tbuckley/cabot-search huggingface dataset:
The usefullness of low-molecular-weight protein tyrosine phosphatase as a prognostic factor in metastatic hormone-sensitive prostate cancer.
Authors: Mari Ohtaka, Takashi Kawahara, Masato Yasui, Kouichi Uemura, Shuko Yoneyama, Taku Mochizuki, Yusuke Hattori, Jun-ichi Teranishi, Yasushi Yumura, Yumiko Yokomizo, Hiroji Uemura, Hiroshi Miyamoto, Masahiro Yao, Yasuhide Miyoshi
Journal: Journal of Clinical Oncology (2017)

277 Background: Protein tyrosine phosphorylation is an important event that is associated with the processes of cellular metabolism. The control of protein tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTP). Thus, these proteins can control diverse processes like cell proliferation, adhesion, and migration. Recent studies revealed the importance of PTP in the oncogenic process, especially, the significance of low-molecular-weight protein tyrosine phosphatase (LMW-PTP) as a prognostic factor in early prostate cancer. In this study, we evaluated the significance of expression of LMW-PTP in metastatic hormone-sensitive prostate cancer (mHSPC) as a prognostic biomarker. Methods: We identified consecutive 48 men with mHSPC. The prostate cancer tissues obtained by needle biopsies were immunohistochemically stained for LMW-PTP. A pathologist blindly evaluated the expression of LMW-PTP and intensity of staining was classified into two groups, high (diffusely strongly positive) and low (at least focally weak-negative). The correlations between clinicopathological characteristics including age, initial PSA levels, Gleason scores, T stage, N stage, extend of disease on bone scan (EOD), and expression of LMW-PTP and overall survival (OS) were analyzed by multivariate analysis using cox proportional hazards regression model. Results: Median age was 70.0 years and median initial PSA level was 85.4 ng/mL. Gleason scores were 6-7 in 16 patients (33.4%) and 8-10 in 32 patients (66.6%). Clinical T stages were T2-3 disease in 34 patients (70.8%) and T4 in 14 patients (29.2%). Clinical N stages were N0 disease in 21 patients (43.7%) and N1 in 27 patients (56.3%). EOD grades were 0 in 13 patients (27.0%), 1 in 12 patients (25.0%), 2 in 14 patients (29.2%), 3 in 8 patients (16.7%), and 4 in 1 patient (2.1%). Multivariate analysis revealed that Gleason score (≥ 8 vs ≤ 7; HR: 5.795, 95%CI: 1.266-26.520, p = 0.024) and LMW-PTP expression (high vs low; HR: 2.736, 95%CI: 1.035-7.232, p = 0.042) were independent prognostic factors for OS. Conclusions: LMW-PTP might be a potential biomarker to predict overall survival for men with mHSPC.
A phase II trial of pre-operative capecitabine and concurrent radiation for locally advanced rectal cancer
Authors: S. J. Wong, C. Sadasiwan, B. Erickson, D. Ota, D. Mulkerin, J. Thomas, K. Holen, S. Meadows, G. Telford, E. Gore
Journal: Journal of Clinical Oncology (2004)

