tbuckley/cabot-search huggingface dataset:
Predictors of differential response to induction chemotherapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG).
Authors: Navin R. Pinto, Emily Hibbitts, Susan G. Kreissman, Meaghan P. Granger, Meredith Irwin, Rochelle Bagatell, Wendy B. London, Emily Gustava Greengard, Arlene Naranjo, Julie R. Park, Steven G. DuBois
Journal: Journal of Clinical Oncology (2018)

10532 Background: Induction chemotherapy plays an important role in the management of patients with high-risk neuroblastoma. Predictors of response to Induction therapy itself are largely lacking. We sought to describe clinical and biological features associated with differential response to Induction. Methods: Patients from the following COG high-risk trials with at least one disease evaluation during Induction were included: A3973; ANBL02P1; ANBL0532; and ANBL12P1. Response at end-Induction was evaluated by the 1993 International Neuroblastoma Response Criteria. The primary endpoint was partial response (PR) or better. A series of univariate analyses (Fisher's exact or chi-squared tests) were performed to compare response as a function of clinical or biologic predictor variables. For each predictor variable, the Holm-Bonferroni method was used to correct for multiple testing, using an overall α=0.05. A multivariate logistic regression model using significant predictors from univariate analyses was constructed to model PR or better. Results: The analytic cohort included 1,242 patients (79.8% with PR or better; 20.8% with CR; 9.1% with PD). Baseline factors significantly associated with a PR or better included age <18 months (87.4% with PR or better vs. 78.7% if older; p=0.0103), age <5 years (82.0% vs. 70.6% if older; p<0.0001), INSS <Stage 4 (89.0% vs. 78.4% if Stage 4; p=0.0016), MYCN amplification (85.5% vs. 77.1% if non-amplified; p=0.0006), 1p loss of heterozygosity (LOH; 85.6% vs. 76.0% if no LOH; p=0.0085), no 11q LOH (84.8% vs. 70.9% if 11q LOH; p=0.0004), and high mitosis-karyorrhexis index (MKI); 84.5% vs. 77.5% if low-intermediate MKI; p=0.0098). On multivariate analysis (n=407), the absence of 11q LOH was the only factor that remained significantly associated with PR or better (odds ratio: 1.962 compared to 11q LOH; 95% confidence interval 1.104-3.487; p=0.0216). Conclusions: Clinical and biological factors are associated with differential response to Induction chemotherapy. These findings may further improve our ability to predict treatment response.
Intramedullary nailing of forearm shaft fractures by biodegradable compared with titanium nails: Results of a prospective randomized trial in children with at least two years of follow-up
Authors: Linda Korhonen, Marja Perhomaa, Antti Kyrö, Tytti Pokka, Willy Serlo, Juhani Merikanto, Juha-Jaakko Sinikumpu
Journal: Biomaterials (2018)
Docetaxel in the treatment of metastatic hormone-sensitive and castration-resistant prostate cancer: A meta-analysis.
