tbuckley/cabot-search huggingface dataset:
Development of a nomogram for predicting survival in microsatellite stable patients with resected colorectal cancer.
Authors: Yaqi Li, Junjie Peng, Ting Hou, Han Han-Zhang, Hao Liu, Jianxing Xiang, Lu Zhang, Xiaoji Ma, Dan Huang, Sanjun Cai
Journal: Journal of Clinical Oncology (2018)

e15679 Background: The benefits of adjuvant chemotherapy remain controversial in microsatellite stable (MSS) stage II resected colorectal cancer (CRC) patients. In this study, we constructed an overall survival (OS) prediction model for this subgroup, integrating a combination of molecular and clinical predictors. Methods: Variables with p-values < 0.05 were entered into multivariate analyses using Cox stepwise regression model to select independent predictors as input for OS prediction nomogram. A final model was selected using a backward step-down process, which used Akaike Information Criterion as a stopping rule. The probability of 3-year and 5-year survival can be obtained by summing up the total score and locating it on the total point scale. Results: We performed targeted sequencing on surgically resected tumor tissue of 122 stage II MSS patients, defined as having less than 15% length-instable loci, using a panel which allows for simultaneous detection of MSI status and mutation in 41 CRC-related genes. Among them, 23, 30 and 69 patients were diagnosed with proximal, distal and rectal cancer, respectively. To predict the probability of 3-year and 5-year survival, we constructed a nomogram incorporating the significant prognostic factors, including APC, ATM, BRAF, PTEN, TP53 (LOF), mutation count (high: > 3, low: < = 3), age, CEA, and the location of the tumor. The actual and predicted survivals were in an excellent agreement, reflected by a C-index of 0.887 (95% CI: 0.816-0.957). Furthermore, Kaplan-Meier curves for survival outcomes showed significant distinction (p < 0.001) after stratifying our cohort into low, median and high risk groups according to total score obtained from our nomogram. Our data also demonstrated high risk patients who received adjuvant chemotherapy are associated with a better OS (p = 0.004). Low and median risk patients did not benefit from adjuvant chemotherapy, reflected by comparable OS. Conclusions: We developed a nomogram model for predicting survival of MSS patients with stage II resected CRC. It can potentially serve as complementary method for clinicians to identify subgroups necessitating adjuvant therapy.
Abstract 16614: Left Ventricular Global Function Index (A Novel Marker of Cardiac Performance) Predicts Incident Cardiovascular Events: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Chike C Nwabuo, Nathan Mewton, Anders Opdahl, Henrique T Moreira, Kofo Ogunyankin, Bharath Ambale-Venkatesh, Pamela J Schreiner, Yuko Inoue, Yoshiaki Ohyama, David Jacobs, Donald Lloyd-Jones, Beth Lewis, Samuel Gidding, João Lima
Journal: Circulation (2015)

Introduction: Left ventricle (LV) function is typically evaluated independent of LV structure and vice versa. LV global function index (LVGFI) is a novel marker of cardiac performance that accounts for LV structural alterations and has been previously validated using magnetic resonance imaging. Hypothesis: We evaluated the prognostic utility of LVGFI assessed by echocardiography for incident cardiovascular disease (CVD) and heart failure (HF) events in comparison to LV ejection fraction (LVEF) and LV mass Methods: Included were 4107 Coronary Artery Risk Development in Young Adults (CARDIA) study participants with available m-mode echocardiographic parameters in 1990-1991 (Year-5). LV volumes were obtained using the Teichholz formula. LVGFI defined as LV stroke volume/LV global volume* 100, where LV global volume was calculated as the sum of the LV mean cavity volume (LVEDV + LVESV)/2) and myocardium volume (LV mass/density). Median follow-up time was 21.9 years. Cox regression models, adjusted for risk factors, were utilized to predict the endpoints of HF, hard CVD and all CVD events. Results: Mean age of participants at Year-5 was 29.8 ± 3.7 years, 55% were female, 51.3% white and mean LVGFI was 34.7 ± 6.2%. A total of 174 incident CVD events were observed during the 21.9 years median follow-up. In multivariable adjusted models, 1-SD increase in LVGFI was significantly associated with lower hazard of HF, Hazard Ratio (HR) =0.55 95% confidence interval (CI) [0.40 - 0.74]; hard CVD, HR=0.74 95% CI [0.63 - 0.88] and all CVD events, HR=0.76 95% CI [0.65 -0.88]. (Table 1). LVGFI provided incremental predictive value for incident CVD compared to LV mass and LV ejection fraction alone.(Figure 1). Conclusions: LVGFI in early adulthood was associated with incident HF, hard CVD and all CVD events. In this longitudinal community study, LVGFI provided robust, independent and incremental predictive value for incident CVD events.
