tbuckley/cabot-search huggingface dataset:
Association of race and ethnicity with hospice use in pediatric oncology patients.
Authors: Rachel Thienprayoon, David Leonard, Simon Craddock Lee, Naomi Joan Winick
Journal: Journal of Clinical Oncology (2012)

e19536 Background: Palliative care is aimed at preventing or relieving symptoms and suffering caused by a life-threatening condition. At the end of life, hospice is an important provider of palliative care. Adult minorities are underserved by hospice, but little is known regarding the prevalence of pediatric hospice use or the characteristics of its users. We sought to determine whether race and ethnicity were associated with hospice enrollment in pediatric cancer patients. Methods: We undertook a retrospective cohort study of oncology patients in our institution who died between January 1, 2006 and December 31, 2010. Inclusion criteria were patients treated for cancer or bone marrow transplant in which a hospice referral was appropriate. Exclusion criteria were age greater than 18 at diagnosis, death off treatment unrelated to cancer, transfer of care, death due to trauma or an acute process, if oncology or bone marrow transplant was not the primary service and if a patient was lost to follow up but recorded as deceased. The primary outcome variable was hospice enrollment, the primary predictor variable was race/ethnicity, and secondary predictor variables were patient diagnosis, religion and payer status. 202 patients were initially identified; 114 were eligible for the study, of which 95 were enrolled on hospice. The most common reason for ineligibility was death due to an acute process (n=46); other reasons included transfer of care (n=18), oncology not the primary service (n=9), patients lost to follow up and recorded as deceased (n=7) and death off treatment unrelated to cancer (n=2). Results: Multivariate logistic regression determined that race was significantly associated with hospice use (p=0.02), even after controlling for patient diagnosis (p=0.01) and payer status (p=0.04). In patients enrolled on hospice, race was not significantly associated with dying on hospice (p=0.10), even after controlling for diagnosis (p=0.08), payer status (p=0.15) and religion (p=0.57). Conclusions: These results indicate that cultural factors play a role in hospice enrollment in pediatric oncology. More studies are warranted to elucidate these factors, and to understand why families choose hospice for children dying of cancer.
Plasma TIMP-1 in patients with metastatic colorectal cancer treated with first-line oxaliplatin-based therapy with or without cetuximab: Results from the Nordic VII study.
Authors: Line Schmidt Tarpgaard, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorbye, Tone Ikdahl, Ib Jarle Christensen, Camilla Qvortrup, Elin Kure, Per Pfeifer, Hans J. Nielsen, Nils Brünner
Journal: Journal of Clinical Oncology (2013)

e14710 Background: Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a biomarker in patients with metastatic colorectal cancer (mCRC). TIMP-1 inhibits matrix metalloproteinases and has tumor promoting functions. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based but not oxaliplatin-based treatment in patients with mCRC. Based on our prior studies, we here tested the hypothesis that high pretreatment plasma TIMP-1 correlate with short overall survival (OS) and short progression-free survival (PFS) but not response rate (RR) in patients with mCRC included in the NORDIC VII Study in which patients received oxaliplatin-based therapy. Methods: In the NORDIC VII Study patients were randomized to: A) Nordic FLOX; B) Nordic FLOX + cetuximab or C) Nordic FLOX intermittently + cetuximab continuously. Plasma samples for TIMP-1 analysis were available from 426 patients. Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic ELISA. Results: The three study populations were comparable and not different from the total intention to treat population. The median pretreatment plasma TIMP-1 was 269 ng/mL (58-1318 ng/mL). KRAS mutated in 149 patients (35%). There was no interaction between treatment arms and pretreatment plasma TIMP-1 either for PFS (p = 0.16) or OS (p = 0.64). High pretreatment plasma TIMP-1 was associated with shorter PFS (HR=1.22, 1.07-1.39, p=0.003) and shorter OS (HR=1.55, 1.36-1.80, p&lt;0.0001). RR did not correlate significantly to pretreatment plasma TIMP-1 (OR=1.16, 0.91-1.49, p=0.22). Multivariate analysis (TIMP-1, Köhne index, KRAS and BRAF status, CRP, CEA, age, gender) demonstrated that high pretreatment plasma TIMP-1 was not an independent biomarker of PFS (HR=1.06, 0.88-1.28, p=0.52) or OS (HR=1.19, 0.96-1.47, p=0.11). Conclusions: Plasma TIMP-1 is a prognostic biomarker in patients with mCRC treated with 1st line oxaliplatin-based therapy +/- cetuximab. A predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment, and no significant treatment by marker interaction was observed.
The use of electronic health record systems to create treatment summaries and survivorship care plans.
Authors: Katherine Ramsey Gilmore, David K Choi, Patricia Chapman, Paula A. Lewis-Patterson, Guadalupe R. Palos, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2017)