Authors: Shijia Zhang, Larysa Jessica Sanchez, Jieqi Liu, Yucai Wang, Narjust Duma, Victor Tsu-Shih Chang, Robert S. Alter, Martin Gutierrez, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2016)

e16505 Background: Docetaxel is a chemotherapeutic agent indicated for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). This study aims to evaluate the efficacy and safety data of docetaxel-based therapy in pts with metastatic hormone-sensitive prostate cancer (mHSPC) and mCRPC. Methods: PubMed and ASCO databases were searched for randomized control trials (RCTs) of docetaxel-based therapy for the treatment of mHSPC and mCRPC through December 31st, 2015. Study endpoints included overall survival (OS), progression free survival/failure-free survival (PFS/FFS), and grade 3 or greater adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and relative risks (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using MedCalc. Results: Eleven RCTs involving 12,468 patients were identified and included in the analysis. Three studies (4,137 pts) compared the addition of docetaxel to androgen deprivation therapy (ADT) vs. ADT alone in pts with mHSPC; 8 studies (8,331 pts) compared docetaxel-based combination with another agent (custirsen, lenalidomide, dasatinib, atrasentan, aflibercept, zibotentan, bevacizumab, or GVAX) to docetaxel alone in pts with mCRPC. Adding docetaxel to ADT improved OS (HR 0.75; 95% CI 0.62-0.90, P = 0.002) and PFS/FFS (HR 0.62; 95% CI 0.56-0.69, P < 0.001) compared to ADT alone in pts with mHSPC. However, it also increased the risks of grade 3-5 AEs, particularly febrile neutropenia (RR 12.91, 95% CI 7.60-21.94, P < 0.001). Docetaxel combined with another agent did not improve OS (HR 1.04; 95% CI 0.94-1.15, P = 0.494) or PFS (HR 0.93; 95% CI 0.83-1.04, P = 0.185) as compared to docetaxel alone in mCRPC pts who were taxane-naïve for metastatic disease. As expected, the combination therapy increased the risks of grade 3-5 AEs (RR 1.20, 95% CI 1.05-1.38, P = 0.009). Conclusions: Addition of docetaxel to ADT in the upfront treatment of mHSPC shows significant improvement in OS and PFS/FFS, but increases the risks of grade 3-5 AEs. In pts with mCRPC, to date, addition of another agent to docetaxel only increases toxicity.
Patient-reported frustrations in renal cell carcinoma (RCC) care delivery: Results of a joint European Association of Urology (EAU)/KCCure survey.
Authors: Cristiane Decat Bergerot, Dena Battle, Paulo Gustavo Bergerot, Daniel J. George, Hans J. Hammers, Eric Jonasch, Axel Bex, Borje Ljungberg, Nazli Dizman, Sumanta K. Pal, Michael D. Staehler
Journal: Journal of Clinical Oncology (2018)

4570 Background: A joint survey was developed by the EAU RCC Guidelines Panel and KCCure, a non-profit patient advocacy group, to ascertain patient perceptions towards adjuvant therapy for RCC (Battle D et al ASCO GU 2018). This survey included open-ended questions pertaining to sources of frustration in cancer-related care, the results of which are summarized herein. Methods: An online survey was conducted from April to June, 2017, publicized through social media and patient networking platforms. The survey obtained basic clinicopathologic, treatment related information, and open-ended questions asking for common sources of frustration in cancer-related care. Patients were also asked how they might reconcile these sources of frustration. Each response was analyzed and categorized into descriptive categories. The Kruskal-Wallis test was used to define associations between baseline characteristics and sources of frustration. Results: Among 450 patients with RCC, median age was 56, and 56% were female. The majority was diagnosed with clear cell histology (85%) and most patients had non-metastatic disease (73%). The most common sources of frustration were related to poor communication (20%), lack of confidence in diagnosis (18%), fear of recurrence/progression (14%) and financial issues (9%). Practical sources of frustration (e.g., lack of information, financial issues) were more common among patients with non-clear cell histology (P = 0.05) and older age (P = 0.01). In contrast, emotional sources of frustration (e.g., fear of recurrence/progression) were more common in females (P = 0.001). Patients posited that care could be improved if physicians demonstrated greater compassion (21%), spent more time supplying information (20%) and if they could circumvent financial issues (11%). Conclusions: RCC patients have varied and multiple concerns around care delivery. Based on this findings, practitioners should aim to better inform patients and should be cognizant of psychosocial issues surrounding their care. Certain baseline characteristics (age, gender and histology) can be considered in individualizing care delivery to minimize patient frustration.
ATALANTE (ENGOT-ov29): A randomized, double-blinded, phase III study of atezolizumab versus placebo in patients with late relapse of epithelial ovarian, fallopian tube, or peritoneal cancer treated by platinum-based chemotherapy and bevacizumab.