Early palliative care for children with cancer: A multi-institutional survey study of pediatric oncology patients and parents.
Authors: Deena R. Levine, Justin N. Baker
Journal: Journal of Clinical Oncology (2016)

10582 Background: Based on strong recent evidence, clinical consensus is growing that early Palliative care (PC) integration for cancer patients is the optimal care model; however, PC remains underutilized in pediatric oncology. We conducted a multi-institutional study of pediatric oncology patient/parent pairs to determine perception of symptom burden and management early in treatment and assess attitudes towards early integration of PC. Methods: Novel survey tools were developed using validated formats when available. After IRB approval and pre-testing, surveys were administered to 129 patient/parent dyads at NIH, Johns Hopkins and St Jude Children’s Research Hospital. Eligibility criteria included patient age 10-17 at diagnosis, time from diagnosis > 1 month and < 1 year, English-speaking and consent/assent of both parties. Survey data was assessed for trends in response content frequencies, percentages and degree of concordance between parent and child. Results: Patients reported a high degree of suffering from symptoms in the first month of cancer therapy with reported overall suffering of: 84% from nausea, 75% from loss of appetite, 74% from pain, 60% from anxiety, 53% from constipation, 50% from depression, and 40% from diarrhea. Most children and parents (54/53%) stated they would probably or definitely want to meet with PC around diagnosis, while few expressed definite opposition (2% children, 6% parents). A large percentage of children and parents (36/40%) felt that PC integration from diagnosis would have been a positive addition to their overall care and the majority (59/50%) indicated that PC teams should be involved from the beginning of cancer therapy. Children were more likely than parents to indicate that PC would have been helpful for treating symptoms 40% vs 18% (p < 0.0001). Conclusions: Pediatric oncology patients experience a high degree of suffering from the beginning of cancer therapy. The majority of patients and parents would welcome early integration of PC which could be beneficial for improved symptom management, reducing suffering, and improved overall care.
Impact of survivorship care plans (SCPs) on adherence to surveillance for second malignant neoplasms (SMNs) and cardiac dysfunction in the Childhood Cancer Survivor Study (CCSS).
Authors: Adam Paul Yan, Yan Chen, Melissa M. Hudson, Todd M. Gibson, Joseph Philip Neglia, Kevin C. Oeffinger, Wendy M. Leisenring, Kirsten K. Ness, Jennifer Ford, Tara O. Henderson, Leslie L. Robison, Gregory T. Armstrong, Yutaka Yasui, Paul C. Nathan
Journal: Journal of Clinical Oncology (2018)

10560 Background: Since specific treatments increase the risk of SMN and cardiac dysfunction in childhood cancer survivors, the Children’s Oncology Group (COG) has published guidelines for SMN and cardiac surveillance. In 2006, the Institute of Medicine recommended that survivors receive a SCP documenting their required surveillance in order to maximize their adherence. The impact of this recommendation on adherence is not known. Methods: A survey completed between 2014-2016 by 10,791 survivors in the CCSS ascertained adherence to COG guidelines among those for whom surveillance for breast cancer (N = 657; mammogram/MRI), colorectal cancer (N = 951; colonoscopy), skin cancer (N = 5468; skin exam) and cardiac dysfunction (N = 4310; echocardiogram) was recommended. We estimated adherence rates and identified factors associated with adherence using multivariable logistic regression. Results: Median age at diagnosis was 7 years (range 0-21) and time from primary cancer diagnosis was 36 years (16-66). Adherence to recommended breast, colorectal, skin and cardiac surveillance was 45.7% (95 % CI 41.9-49.5%), 38.2% (CI 35.1-41.3%), 22.6% (CI 21.6-23.7%) and 42.3% (CI 41.0-43.6), respectively. 26.9% of survivors and 19.8% of primary care providers (PCPs) had a copy of the SCP. Providing the PCP with a SCP was associated with increased skin cancer surveillance (OR 1.4, CI 1.1-1.7) only. Survivors’ having a SCP was associated with increased cardiac surveillance (OR 1.8, CI 1.5-2.2) only. Visiting a specialized survivor clinic in the last year (vs. never) was associated with increased breast (OR 2.0, 95% CI 1.1-3.8), skin (OR 1.3, CI 1.1-1.7) and cardiac (OR 8.9, CI 6.4-12.7) surveillance. Conclusions: Less than half of survivors at high risk for SMN or cardiac dysfunction adhere to surveillance guidelines. Few survivors and PCPs have SCPs, and possession of SCPs has limited impact on surveillance. Adherence was most strongly associated with attending a specialized survivor clinic. New initiatives to improve adherence must be developed and tested.