3771 Background: Concurrent 5-FU-based chemotherapy and radiation therapy (RT) have an established role in the pre-operative management of locally advanced rectal cancer. Pathologic complete response (CR) rates have been reported from 10% to 50%. We sought to examine the efficacy and toxicity of capecitabine, an oral fluoropyrimidine prodrug, with concurrent RT for this disease. Methods: Between 1/02 and 12/03, 22 patients were enrolled and clinically staged by endorectal US, and CT or MRI. Patients with T3, T4, or lymph node (LN) positive adenocarcinoma of the rectum were eligible. RT was administered in 1.8 Gy fractions to a total dose of 50.4 Gy. Capecitabine (1650 mg/m2/d) was administered by mouth divided in two daily doses Monday through Friday during the entire course of radiation. Surgery was performed 6 to 8 weeks following completion of radiation. Four to 6 weeks after surgery an adjuvant course of capecitabine (2500 mg/m2/d) was administered for 14 days of a 3 week cycles for a total of 6 cycles. Results: Thus far, 22 patients have been enrolled in this study. Eighteen patients were analyzed for toxicity and response. Stage of disease was: 11 T3N0M0, 6 T3N1M0, and 1 T3N2M0. Median age was 55. Pathologic CR was observed in 3 patients (17%), however a near pathologic CR was noted in 2 (11%) additional patients that had only microscopic foci. Primary tumor and LN downstaging occurred in 5 of 18 (28%) and 6 of 7 (86)% patients, respectively. Overall downstaging of tumors (including LN+ disease) occurred in 9/18 (50)% of patients. Of 8 patients who had primary tumors ≤6 cm from the anal verge, sphincter-preserving therapy was performed in 3 (38%) patients. No grade III or IV hematologic toxicity was noted. Two patients (11%) experienced Grade III diarrhea, and 2 patients had grade II diarrhea. Grade III hand foot syndrome was observed in 2 patients. Grade III cardiac toxicity was noted in 2 patients. Conclusions: Concurrent capecitabine and RT is a well-tolerated, safe, and effective treatment for locally advanced operable rectal cancer. This regimen was highly active, leading to frequent tumor downstaging and sphincter preservation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
Thrombosis in a population of phase I trial patients.
Authors: Alan David Smith, Begona Jimenez, Rajiv Kumar, L Rhoda Molife, Udai Banerji
Journal: Journal of Clinical Oncology (2014)

e17671 Background: Thromboembolic events are a well-recognized complication of malignancy, accounting for the 3rd leading cause of death in cancer patients (pts) and an annual incidence of 0.5-1.0%. Hospitalized pts with cancer and those receiving active therapy, two common factors in phase I pts, are at the greatest risk for thromboembolism. We proposed to study the incidence and risk factors associated with thromboembolism in pts on a phase I study. Methods: Retrospective analysis of pts enrolled on a phase I trial between January 2010 and December 2012, in the Drug Development Unit at the Royal Marsden Hospital (RMH). Data was collected on incidence of thrombosis, class of phase I drug, type of cancer and common risk factors associated with thrombosis such as previous thrombosis, BMI and performance status. Results: 404 patients were reviewed, and 17 (4.2%) experienced a thrombotic event. Six events (35%) were pulmonary emboli, and 11 (65%) were symptomatic. Five events (29%) occurred despite antithrombotic therapy. The prevalence of prior thrombosis was 13.9% (64.3% of whom were on an anticoagulant during the trial) and 11% of patients started a trial on antithrombotic therapy. Phase I anticancer treatment strategies included androgen manipulation, drug combinations involving chemotherapy and/or targeted agents, HDAC inhibitors, monoclonal antibodies, PARP inhibitors, PI3K pathway manipulation, vascular targeting agents, oncolytic viruses and other. On univariate analysis, history of prior thrombosis predicted an increased risk of thromboembolism (p=0.02; RR=1.09). No other factors were significantly associated with thrombosis (i.e., gender, type of malignancy, class of phase I drug, BMI, anticoagulant use, coagulation profile, RMH score, ECOG performance status). The median survival of patients with a thrombosis was 5.9 months, which is within the range of patients treated on phase I studies (6.8 months; p=0.78). Conclusions: History of prior thrombosis is associated with a significantly increased risk of thromboembolism for patients on a phase I trial; however the relative risk appears to be marginal. Patients with a history of thromboembolism should be considered for phase I studies if they meet other inclusion criteria.
Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Kimberly A. Morishita, Lakshmi N. Moorthy, Joanna M. Lubieniecka, Marinka Twilt, Rae S. M. Yeung, Mary B. Toth, Susan Shenoi, Goran Ristic, Susan M. Nielsen, Raashid A. Luqmani, Suzanne C. Li, Tzielan Lee, Erica F. Lawson, Mikhail M. Kostik, Marisa Klein‐Gitelman, Adam M. Huber, Aimee O. Hersh, Dirk Foell, Melissa E. Elder, Barbara A. Eberhard, Paul Dancey, Sirirat Charuvanij, Susanne M. Benseler, David A. Cabral
Journal: Arthritis & Rheumatology (2017)