Authors: Jean Emmanuel Kurtz, Christian Marth, Ana Oaknin, Bernard Asselain, Klaus H. Baumann, David Cibula, Ignace Vergote, Tally Levy, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2018)

TPS5607 Background: The immunosuppressive environment is increased in Ovarian Cancer (OC) by the expression of T cell inhibitory receptors on tumor cells and immune cells. Targeting PD-1/PD-L1 pathway (an inhibitory immune pathway exploited by cancer) may restore CD8+ anticancer response from exhausted Tumor Infiltrating Lymphocytes (TILs). Bevacizumab (bev) is an anti-VEGF monoclonal antibody approved in the EU in first line or relapse for the treatment of advanced OC in combination with platinum-based chemotherapy (Cx) and in maintenance. VEGF has immunosuppressive properties, decreasing tumor access by TILs, increasing both PD-L1 expression on tumor cells and Treg activity. Hence there is evidence that anti-VEGF therapy and immunotherapy act synergistically. Methods: ATALANTE is a randomized (2:1), double blinded, phase III trial evaluating the efficacy and safety of adding the anti-PD-L1 monoclonal antibody atezolizumab (At) to Cx and bev in 405 OC patients (pts) in platinum-sensitive relapse. Main eligibility criteria include: ECOG ≤1, first or second platinum-sensitive relapse ( > 6 months), ECOG 0 or 1, normal organ function, absence of auto-immune disease or of chronic corticosteroid therapy. All patients must have a tumor biopsy at study entry for PD-L1 testing (stratification factor). Pts are treated with 6 cycles of platinum-based Cx (q3 or q4 weeks) plus bev + At (1200mg q3 weeks)/placebo followed by bev (15 mg/kg q3 weeks) plus At/placebo maintenance until progression or prohibitive toxicity. The primary endpoint is PFS based on RECIST v1.1 according to investigator assessment. The final PFS analysis will be performed when the number of predefined events is reached. The latest review by the Independent Data Monitoring Committee in July 2017 did not identify any safety issue and suggested that the trial can continue as planned. The study is currently recruiting internationally. Clinical trial information: NCT02891824.
A CNV computational model for clonal origin analysis of synchronous multifocal hepatobiliary and pancreatic tumors.
Authors: Weiqin Jiang, Weijia Jia Fang, Yongfeng Ding, Yi Zheng, Peng Zhao, Lulu Liu, Zhou Tong, Weilin Wang
Journal: Journal of Clinical Oncology (2016)

e15613 Background: Synchronous multifocal tumors are invariably seen in hepatobiliary and pancreatic cancer, however, because of the similar histological features, it is hard to identify the precise tissue clonal origin of the different lesions through routine pathologic diagnosis. Herein, we use genome-wide copy number variation (CNV) platform to explore the situation. Methods: CNV data of 598 cancer samples across hepatocellular cancer , cholangiocarcinoma and pancreatic cancer were compiled from The Cancer Genome Atlas dataset. We use Cancer Browser to structure their heatmaps and randomly allocated them to the training or test sets. A 10-fold cross-validation method was used to train the model on 9-fold and test it on the remaining 1-fold. GISTIC 2.0 extracted the landmark CNV events for each cancer. Stepwise logistic regression was performed to generate corresponding signature. Finally, the model was verified by two patients with synchronous multifocal hepatobiliary and pancreatic tumors. Results: The above algorithms showed CNV platform had good tissue specificity, yielding high sensitivity (91.4% ± 4.05%) and specificity (96.7% ± 2.49%) for analysis of tissue clonal origin in hepatobiliary and pancreatic cancer. When it came to clinical application, the model yielded an accuracy of ≥90%.The first application is a patient suffered from multiple nodules in pancreatic tail, upper biliary duct and omental. CNV analysis identified two different clones. Model matching found that the tumors in biliary duct and omental originated from the common biliary duct while the pancreatic lesion was originated just from pancreas. Another application is a patient who had multiple nodules in left liver, pancreas and abdominal lymph nodes. Unlike the first patient, CNV analysis showed these tumors belonged to the same clone. Model matching then proved it a clone of intrahepatic cholangiocarcinoma. Conclusions: We demonstrate a CNV computational model to accurately identify tissue clonal origin for synchronous multifocal hepatobiliary and pancreatic cancer. It is more meaningful that the model itself might be extended to other cancer types, as well as its diagnostic value for the cancer of unknown primary.