56 Background: The Commission on Cancer’s recent mandate stated that accredited programs issue treatment summaries (TSs) with survivorship follow-up care plans (SCPs). ASCO’s model of survivorship care also supports the use of these documents. One of the primary purposes of the documents is to enhance coordination and communication between the oncology team and primary care providers. Here we describe the experience of a survivorship program in using electronic health records (EHR) to develop TSs and SCPs. Methods: An interdisciplinary team at an academic cancer center was appointed to develop clinical tools to facilitate the creation and dissemination of TSs and SCPs. Enhancements were made to an institutional off-the-shelf EHR system that automatically populated available treatment information to the TS. This system used SmartLinks to pull data from the primary source of entry (e.g. surgical history, chemotherapy administered, and cancer stage). Clinicians edited and added pertinent information not automatically generated using one of the 19 disease-specific templates that provided lists of common treatments for various cancers. Electronic routing functions existed to share TSs with external providers through the medical records department. Results: From March-Sept, 2016, 766 SCP were completed by 50 providers in 14 clinics. Reports were created in the EHR to track SCPs and TS metrics. Data was reported from the TS on both a patient level and aggregate level by provider and clinic. Patient level data allowed providers to track incomplete TSs and edit them directly from the report. Of the TSs completed, 528 (69%) have been shared with patients and 261 (34%) have been shared with their community-based providers. Conclusions: EHRs provide a mechanism to successfully create and share TSs and SCPs among team members and primary care providers. They promote patient-provider education and communication about follow-up care. Research is needed to determine how they enhance coordination and ultimately outcomes for long-term survivors.
Correlation of breast cancer risk in European BRCA2 mutation carriers with birth cohort.
Authors: Muy-Kheng Maria Tea, Regina Kroiss, Daniela Muhr, Christine Fuerhauser-Rappaport, Teresa M. U. Wagner, Christian F. Singer
Journal: Journal of Clinical Oncology (2012)

1537 Background: Mutations in the Breast Cancer Gene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2) lead to an elevated risk of developing breast (BC) and ovarian cancer (OC). However, risk estimates vary, depending on the study population. Furthermore, there are indications that birth cohort can influence the cancer risk. We investigated the risks for BC and OC associated with BRCA2 mutations in a cohort of female mutation carriers of a genetically heterogeneous central European population who were identified by molecular genetic testing in our institute. Methods: This study included 171 Caucasian women from Austria who underwent genetic counseling and where molecular genetic analysis identified a mutation in the BRCA2 gene at the Medical University of Vienna, Division of Senology, in Austria. A total of 57 healthy and 114 affected BRCA2-carriers were detected. The risk was estimated using the product limit method. The log rank test was used to compare different strata. Results: The risk of developing cancer to age 70 was found to be 85% for BC (95% CI 77–93%) and 31% for OC (95% CI 16–46%) in our BRCA2 study population. Female BRCA2-carriers born in 1958 or later were at a significantly higher risk of developing BC (p&lt;0.001; 88% vs. 46% to age 40) but not of OC (p is not significant; 0% vs. 2% to age 40) compared to mutation carriers born earlier. Conclusions: We conclude that female BRCA2 mutation carriers should also be counseled about their cohort-dependent cancer risk, especially for breast cancer. Further research about variables that may affect cancer risk like lifestyle-related factors should be considered.
"Randomized, placebo-controlled, double-blind trial of (purified) dry extract of Paullinia cupana (guaraná) for chemoradiation-related fatigue and quality of life in patients with head and neck cancer.
Authors: Suelen Patrícia dos Santos Martins, Cynthia lemos Ferreira, Lilian Martins Arruda, Auro Del Giglio
Journal: Journal of Clinical Oncology (2015)