To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV.Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months.In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months.This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.
Multisite experience of fluciclovine (<sup>18</sup>F) PET/CT imaging in biochemically recurrent prostate cancer: Impact of clinical factors and intersite variation.
Authors: Lucia Zanoni, Christina Nanni, Tore Bach-Gansmo, Trond V Bogsrud, Peter Nieh, Jesse Kieboom, Katrine Andersen Korsan, Heidi Sletten, Funmilayo I Tade, Oluwaseun Odewole, Penny Ward, Albert Chau, Mark Goodman, Stefano Fanti, David M. Schuster, Frode Willoch
Journal: Journal of Clinical Oncology (2017)

163 Background: Fluciclovine ( 18 F) is an FDA-approved positron emission tomography/computerized tomography (PET/CT) tracer in clinical use for the detection and localization of biochemically recurrent (BCR) prostate cancer. Here, we report the impact of clinical factors and study site on its performance. Methods: In total, 596 subjects with BCR prostate cancer underwent fluciclovine ( 18 F) PET/CT scanning at four sites in Italy, Norway and USA. Detection Rates (DR), including region level analyses, were stratified by prostate specific antigen (PSA) levels, PSA doubling time (PSAdt), Gleason score (GS), and by investigator/site. Extra-prostatic disease was defined as all positivity outside of residual prostate, prostate bed and seminal vesicles. Results: Fluciclovine ( 18 F) PET/CT was positive in 67.7% (403/595) of subjects. Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232/599) and 32.6% (194/596) of scans, respectively. Metastatic involvement outside the pelvis was found in 26.2% (155/591) of scans. Generally, DR increased with increasing baseline PSA (Table 1). While subject level DR did not vary significantly with PSAdt (DR = 60-69% across all categories), a positive extra-prostatic scan was more likely in patients with shorter PSAdt (DR = 52%, 48%, 37% and 28% for PSAdt &lt;3, 3-&lt;6, 6-&lt;12 and &gt;12 months, respectively). Among 361 subjects for whom baseline GS was available, scores ≥9 were associated with the highest extra-prostatic DR (55%) compared with 23% in patients with GS ≤6. Inter-site variations in acquisition protocols may have impacted DR at low baseline PSA values; with subject level DR at PSA &gt;0.2-0.5 ng/ml = 20%, 38%, 46% and 73% at site A, B, C and D, respectively. Conclusions: Fluciclovine ( 18 F) can detect and localize BCR prostate cancer in a wide range of subjects and, with appropriate imaging protocols, has a clinically useful DR at PSA &lt;0.5 ng/ml. Clinical trial information: NCT02443571. [Table: see text]
An examination of crizotinib activity in human tumor primary culture micro-spheroids isolated from patients with advanced non-small cell lung cancer.
Authors: Robert Alan Nagourney, Sai-Hong Ignatius Ou, Paula J Bernard, Federico R Francisco, Steven S Evans
Journal: Journal of Clinical Oncology (2013)