Immune cell surface proteins from tumor samples to predict patient clinical outcome.
Authors: Jasmin Radhika Desai, Aiwu Ruth He, Yuriy Gusev, Krithika Bhuvaneshwar, Coleman Smith, Alexander H Kroemer, Petra Prins
Journal: Journal of Clinical Oncology (2017)

e15630 Background: The incidence and mortality of Hepatocellular carcinoma (HCC) are rapidly increasing in the US. Treatments for advanced HCC are limited despite best efforts to develop therapeutics that target the deregulated pathways of HCC. Recent studies reveal a direct causal relationship between cancer and immune dysfunction, whereby tumor cells and their microenvironment can evade immune attack by exploiting various immunoregulatory mechanisms in a process termed “cancer immune editing”. The objective is to determine the relationship between immune cell surface protein transcripts from tumor samples and the clinical outcome of pts by performing exploratory analyses of liver cancer data from the cancer genome atlas (TCGA). Methods: We analyzed RNAseq data from a cohort of 75 HCC samples in the TCGA collection. We explored the association of expression of a group of specific markers for infiltrating lymphocytes (several subtypes) with overall survival (OS) and these results were confirmed by IHC analysis of the same cell subtypes in HCC samples from patients at GUH. Results: Among the 75 HCC cases analyzed, 25 pts had Hepatitis C (HCV), 25 had Hepatitis B (HBV), and 25 had HCV and HBV co-infection. Fourteen of the 75 cases were found to express the CD8B isoform. The LOG RANK survival test showed a significant association between CD8B levels and OS (ChiSq = 5.2, 1df; p = 0.0222), as did the Cox proportional hazard model for survival. The latter test showed that pts with HCC that did not express CD8B were at a higher risk of death compared with those who had CD8B-expressing HCC. Additional immune cell subtype specific transcripts are being tested. Based on analysis of differentially expressed gene differences between immune cell subtype ‘low’ vs. ‘high’ groups, pathways highly relevant to lymphocyte signaling and immune response and infiltration were identified. Thus, 5 tumor-infiltrating immune cell subtypes were found to have wide variability among patients. Using IHC, these cell subtypes were assessed in HCC samples from patients and correlated to clinical outcome. Conclusions: Immune cell specific transcripts in tumor samples may serve as a predictor of response to treatments that target immune evasion in cancer patients.
Phase 1 trial of trametinib alone and in combination with dabrafenib in children and adolescents with relapsed solid tumors or neurofibromatosis type 1 (NF1) progressive plexiform neurofibromas (PN).