Dose finding study of varlitinib ± trastuzumab with carboplatin/paclitaxel in advanced solid tumors.
Authors: Matilda Lee, Andrea Li Ann Wong, Samuel Guan Wei Ow, Raghav Sundar, Ling-Zhi Wang, David Shao Peng Tan, Ross A. Soo, Cheng Ean Chee, Valerie Heong, Ying-Chen Chen, Joline Si Jing Lim, Wei Peng Yong, Siew Eng Lim, Boon C. Goh, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2018)

2588 Background: Varlitinib (V) is a reversible inhibitor of HER1/HER2/HER4. This is a phase 1b dose confirmation study to determine safety and early efficacy signals of V ± T combined with weekly P 80mg/m2 and C AUC = 2 (NCT02396108). Methods: Eligible patients had metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic (PK) analyses of V and P were done. Results: 37 patients (median age 56.8 years [31.8 – 73.8]) were enrolled into 8 cohorts with median 3 (0-14) prior lines of palliative therapies. PC + V 500mg BD continuously (cont) was deescalated to 300mg BD intermittently (int) (4 days on, 3 days off) due to DLTs, most commonly febrile neutropenia (FN) and electrolyte disturbances, and was deemed intolerable. Recommended dose (RD) was V 300mg BD int with P alone; addition of T to RD of P+V was safe with no DLTs (Table). 20/37 had HER2+ metastatic breast cancer (MBC) with median 4 (0-14) prior treatment lines. 7 achieved partial response (PR) and 3 stable disease (SD); 6 had disease control with single agent V for a median 7.0 more months (4.3 – 13.3) after chemotherapy ceased. 2/17 with other tumor types achieved PR (HER2- MBC = 1, NSCLC = 1). 3/10 patients (HER2+ MBC = 2) in the V 300mg BD int cohorts achieved PR. No correlation was seen between V and P mean AUC (ng.h/mL) in those with and without DLTs (V 10336.5 vs 20758.8, p = 0.21; P 4882.1 vs 5197.6, p = 0.77). No interaction was seen between V dose/schedule with P PK. Conclusions: The RD of V combined with P is 300mg BD int, and is active in HER2+ MBC; T can be added safely. The triple combination will be evaluated as neoadjuvant therapy in HER2+ breast cancer. Clinical trial information: NCT02396108.Cohorts DLT in cycle 1 No. with PR/SD N = 3 3/3 (G3 hyperbilirubinemia = 1, received < 75% intended V dose due to toxicities = 2) 1/0 V 500mg BD cont CP N = 5 3/5 (FN = 3) 2/3 V 400mg BD cont CP N = 4 2/4 (G3 hypophosphatemia = 1, G3 hyponatremia, G3 hypokalemia, intolerable G2 fatigue = 1) 2/2 V 400mg BD int CP N = 6 2/6 (FN = 1 , G3 hypophosphatemia, G3 vomiting = 1) 1/2 V 300mg BD int CP N = 6 0/6 2/2 V 300mg BD int P N = 4 2/4 (FN = 1, G3 transaminitis = 1) 1/1 V 400mg BD int P N = 6 4/6 (G3 diarrhea = 1, G4 neutropenia > 7days = 1, received < 75% intended V dose due to toxicities = 2) 1/1 V 300mg BD cont P N = 3 0/3 Ongoing V 300mg int P SC T 600mg
Cerebrovascular event (CVE) outcome and overall survival (OS) in patients (pts) treated with sipuleucel-T (sip-T) for metastatic castration-resistant prostate cancer (mCRPC): results from the PROCEED registry.