e13558 Background: The amino-pyridine, Crizotinib (Criz) (PF02341066, Xalkori), active against c-MET is an inhibitor of anaplastic lymphoma kinase (ALK). Identification of ALK-gene rearrangement in NSCLC led to clinical trials &amp; FDA approval. Recognition of ROS-1 mutations as Criz targets provided additional therapy options. ALK mutations found in NSCLC also occur in lymphoma, neuro &amp; myofibroblastic tumors but may participate in the oncogenesis of other tumors. Methods: We used ex vivo analysis of programmed cell death (EVA/PCD) (Nagourney, R. Curr Treat. Op Oncol, 2006) to examine Criz activity in human tumor 1°culture micro-spheroids, from 60 surgical specimens, with a focus on NSCLC. Using metabolic (ATP-content; mitochondrial) &amp; morphologic (membrane integrity) endpoints, dose response curves were interpolated to LC50 values for comparison of activity by patient &amp; tumor type. Patients were screened for ALK &amp; ROS-1 by FISH. Results: ALK (+) tumors reveal lower LC50’s (3.4 uM) vs. ROS-1 (+) (11.5 uM), despite clinical responses in both groups. A Criz-responding patient, at 2 nd biopsy for progression, reverted to Criz-resistance but developed collateral sensitivity to cytotoxics that provided durable response. Despite FISH (-), a 39 y/o nonsmoker male, revealed exquisite sensitivity to Criz by repeat EVA/PCD. At our insistence, FISH conducted at a 2 nd reference lab correctly identified ALK(+) qualifying for Criz, to which he responded, now at year 2. Using low LC50 as a phenotypicmarker of Criz responsiveness, we identified activity in an extremely rare pediatric sarcoma patient. When, secondarily screened, patient found ALK (+), followed by rapid objective response to Criz. Conclusions: Primary culture analyses provide insights into Criz activity including ALK (+) vs. ROS-1(+), individual patient response profiles, and the identification of Criz candidates, who might otherwise not be screened for sensitizing mutations. By capturing human tumors in their “native” state EVA/PCD offers opportunities to study Criz for unrecognized targets and analyze novel strategies including synergy &amp; sequence dependence, less readily examined with genomic platforms.
Nationwide incidence, treatment, and outcomes of patients 80 years and older with rectal adenocarcinomas: Analysis of 5,076 patients.
Authors: Richard John Cassidy, En Cheng, Jeffrey M. Switchenko, Renjian Jiang, Jaymin Jhaveri, Daniel G Tanenbaum, Theresa Wicklin Gillespie, Mark William McDonald, Jerome C Landry
Journal: Journal of Clinical Oncology (2017)

723 Background: Elderly patients have been underrepresented in randomized clinical trials of rectal cancer, and the value and tolerance of treatment options in this population remain unclear. We used the National Cancer Data Base (NCDB) to assess the incidence, treatment patterns, and overall survival (OS) outcomes of patients 80 years or older with newly diagnosed non-metastatic rectal adenocarcinomas. Methods: 5076 patients 80 years and older diagnosed with non-metastatic rectal adenocarcinomas from 2004 to 2013 were identified. Univariable and multivariable (MVA) analysis were performed to identify patient, tumor, and treatment characteristics associated with receipt of standard of care therapy (SOCT) and factors predictive of OS. SOCT was defined as surgical resection for Stage I patients and receipt of neoadjuvant therapy followed by surgical resection for Stage II/III patients. Kaplan-Meier curves were generated to assess the effect of stage and treatment received on overall survival. Results: At presentation, 935 (18.5%) were TXN0, 1557 (30.8%) were Stage I, 1552 (30.6%) were Stage II, and 1,032 (20.1%) were Stage III. The rates of patients receiving no therapy were: 29.6% for TXN0, 22.6% for Stage I, 16.5% for Stage II, and 12.2% for Stage III. The rates of patients not receiving SOCT were: 22.6% for Stage I, 51.4% for Stage II and 39.4% for Stage III cases. Survival was significantly worse for patients not receiving standard of care therapy: Stage I (52.1% receiving SOCT vs. 7.6% not receiving SOCT; p &lt; 0.01), Stage II (49.8% receiving SOCT vs. 14.5% not receiving SOCT; p &lt; 0.01), and Stage III (47.5% receiving SOCT vs. 10.2% not receiving SOCT; p &lt; 0.01). On MVA of patient, tumor, and treatment variables, receipt of SOCT was associated with improved OS for the entire cohort (p &lt; 0.01) and when examined by stage (p &lt; 0.01). Conclusions: In this nationwide sample of patient’s ≥ 80 years old with rectal cancer, there was a high rate of patients receiving no therapy. Those that did receive standard therapy achieved reasonable outcomes, suggesting avoidance of guideline care in this population should not be advised.
Assessment of the 7th edition of the AJCC classification and a proposal of a new classification in patients with gastric cancer undergoing D2 gastrectomy.
Authors: Vincenzo Catalano, Valerio Sisti, Daniele Spada, Francesco Graziano, Moreno Cicetti, Paolo Giordani, Paolo Alessandroni, Anna Maria Baldelli, Virginia Casadei, Stefano Luzi Fedeli, David Rossi, Silvia D'Emidio, Michele De Nictolis, Enrica Testa, Giammaria Fiorentini, Costantino Zingaretti
Journal: Journal of Clinical Oncology (2012)