Authors: Birgit Geoerger, Christopher L. Moertel, James Whitlock, Geoffrey Brian McCowage, Mark W. Kieran, Alberto Broniscer, Darren R Hargrave, Pooja Hingorani, Lindsay Baker Kilburn, Sabine Mueller, Lillian Tseng, Noelia Nebot, Kohinoor Dasgupta, Mark W. Russo, Elizabeth Fox
Journal: Journal of Clinical Oncology (2018)

10537 Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer and NF1 PN. Dabrafenib, a BRAF inhibitor, is active in children with BRAF V600–mutant tumors; however, activation of MAPK signaling in BRAF WT cells increases skin toxicity. Trametinib, a MEK inhibitor, targets MAPK activation in tumors harboring BRAF fusions and NF1 gene loss. This trial sought to establish the trametinib dose alone and in combination with dabrafenib in patients (pts) with relapsed solid tumors or progressive PN. Methods: Part A: safety and pharmacokinetics (PK) of trametinib (0.0125, 0.025, 0.04 mg/kg daily) were evaluated. Dose-limiting toxicity (DLT) during the first 4 wk and trough concentrations were used to determine the recommended dose (RD). Three age groups ( < 2 y, 2-12 y, > 12 y) were evaluated based on initial PK; trametinib 0.032 mg/kg was assessed in pts < 6 y. Part C: pts with BRAF V600–mutant tumors received the trametinib RD in combination with 50% or 100% of the established age-specific dabrafenib RD. Results: Part A: 40 pts (median age, 8 y [range, 0-18 y]) were enrolled. Median treatment (Tx) duration was 81 wk (range, 3-124 wk); 21 (53%) continue on Tx. DLTs (mucositis [n = 3 overall]) occurred in 5/15 pts receiving 0.04 mg/kg and 3/19 receiving 0.025 mg/kg. Frequent Tx-related adverse events (TRAEs) were paronychia (58%), diarrhea (48%), and rash (45%). Tx-related serious AEs (TRSAEs) occurring in > 1 pt included hyponatremia and pyrexia (2 each). The trametinib RD is 0.025 mg/kg daily for pts ≥6 y and 0.032 mg/kg for pts < 6 y. Part C: 12 pts (median age, 12 y [range, 2-18 y]) were enrolled. No DLTs were observed at 50% or 100% of the dabrafenib age-specific RD in combination with trametinib 0.025 mg/kg in pts ≥6 y. Median Tx duration was 41 wk (range, 11-67 wk); 8 pts continue on Tx. Frequent TRAEs were rash (67%) and pyrexia (50%). Decreased ejection fraction (n = 2) was the only TRSAE in > 1 pt. Assessment of pts < 6 y is ongoing. Conclusions: Age-specific dose, safety, and tolerability of trametinib alone and combined with dabrafenib were defined for children and adolescents; > 50% of pts continue on Tx. Clinical trial information: NCT02124772.
The Long-Term Effects of Exposure to Low Doses of Lead in Childhood
Authors: Herbert L. Needleman, Alan Schell, David Bellinger, Alan Leviton, Elizabeth N. Allred
Journal: New England Journal of Medicine (1990)

To determine whether the effects of low-level lead exposure persist, we reexamined 132 of 270 young adults who had initially been studied as primary schoolchildren in 1975 through 1978. In the earlier study, neurobehavioral functioning was found to be inversely related to dentin lead levels. As compared with those we restudied, the other 138 subjects had had somewhat higher lead levels on earlier analysis, as well as significantly lower IQ scores and poorer teachers' ratings of classroom behavior.
Targeted therapy for advanced salivary cancer with HER2 or hedgehog alterations: Interim data from MyPathway.
Authors: Razelle Kurzrock, Funda Meric-Bernstam, Herbert Hurwitz, John D. Hainsworth, David R. Spigel, Ron Bose, Charles Swanton, Howard A. Burris, Christopher Sweeney, Bongin Yoo, Mary Stanley Beattie, Rajesh Patel, Katja Schulze, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2017)

6086 Background: Salivary gland cancers comprise &lt;1% of cancers. Advanced cases have a 40% 5-year survival rate. Due to their rarity, no standard treatment guidelines exist. However, salivary duct carcinomas have morphological and gene expression profiles similar to breast cancers, and 20–40% of this subset have HER2 alterations. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatments in nonindicated tumor types with alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. We present interim data for patients with salivary cancer. Methods: Patients had advanced salivary cancer with HER2 (amplification, overexpression, and/or mutation) or Hh (SMO or PTCH-1) alterations, locally assessed by gene sequencing, FISH, or IHC, as applicable. Patients received standard doses of pertuzumab + trastuzumab or vismodegib, respectively, until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) by RECIST v1.1. Results: As of Nov 30, 2016, 8 patients had been treated for salivary cancer, all carcinomas (7 had HER2 alterations; 1 had an Hh alteration). One HER2 patient without a post-baseline tumor assessment by data cut-off was not evaluable for efficacy. Characteristics and outcomes are shown (Table). Of 6 patients with a complete response (CR) or partial response (PR), 5 patients were still receiving study treatment by the data cut-off, with a median time on treatment of 4.6 months (range 1.4–12.5). There were no new safety signals. Conclusions: Six of 7 patients (86%) with advanced salivary carcinoma achieved CR or PR by targeting HER2 (n=5) or Hh (n=1) alterations. These promising results merit study of these treatments in additional patients. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Impact of second-line treatment (2L T) in advanced pancreatic cancer (APDAC) patients (pts) receiving first line Nab-Paclitaxel (nab-P) + Gemcitabine (G): An Italian multicentre real life experience.
