional study objectives include safety and tolerability of 18 F-DCFPyL, impact on intended treatment plans, detection rates and PPV of 18 F-DCFPyL by region, and detection rates by baseline PSA. 18 F-DCFPyL PET/CT results are centrally reviewed by independent readers blinded to all clinical and other imaging information. As of February 9, 2019, a total of 36 patients have been dosed in the study. Clinical trial information: NCT03739684.
Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population.
Authors: Jie Liu, Huizheng Li, Rong Du, Nan Fang, Jingbo Zhang, Yu Tang, Jianwei Wang, Qixi Wu
Journal: Journal of Clinical Oncology (2019)

e17574 Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.
Abstract 9422: Electronic Personal Health Record Use in Congenital Heart Disease Patients
Authors: Linda Bradley Tiernan, Munziba Khan, Anitha John, Karen Kuehl
Journal: Circulation (2012)

Background: We evaluated if providing congenital heart disease (CHD) patients (pts) with an electronic personal health record would improve medical knowledge, psychological adjustment to illness (PAIS), and satisfaction with medical care. Methods: Since 2/2011, 81 CHD pts &gt; 15 years were enrolled in accounts on www.followmyheart.org (FMH). Using standardized surveys, medical knowledge and psychological adjustment were assessed prior to and 12 months after enrollment. Non-parametric testing was used to compare baseline and post-enrollment responses. Results: Mean age of pts (44% M) was 28 + 10 years. Ethnic breakdown included: 72% Caucasian, 17% African American, 5% Hispanic, and 6% other. Disease severity ranged from mild (24%), moderate (43%), to severe (33%); moderate to severe disease occurred more frequently in older patients (p&lt;.05). Half of pts reported regular FMH use and two-thirds found the site helpful. There were no differences between FMH users and non-users in gender, race, disease complexity or education level. 23% had lapses in care &gt;3 years and 6% had lapses &gt;10 years. Mean age at first lapse was 19 years due to insurance issues (63%), relocation (56%), and lack of symptoms (50%). Pre-enrollment, few pts were able to identify symptoms of endocarditis (10%) and arrhythmia (38%). Females were unaware of the risks of CHD on contraceptive choices (55%) and pregnancy (48%). Pre-enrollment PAIS analyses revealed worse adjustment with increasing age in the sub-scores of domestic (p&lt;0.005), sexual (p &lt;0.05), social environmental (p&lt;0.005), and psychological distress (p&lt; 0.001) and total T-score (p&lt;0.005). One year post-enrollment, data was available in 49% of eligible patients. More pts were able to identify symptoms of endocarditis (23%) and arrhythmia (44%). Pts reported increased satisfaction with medical care and increased confidence in obtaining medical care without undue financial hardship (p=0.05). There were no statistical differences in PAIS score. FMH use increased with age. Conclusions: Use of FMH by CHD pts resulted in improved knowledge of cardiac complications and improved satisfaction with medical care. Longer follow-up is needed to assess the utility of FMH in decreasing lapses in care.
Biological behavior of HER2+ breast cancer: Differences based in hormone receptor expression.
Authors: Maria Joao Ribeiro Da Silva, Miguel Henriques Abreu, Sergio Xavier Azevedo, Tiago Alpoim, Susana Sousa, Deolinda Pereira
Journal: Journal of Clinical Oncology (2019)

e12120 Background: Breast carcinoma is a heterogeneous disease whose therapeutic approach idepends on the classification into molecular subtypes. Despite the impact the expression of hormone receptors (HR) among patients with overexpression of HER2 is already the target of some studies, there is a lack of analysis in the era of treatment with adjuvant trastuzumab. Methods: This stydy consists in a retrospective analysis of cases of tumors with overexpression of the HER2 receptor (HER2 +), and HR- treated at an oncological center, comparing their biological behavior with cases of HR +/ HER2 + tumors, thus controlling for classic prognosis. Results: We analised a total of 420 patients, of whom 210 with HR+/HER2+ tumors and 210 HR- / HER2 +, with median ages of 52 years and 53 years, respectively. They accounted for 89.5% of cases of stage I to III disease. The groups were balanced in clinical characteristics. There was a higher proportion of undifferentiated and inflammatory tumors in the RH-/ HER2 + group, and in this group higher rates of complete pathological responses to treatment were observed (50.8% vs. 30.0%, p &lt; 0.001). During the follow-up 30 recurrences occurred, 18 in the HR- / HER2 + group, and 12 in the HR + / HER2 +. There was lower disease-free survival in the HR-/HER2 +, on average 69.1 months, compared to 74.3 months in the group HR+/HER2 + (p = 0.001). The first metastatic site involved visceral location in 13 cases (72.2%) in HR- / HER2 + tumors (CNS involved in 8 cases), and in 8 cases (66.6%) in HR + / HER2 + tumors (CNS in 1 case). There was an association between relapse and response to primary systemic treatment (p = 0.003), with no relation demonstrated with other clinicopathological characteristics. In the global sample, there were 28 deaths, corresponding to 17 in the HR-/HER2 +, and 11 in the HR+/HER2 + group. There were significant diferences in OS, showing worse prognosis of HR- disease (mean of 70.7 months vs. 106.6 months, p = 0.001). There was an association of mortality with the presentation as an inflammatory tumor and involvement of the CNS. Conclusions: This study supports the concept of two distinct entities according to the expression in HER2 + disease, justifying therapeutic approaches and eventually different follow-up strategies.
A phase I clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of FN-1501 monotherapy in patients with advanced solid tumors.
Authors: Gary Edward Richardson, Ulka N. Vaishampayan, Lin Lin, Viviana Bozon, Ai-Min Hui, Stephen K. Williamson
Journal: Journal of Clinical Oncology (2019)