e17041 Background: Fatigue is a symptom in chemoradiation patients and currently there is no effective treatment for its management. Guarana (Paullinia cupana) is an amazonic plant which has shown an activity for chemotherapy induced fatigue. We aimed at evaluating Guarana’s activity in fatigue and Quality of Life (QOL) in head and neck cancer patients subjected to chemoradiation. Methods: This prospective phase II study, we evaluated 60 patients with head and neck cancer, stages I-IV, randomized into two arms: placebo versus Guarana 50mg twice-daily during Cisplatin given every three weeks during radiation. We used FACT-HN , EORTC-HN35 and EORTC -Q30 questionnaires before treatment, after second and third chemotherapy to assess fatigue and quality of life. Results: There was significant worsening of overall EORTC-Q30 (p = 0.0054), functional (p = 0.018) and symptomatic (p = 0.0042) domains after the first cycle of chemotherapy during radiation in patients who used guarana. However, there were no significant differences between two groups in any of the aforementioned domains when we compared the first baseline scores and the last one, at the end. Considering the FACT - HN35 questionnaire, the guarana group showed significant improvement after the first cycle of chemoradiotherapy for
TH-4000, a hypoxia-activated EGFR/Her2 inhibitor to treat EGFR-TKI resistant T790M-negative NSCLC.
Authors: Adam Vorn Patterson, Shevan Silva, Chris Guise, Matthew Bull, Maria Abbattista, Annie Hsu, Jessica D Sun, Charles P Hart, Tillman E. Pearce, Jeff Bruce Smaill
Journal: Journal of Clinical Oncology (2015)

e13548 Background: TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible tyrosine kinase inhibitor (TKI) of wild type (WT) EGFR, mutant (Δ19) EGFR and Her2. Hypoxia tumor targeting may allow for greater intratumoral dose intensity without dose limiting systemic toxicity. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that mutant EGFR NSCLC with WT EGFR present (heterozygous) is associated with limited response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of current EGFR-TKI resistance. Phase 1 clinical trial established the MTD of TH-4000 at 150 mg/m2/wk. Here we report translational studies supporting initiation of a Phase 2 trial. Methods: The activity of TH-4000 and erlotinib were assessed in a heterozygous (WT/ Δ19) EGFR PC9 tumor xenograft model (n = 6-9/grp). Erlotinib was dosed daily at a human-matched plasma PK equivalent (10 mg/kg, po). TH-4000 was dosed weekly (15 mg/kg, ip) as a single-agent or added to erlotinib at Day 14. Multi-time point detection of plasma and tumor TH-4000 and TKI were measured by LC/MS/MS. Tumor biomarkers were assessed by western blot. Results: PC9 was 8% hypoxic. All PC9 tumors progressed on erlotinib while all tumors regressed on TH-4000 alone or when added 14 days into erlotinib therapy, suggesting an ability to prevent or overcome resistance to TKI treatment. In the same model, single-dose administration of 15 mg/kg (ip) TH-4000 achieved a plasma AUC equivalent to 32 mg/m2 (IV) in humans, well below the MTD defined in Phase 1 trial. Preclinical PK/PD studies of single-dose TH-4000 (15 mg/kg) showed prolonged prodrug residency in tumor tissue (T½39 h) releasing TKI steadily over 7 days with EGFR shut down maintained for a week. Conclusions: TH-4000 was more effective than erlotinib in a heterozygous (WT/Δ19) EGFR PC9 model either upfront as a single-agent or when added to erlotinib after progression. Based on these data, once weekly administration of TH-4000 (150 mg/m2) is proposed in a Phase 2 trial planned in EGFR activating-mutation confirmed NSCLC patients who have progressed on TKI therapy and are T790M-negative.
Quality assurance study of real-time targeted massive parallel sequencing (MPS) comprehensive cancer panel (CCP) and network pathway analysis in early breast cancer (EBC).
Authors: Paul N. Mainwaring, Christopher Pyke, Darren Korbie, Michael Pheasant, Kate O'Neill, Ken Musgrave, Mattias Trau
Journal: Journal of Clinical Oncology (2014)