Authors: Celestia S. Higano, Andrew J. Armstrong, A. Oliver Sartor, Nicholas J. Vogelzang, Philip W. Kantoff, David G. McLeod, Christopher Michael Pieczonka, David F. Penson, Neal D. Shore, Jeffrey L. Vacirca, Raoul S Concepcion, Ronald F Tutrone, Luke T. Nordquist, David I. Quinn, Vahan Kassabian, Mark C. Scholz, Robert C. Tyler, Nancy N. Chang, Bruce Brown, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2018)

e17018 Background: Sip-T is a cellular immunotherapy approved for treatment of asymptomatic/minimally symptomatic mCRPC on the basis of improved OS. Across 4 clinical trials, CVEs occurred in 3.5% of sip-T vs 2.6% of control pts. The PROCEED registry (NCT01306890) assessed the risk of CVEs after sip-T treatment in mCRPC pts. Methods: Pts with mCRPC scheduled to receive sip-T or who had received sip-T ≤6 months prior were eligible. Treatment consisted of 3 sip-T infusions ~2 weeks apart. Primary objective was to define CVE risk after sip-T treatment. Secondary objective was to quantify OS. Follow-up was every 3 months after sip-T for a minimum of three years, death, or until otherwise off study. Results: Between 2011–2017, 1976 pts enrolled; median age 72 years; 87% Caucasians, 12% African American; 84% had bone, 32% lymph node, 4.6% visceral metastases. 1813 (95%) pts had all 3 and 1902 had ≥1 sip-T infusions. 1763 (93%) pts had CVE risk factors, including smoking (54%), alcohol use (57%), hypertension (65%), cardiovascular disease (61%). Median follow-up was 46.5 months. Of 1902 pts, 54 (2.8%) had a CVE (excluding transient ischemic attacks) after sip-T therapy or CVE rate (95% confidence interval [CI]) of 1.2 (0.9–1.6)/100 person-years compared with 1.52 (1.37–1.70)/100 person-years in 11,972 mCRPC pts from the SEER-Medicare database (1999–2013). Grade 3–4 catheter-related infection or sepsis was 0.4 and 0.2%, respectively, with no grade 5 catheter-related adverse events. Median OS was 30.7 (95% CI 28.6, 32.2) months. Of 1255 deaths, 77% were due to mCRPC progression with a median time to death from disease progression of 42.7 months (95% CI 39.4, 46.2). CD54+ counts, CD54 upregulation, and total nucleated cell counts in the sip-T product significantly correlated with OS, p < 0.001, hazard ratio (HR) 0.82, (95% CI 0.76, 0.93), p < 0.001, HR 0.51 (95% CI 0.44, 0.60), and p < 0.001, HR 0.57 (95% CI 0.50, 0.64), respectively. Conclusions: There was no excess rate of CVEs in men with mCRPC treated with sip-T compared with those who were not. In vitro immune activation measured in the sip-T product significantly correlated with OS. Clinical trial information: NCT01306890.
Risk of biochemical recurrence (BCR) in prostate cancer (PCa) patients (pts) with perineural invasion (PNI): Systematic review and meta-analysis.