Authors: Guido Giordano, Antonio Febbraro, Michele Milella, Vanja Vaccaro, Davide Melisi, Luisa Foltran, Vittorina Zagonel, Alberto Zaniboni, Paola Bertocchi, Francesca Bergamo, Alessandro Passardi, Gianna Musettini, Elisa Giommoni, Aldo Iop, Maria Bernardetta Aloi, Silvia Vecchiarelli, Enrico Vasile, Giovanni Lo Re, Mariacristina Di Marco, Ferdinando De Vita
Journal: Journal of Clinical Oncology (2016)

4124 Background: There is no standard of care for 2L T in APDAC. Nab-P + G combination has showed superior efficacy compared to G alone in MPACT phase III study. Here we report data of a retrospective analysis evaluating outcomes of 2L T following first line Nab-P + G. Methods: Clinical records of 250 APDAC were retrospectively reviewed, evaluating survival outcomes in pts receiving 2L T according each treatment schedule. OS and PFS were estimated by Kaplan-Meier method with 95% CI. Pearson correlation analysis was performed to investigate correlation between first line outcomes and 2L T response or survival. Results: At time of data analysis among 221 pts who experienced disease progression 122 (55%) received 2L T and 99 (45%) best supportive care (BSC). Baseline characteristics of pts receiving 2L T were: median age 66 (range 39-79), M/F:66/56, ECOG PS 0/1/2: 41/55/26. 35.5% had multiple organ involvement and 28.7% had received adjuvant treatment. In 2L T pts FOLFOX/XELOX, FOLFIRI, FOLFIRINOX (classic or modified) and single agent therapies were used in45%, 22%, 18% and 15% respectively. Median OS in pts receiving 2L T was 13.5 months (95% CI 12.659-14.341) vs 6.8 months in pts receiving BSC (95% CI 5.567-8.033), p < 0.0001. According to 2L T schedule median OS was 12.9 (95% CI 11.772-14.028), 13.2 (95% CI 10.909-15.491), 13.8 (95% CI 11.069-16.531), 12.3 (95% CI 10.620-13.980) in pts FOLFOX/XELOX, FOLFIRI, FOLFIRINOX (classic or modified) and other single agent therapies respectively, with no significant differences between each group. A trend to significant correlation was observed between response to first line treatment and response to 2L T (Pearson correlation 0.298, Sig 2 tails p = 0.06) as well as between longer first line PFS ( ≥ 6 months) and 2L PFS ≥ 4 months (Pearson correlation 0.321, Sig 2 tails p = 0.002). Conclusions: Our data show that 2L T is an option to improve outcome for more than a half of pts following first line Nab-P + G. Both response and PFS during first line Nab-P + G treatment may influence 2L T outcomes.
TCT-674 Impact of coronary calcification on the agreement between coronary CTA and conventional angiography in the SYNTAX score treatment decision
Authors: None Saima Mushtaq, Carlos Collet, Laurent Macron, Francesco Maisano, Yosuke Miyazaki, Maurizio Roberto, Giorgia Bonalumi, Marco Guglielmo, Cristina Ferrari, Paolo Olivares, Laura Cavallotti, Gianluca Pontone, Yoshinobu Onuma, Antonio Bartorelli, Patrick Serruys, Daniele Andreini
Journal: Journal of the American College of Cardiology (2018)