11092 Background: We undertook a prospective quality assurance study in 63 women with early breast cancer (EBC) identifying technical issues that required modification for real-time integration of MPS with clinical and pathology parameters for clinical decision making. Methods: Pre-operatively, patients underwent a 2 step formal informed consent process. Samples were collected fresh into Qiagen PaxGene Tissue Container preserving both morphology and biomolecules with lysis of tissues overnight. Day 2 and 3; DNA extraction was performed using the Qiagen DSP kit over 1 hour. DNA and RNA MPS Ampliseq CCP was performed on Life technologies Proton P1 chip using in-house modifications in order to increase the fidelity of library preparation. Days 4-6 manually curated bioinformatics against publicly available mutation databases (e.g. COSMIC etc.) Day 7 communication of results. Results: The median age was 55, (32-84), 43 (66%) were postmenopausal. Histopathology IDC 47 (72%), ILC 8 (12%), NOS 5 (8%) metaplastic 2 (3%), mucinous 1 (2%). TNM Staging: Tis 1 (2%), T1a 2 (3%), T1b 13 (20%), T1c 25 (38%) T2 21 (32%); N0 48 (74%), N1mi 1 (2%), N1a 3 (45%), N2a 1 (2%), N3 5 (8%). Hormone receptors antibodies: ER (Roche SP1) Strong 46 (71%), Moderate 3 (5%), Weak 3 (5%), Negative 12 (18%); PR (Roche 1E2) Strong 25 (38%), Moderate 20 (31%), Weak 4 (6%), Negative 15 (23%); HER2 IHC (Ventana 4B5) Strong 2 (3%), Moderate 116 (17%), Weak 19 (29%), Negative 31 (48%); HER2 SISH (Ventana inform single probe); 2 SISH positive (mean copy number 20 & 29.6); 12 patients (18%) triple negative. Molecular aberrations identified included oncogenes TP53 7(13%), PIK3CA 16(29%) HRAS 2(4%), RUNX1 1(2%), STK11 1(2%), AKT1 1(2%) JAK2 1(2%); tumour suppressor genes MLL3 3 (5%), MSH6 1(2%), ARID1A 1(2%) UBR5 4(7%), and in the germline in tumour suppressor genes EPHB6 1(2%) NF1 1(2%) and LTK 1(2%). CNV, MethylSeq & RNASeq data will be presented in the context of network analysis. Conclusions: In summary, many challenges face the clinical laboratory developing high throughput desktop MPS. However, multilevel genomic information integration is possible within clinically relevant time-frames.
Abstract A15: Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells
Authors: Alice Galbiati, Marianna Penzo, Maria Giulia Bacalini, Carmine Onofrillo, Ania Naila Guerrieri, Paolo Garagnani, Claudio Franceschi, Davide Treré, Lorenzo Montanaro
Journal: Cancer Research (2017)