Authors: Stephanie Fletcher, Nimer Alsaid, Chinmayee Katragadda, Jennifer Martin, Hani M. Babiker, Amit Mohan Algotar, Ali McBride, Karen MacDonald, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

e17060 Background: The association between PNI observed in radical prostatectomy and the risk of BCR in pts with PCa remains unclear. We performed a systematic review and meta-analysis to quantify overall BCR risk in subgroups of individuals with PNI. Methods: Eligible studies were retrieved from PubMed, Embase, Web of SCIENCE, Scopus and Google Scholar. Pooled multivariate hazard ratios (MHR), univariate hazard ratios (UHR) and univariate odds ratios (UOR) were calculated for eligible studies. Sub-analyses were performed for studies with mean follow-up time (MFU) of < 2 years (y), 2-3 y and > 3 y. Analyses were performed using random effect (RE) models to assess the pooled relative effects under consideration of heterogeneity among included studies. Results: A total of 29 studies were retained. The MHR analysis (n = 22) indicated that PNI is significantly associated with BCR events (HR = 1.53, 95%CI = 1.33-1.78). MHR sub-analysis revealed that the PNI~BCR association was not significant for studies with MFU < 2 y (HR = 1.39, 95%CI = 0.92-2.08), but was for 2-3 y (HR = 2.01, 95%CI = 1.48-2.72) and > 3 y (HR = 1.48, 95%CI = 1.25-1.75). The UHR analysis for 16 studies showed that PNI is significantly associated with BCR events (HR = 1.94, 95%CI = 1.46-2.57). UHR sub-analysis revealed that the PNI~BCR association was not significant for studies with MFU 2-3 y (HR = 1.35, 95%CI = 0.48-3.85), but was for < 2 y (HR = 1.78, 95%CI = 1.06-2.99) and > 3 yr (HR = 2.09, 95%CI = 1.69-2.58). The UOR analysis for 3 studies showed that PNI is significantly associated with BCR events (OR = 1.59, 95%CI = 1.19-2.11). UOR sub-analysis revealed that the PNI~BCR association was significant for studies with MFU 2-3 y (OR = 7.59, 95%CI = 2.66-21.70) and > 3 y (OR = 3.70, 95%CI = 2.27-6.04). Conclusions: Although individual studies differed in their findings about the association between PNI and predicted BCR risk, our meta-analyses revealed a significant association between PNI and predicted BCR risk in studies with longer follow-up. This suggests that BCR, if it were to occur, is likely to be detectable 2-3 y post-surgery. Thus, there is an increased risk of BCR in pts with PNI; if expressed, this risk is to show anytime 2-3 y post-surgery.
PARP1 expression in high-grade neuroendocrine carcinoma of the lung.
Authors: Hye Sook Kim, Ji-Youn Han, Geon Kook Lee, Jeong Hyun Lee
Journal: Journal of Clinical Oncology (2018)

e20562 Background: Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinoma (HGNEC) of the lung and remain among the fatal malignancies. Recent genetic studies revealed that poly-ADP ribose polymerase 1 (PARP1) is potential therapeutic targets in SCLC. However, the clinical significance of PARP1 expression in HGNEC remains to be defined. Methods: Between March 2001 and February 2014, 191 formalin-fixed, paraffin-embedded samples from patients with HGNEC of the lung at National Cancer Center were analyzed with immunohistochemistry. Results: PARP1 expression was observed in all HGNEC specimens with strong intensity in most specimens (intensity 3+ in 153/191, 80.1%). Strong PARP1 intensity was more frequently observed in SCLC histology than LCNEC histology (87.5% vs. 67.6%, p = 0.001). Total PARP1 score was higher in chemotherapy non-responders (278.1 vs. 259.7, p = 0.028) and PIK3CA mutated tumors (278.5 vs. 255.1, p = 0.03). Conclusions: PARP1 was highly expressed on the most HGNEC cells; however the pattern of expression were different from histology, PIK3CA mutation status and responsiveness to chemotherapy. Results of this study may suggest a need for biomarkers to be evaluated in the context of DNA repair pathways of HGNEC.
Expression of PD-L1, PD-L2 and PD-1 in thymic epithelial tumours (TETs).