TPS3150 Background: Receptor tyrosine kinases (RTK), a group of transmembrane proteins, are responsible for growth factor signaling transduction in normal cellular functions. Abnormal RTK functions are associated with human tumorigenesis. FMS-like tyrosine kinase 3 (FLT3) belongs to the type III receptor tyrosine kinase family and plays a well-established role in normal growth and differentiation of hematopoietic precursor cells. FLT3 mutations have been reported to occur in approximately 30% newly diagnosed AML patients. The internal tandem duplications mutation (FLT3/ITD) is the major mutation and correlated with more aggressive progress and poor prognosis. FN-1501 is an inhibitor of various tyrosine kinases such as cyclin-dependent kinase 4/6(CDK4/6), platelet-derived growth factor receptor (PDGFR), KIT protein, anaplastic lymphoma kinase (ALK) and RET protein, particularly potent on FLT3. The preclinical data generated from biochemical, cell based and animal in vivo studies suggest that FN-1501 as a single agent could offer cancer patients clinical benefit by inhibiting multiple tyrosine kinases including FLT3, PDGFR, KIT, ALK, and RET. Methods: This is a Phase1, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of FN-1501 in up to 33 cancer patients with solid tumors. There is a dose escalation phase that will be followed by an expansion cohort. The dose escalation phase utilizes a standard “3 + 3” design where doses of FN-1501 will be escalated up to the Maximum-Tolerated Dose (MTD) or until the Recommended Phase 2 dose (RP2D) is identified. Once the MTD or RP2D dose is identified, an expansion cohort including patients with hematologic malignancies will be enrolled to further evaluate the safety and efficacy of FN-1501. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of FLT3 mutations. As of February 8, 2019, cohorts 1 and 2 have been completed without a dose limiting toxicity (DLT). A total of 11 patients have been treated. Enrollment to cohort 3 is on-going. Clinical trial information: NCT03690154.
Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer
Authors: Janet E. Murphy, Jennifer Y. Wo, David P. Ryan, Jeffrey W. Clark, Wenqing Jiang, Beow Y. Yeap, Lorraine C. Drapek, Leilana Ly, Christian V. Baglini, Lawrence S. Blaszkowsky, Cristina R. Ferrone, Aparna R. Parikh, Colin D. Weekes, Ryan D. Nipp, Eunice L. Kwak, Jill N. Allen, Ryan B. Corcoran, David T. Ting, Jason E. Faris, Andrew X. Zhu, Lipika Goyal, David L. Berger, Motaz Qadan, Keith D. Lillemoe, Nilesh Talele, Rakesh K. Jain, Thomas F. DeLaney, Dan G. Duda, Yves Boucher, Carlos Fernández-Del Castillo, Theodore S. Hong
Journal: JAMA Oncology (2019)

Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted.To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer.A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion.Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine.R0 resection rate.Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached).Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%.ClinicalTrials.gov identifier: NCT01821729.
Long term morbidity and mortality among survivors of infant neuroblastoma: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Danielle Novetsky Friedman, Pamela J Goodman, Wendy Leisenring, Lisa Diller, Susan Lerner Cohn, Emily S. Tonorezos, Rebecca M. Howell, Susan A Smith, Suzanne L. Wolden, Paul C. Nathan, Joseph Philip Neglia, Kirsten K. Ness, Leslie L. Robison, Kevin C. Oeffinger, Gregory T. Armstrong, Charles A. Sklar, Tara O. Henderson
Journal: Journal of Clinical Oncology (2019)