4084 Background: Studies on Asian, US, and German patients have moved some criticisms on the validity of the 7th edition of the AJCC classification to discriminate outcome of gastric cancer stages. We investigated the effect of this AJCC classification in a high-quality surgical populations of patients receiving D2 lymphadenectomy. Methods: From the prospective database at San Salvatore Hospital, Pesaro, we identified 515 patientswith gastroesophageal junction (Siewert II and III) or stomach adenocarcinoma who underwent gastrectomy with curative intent from 1998 to 2010. Lymphadenectomy extended to the 3rd level 12p/b nodes (D2/D3) was performed in all patients. Overall survival (OS) probabilities, calculated from the date of surgery to the date of death, from any cause, were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 58% of patients were male,median age was 73 years (range 36-96). Median number of examined lymph nodes was 32 (range, 1-89), and only 8.9% of patients had less than 15 examined lymph nodes; 96 patients received adjuvant chemo- or chemoradiotherapy. As shown in the table, we proposed a revised staging system (Pesaro Staging System, PSS), which performs better than the 7th edition of AJCC classification in terms of survival differences between stages. Conclusions: This study confirms once again that the 7th edition of the AJCC classification does not discriminate adequately the outcome from stage to stage. In a European population of patients undergoing gastrectomy plus at least D2 lymphadenectomy, the revised staging system, PSS, better defines patient prognosis. [Table: see text]
Comprehensive profiling of cardiac dysfunction in asymptomatic childhood cancer survivors (CCS) treated with anthracyclines.
Authors: Saro Armenian, Sarah Gelehrter, Tabitha Vase, Rajkumar Venkatramani, Wendy Landier, Karla Wilson, Claudia Herrera, Leah Reichman, John David Menteer, Leo Mascarenhas, David Robert Freyer, Kalyanasundaram Venkataraman, Smita Bhatia
Journal: Journal of Clinical Oncology (2013)

10020 Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m 2 (high-risk [HR]: n=100) compared with: i) CCS exposed to &lt;300 mg/m 2 (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P&lt;0.01) as well as increased LV wall stress ([ESWS] HR: 66 g/cm 2 , LR: 58 g/cm 2 , Con: 55 g/cm 2 , p&lt;0.01) and higher myocardial performance index ([MPI] HR: 0.51, LR: 0.46, Con: 0.46; P&lt;0.01). Blood biomarkers: HR had higher plasma NT-pro BNP (HR: 71 pg/dL, LR: 37 pg/dL, Con: 26 pg/dL; P&lt;0.01); there were no differences in troponins, Galectin-3 or ST-2. Metabolomics:Individuals with LV dysfunction (&gt;2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p&lt;0.01) contributing to altered fatty acid β-oxidation and accumulation of cardiotoxic long-chain (docosadienoate [RR=1.26], adrenate [RR=1.29]; p&lt;0.05) and essential fatty acid intermediates (dihomo-linolenate [RR=1.27], eicosapentaenoate [RR=1.23], docosapentaenoate [RR=1.46]; p&lt;0.05). Conclusions: Comprehensive profiling of anthracycline-exposed CCS with preserved EF revealed dose-dependent echo (LV ESWS, T-D ratio, MPI) and blood (NT-ProBNP) abnormalities 10+years from dx; metabolomic studies demonstrated the role of carnitine in the pathogenesis of LV dysfunction. Taken together, these findings may facilitate early detection and targeted interventions in CCS at highest risk for CHF.