Authors: Spyridon Gennatas, Angeles Montero Fernandez, Alex Bowman, John Ronquillo, Andrew G Nicholson, Sanjay Popat, Anne Bowcock
Journal: Journal of Clinical Oncology (2016)

e20107 Background: Targeting the programmed-death (PD-1) axis has achieved remarkable success in a variety of tumours. The expression and significance of PD-1, PD-L1 and PD-L2 in TETs is unclear. Methods: A tissue microarray (TMA) was constructed with 3 cores from each of 124 TETs and 18 thymic hyperplasias. The TMA was stained separately with PD-L1 and PD-L2 antibodies (both rabbit polyclonal, ThermoScientific) and PD-1 (mouse monoclonal, clone NAT105, Roche Ventana). CD45 and cytokeratin (MF116) stains were used to differentiate epithelia and lymphocytes. A pathologist and an oncologist blind to the diagnosis assigned an H-score to each sample, scoring the lymphocytic and epithelial component separately. All 142 cases were grouped as follows: A and AB (A), B1/B2/B3 (B), Carcinoma and NETT (C) and Hyperplasia (H). The Kruskal-Wallis (KW) test compared the average H-score between all groups and the Wilcoxon rank sum test was used for pairwise comparisons between the 4 groups. These were performed independently for PD-L1, PD-L2 and PD-1. Results: The histological breakdown of analyzed samples was 21 A, 29 AB, 25 B1, 26 B2, 5 B3, 10 CA, 8 NETT and 18 Hyperplasias. The expression of PD-L1, PD-1 and PDL differed significantly between the 4 groups (KW X2= 26.942, p = 6.05x106; KW X2= 23.367, p = 3.386x105 and KW X2= 40.249, p = 9,434x109 respectively). The epithelial PD-L1 H-score was high in TETs (119) with significantly higher staining of PD-L1 in C and B compared to A (p = 0.0455 for both). Epithelial PD-L2 H-score in TETs (84) was overall lower than for PD-L1 but exhibited the same trend with C > B (p = 0.00191), B > A (p = 0.01665), A > H (p = 0.00649). PD-1 staining was exclusively lymphocytic with H > A > B > C. PD-L1 and PD-L2 were present in lymphocytes of all TET subtypes, particularly A, AB and B1. Conclusions: Our resultsconfirm the presence of PD-L1 and demonstrate PD-L2 staining in the epithelium of TETs. The expression of PD-L1 and PD-L2 was higher in carcinomas and in the more aggressive B subtypes compared to A and AB. The significance of the extensive lymphocytic expression of these proteins is unknown. Staining heterogeneity was evident in all TETs, particularly in AB. These findings are of major importance in the face of ongoing Phase 1 trials in TETs with PD-1 inhibitors.
HAT1 as a target for the combination therapy with pazopanib and hyperthermia.
Authors: Chyong-Huey Lai, Chiao-Yun Lin, Angel Chao
Journal: Journal of Clinical Oncology (2016)

e17120 Background: Pazopanib, a multitargeted tyrosine kinase inhibitor, has been shown to have significant activity in the treatment of soft tissue sarcoma. However, the benefit of combining pazopanib and regional hyperthermia in treating leiomyosarcoma remains unclear. Methods: Effects of pazopanib and hyperthermia in leiomyosarcoma cell lines (SKN and SK-LMS-1 cells) were determined by cell viability, cell cytotoxicity, proliferation, cell apoptosis, colony formation assay, chromatin immunoprecipitation (IP) analysis, and in tumor xenograft model. Affymetrix oligonucleotide microarrays were used to screen the differential gene expression of leiomyosarcoma cancer cells treated with pazopanib and hyperthermia. The significantly differentially expressed genes were confirmed in 63 clinical specimens of leiomyosarcoma and 10 benign leiomyoma tissues by immunohistochemical analyses (IHC). Results: Synergistic effect of pazopanib and hyperthermia in leiomyosarcoma cells was observed in cell viability, cell cytotoxicity, proliferation, cell apoptosis, colony formation assay and in tumor xenograft model. HAT1 (histone acetyltransferase 1) was downregulated in pazopanib and hyperthermia treated leiomyosarcoma cell lines. HAT1 was significantly higher in the leiomyosarcoma than leiomyoma tissues in IHC analysis (p < 0.0001). Moreover, patients with high HAT1 histoscores had worse outcomes than those with low HAT1 expression (p < 0.05). Combination of pazopanib and hyperthermia had synergistic effects on acetylation of histone 4 on Lys 5 and Lys 12. Chromatin IP assay showed that -1250~-850 site is required for pazopanib and hyperthermia-repressed HAT1. Conclusions: Therapeutic effects of pazopanib and hyperthermia in leiomyosarcoma cancer cells were observed to converge at HAT1. The combined treatment may provide a potential option for patients with leiomyosarcoma.