10051 Background: Infants with neuroblastoma typically have low-risk disease with excellent survival. Therapy has been de-intensified over time to minimize late effects, however the impact on survivors’ risk of late mortality, subsequent malignant neoplasms (SMN), and chronic health conditions (CHC) is unclear. Methods: We evaluated late mortality, SMNs and CHCs (graded according to CTCAE v4.03), overall and by diagnosis era, among 990 5-year neuroblastoma survivors diagnosed at &lt; 1 year of age between 1970-1999. Cumulative mortality, standardized mortality ratios (SMR), and standardized incidence ratios (SIR) of SMNs were estimated using the National Death Index and SEER rates, respectively. Cox proportional hazards estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC, compared to 5,051 CCSS siblings. Results: Among survivors (48% female; median attained age: 24 years, range 6-46), there was increased treatment with surgery alone across the 1970s, 1980s and 1990s (21.5%, 35.3%, 41.1%, respectively), but decreased treatment with combination surgery + radiation (22.5%, 5.3%, 0.3%, respectively) and surgery + radiation + chemotherapy (28.7%, 14.7%, 9.3%, respectively). The 20-year cumulative mortality was 2.3% (95% CI, 1.4-3.8), primarily due to SMNs (SMR SMN = 10.0, 95% CI, 4.5-22.3). The 20-year cumulative incidence of SMN was 1.2% (95% CI, 0.3-3.2), 2.5% (95% CI, 1.3-4.4), and zero for those diagnosed in the 1970s, 1980s, and 1990s, respectively. SIR was highest for renal SMNs (SIR 12.5, 95% CI, 1.7-89.4). Compared to siblings, survivors were at increased risk for grade 1-5 CHC (HR 2.1, 95% CI, 1.9-2.3) with similar HR across eras (HR 1970s = 1.9, 95% CI, 1.6-2.2; HR 1980s = 2.2, 95% CI, 1.9-2.6; HR 1990s = 2.0, 95% CI, 1.7-2.4). The HR of severe, disabling, life-threatening and fatal CHC (grades 3-5) decreased in more recent eras (HR 1970s = 4.7, 95% CI, 3.4-6.6; HR 1980s = 4.4, 95% CI, 3.2-6.2; HR 1990s = 2.9, 95% CI, 2.0-4.3). Conclusions: Survivors of infant neuroblastoma remain at increased risk for late mortality, SMN, and CHCs many years after diagnosis. However, the risk of grade 3-5 CHCs has declined in more recent eras, likely reflecting de-intensification of therapy.
Pathological complete response rate (pCR) in thirty-three women with triple-negative breast cancer (TNBC) treated with a neoadjuvant carboplatin-based regimen.
Authors: Avani Chopra, Mark Wojtowicz, Jesse Manikowski, Bhumika Maddineni, Lester Kirchner, Rajiv Prasanna Panikkar, Victor G. Vogel
Journal: Journal of Clinical Oncology (2019)

e12099 Background: The purpose of this retrospective case series was to assess pCR rate, progression-free survival and prognostic factors in TNBC. Methods: We reviewed medical records for 33 consecutive female patients with TNBC (41% node+) treated between July 2015 and April 2018 with neoadjuvant paclitaxel 80 mg/m 2 IV weekly plus concurrent carboplatin (AUC 4) every 3 weeks for a total of 12 weeks followed by dose-dense doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 every 2 weeks for a total of 4 cycles. Surgical pathology was studied to determine the presence or absence of residual disease at surgery. Age at treatment, tumor stage, subsequent hospitalizations, and genetic testing were recorded. Patients with residual disease were treated with adjuvant capecitabine 1500 mg PO BID, one week on, one week off, for 6 monthly cycles ± radiation; some patients with a complete pathological response also received postoperative radiation. Results: Among 33 patients, 17 patients had pCR (52%, median age 58 yrs), 10 had a partial response and 6 had no response or progression (median age 63.5). After surgery 24 patients received radiation therapy (XRT). There were 6 hospitalizations, 3 that were treatment related, 2 for neutropenic fever and one for renal failure induced by carboplatin; all 3 resulted in chemotherapy dose reductions; all 3 had pCR. 3 progressions/recurrences were recorded: 2 after treatment and 1 progression during treatment. Two deaths occurred, 1 secondary to progressive disease. Median progression free survival time was 8.5 months (range 0.1 to 24.0 mos). Median time since diagnosis is 16.7 months (range 8.1 to 37.6 mos). There was no significant difference in the median age of patients who had a pCR compared with patients with residual disease. Conclusions: We observed pCR in patients with TNBC treated with a pre-operative carboplatin-containing regimen (superior to historical pCR rates in patients receiving taxanes and anthracyclines only). Although there are insufficient data to demonstrate increased overall survival, we show an improvement in prognosis with a carboplatin-containing regimen for TNBC.