Abstract Alterations of ribosome biogenesis and protein synthesis play a direct role in the development and the behavior of tumors. The accessibility and transcription of ribosomal genes are controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by its downregulation. We studied the consequences of inducible JHDM1B knock-down (KD) in cell lines derived from transformed (MDA-MB-231) and untransformed (MCF-10A) mammary epithelial cells. In these cellular models, sustained JHDM1B down-regulation triggered an increase in 45S pre-rRNA transcription and processing, associated with a re-modulation of the H3K36me2 levels at the rDNA loci. By means of the EpiTYPER assay, we observed that JHDM1B KD reproducibly induced quantitative changes in DNA methylation of specific CpG sites in rDNA genes. By polysomal profile analysis, we also found that JHDM1B KD induced an higher content of ribosomes in both the pre-polysomal and polysomal fractions indicating an increase in global protein synthesis. We then investigated in vitro and in vivo the behavior of cells after JHDM1B KD and the associated stimulation of ribosomes biogenesis. JHDM1B down-regulation conferred more aggressive features to the tested cellular models, which acquired a greater clonogenic and invasive potential in vitro. The study of tumors generated in nude Balb/c mice after xenografting MDA-MB-231 cells, indicated that JHDM1B KD triggered an incremental (although not statistically significant) trend in tumor growth. In addition, the selective nucleolar staining of sections from these tumors revealed a significant increase in the average nucleolar area after JHDM1B KD. Taken together, these data indicate that the reduction of JHDM1B leads to an increase in ribosome production and to a more aggressive cellular behavior in mammary gland cells. Citation Format: Alice Galbiati, Marianna Penzo, Maria Giulia Bacalini, Carmine Onofrillo, Ania Naila Guerrieri, Paolo Garagnani, Claudio Franceschi, Davide Treré, Lorenzo Montanaro. Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A15.
Whole-genome DNA and RNA sequencing in patients with metastatic colorectal cancer (mCRC).
Authors: Simon Daniel Baxter, Howard John Lim, Yaoqing Shen, Janessa J. Laskin, Daniel John Renouf, Stephen Yip, David Huntsman, Stephen K. L. Chia, Yvonne Li, Katayoon Kasaian, Peter Eirew, Sreeja Leelakumari, Yussanne Ma, Samuel Aparicio, Steven Jones, Marco Marra
Journal: Journal of Clinical Oncology (2014)

e22078 Background: mCRC carries a high mortality rate, and invariably becomes resistant to treatment. Whole genome sequencing (WGS) of DNA and RNA, and bioinformatic analysis can be performed in a clinically relevant timeframe. We describe our experience with WGS in 3 pts with mCRC. Methods: Pts with refractory mCRC were recruited. Fresh tumor biopsy, blood samples, and archival tumors were analyzed. Samples underwent Ion Torrent AmpliSeq cancer panel analysis and comprehensive DNA (80X) and RNA sequencing followed by in-depth bioinformatic analysis. Signalling pathway abnormalities including somatic mutations, copy number alterations, structural rearrangements, and corresponding gene expression changes were identified. Aberrant pathways were matched to drug databases and literatures searches to identify potential therapeutics. Results: We recruited 3 pts with mCRC, all of whom had received at least two lines of systemic therapy. Pt #1 was a 30 yo woman with KRAS-wild-type mCRC. Tissue was analyzed from the liver and primary colon lesions. The tumor was found to have a BRAF V600E mutation. In the metastatic lesion, a striking upregulation of VEGF-A was seen compared with archival tissue, possibly representing the tumor’s response to bevacizumab therapy. There was also upregulation of MAGI1 which may reflect COX-2 inhibition from aspirin treatment. Pt #2 was a 64 yo woman with KRAS-mutant mCRC. Tissue was analyzed from an abdominal wall mass. Aberrations were concentrated in FGFR, cell cycle, Notch, and Wnt signaling pathways. While originally characterized as KRAS-mutant, WGS revealed that this activating KRAS mutation was not actually expressed in tumor cells. Pt #3 was a 63 yo male with KRAS-mutant mCRC. Tissue was analyzed from a liver biopsy. Aberrations again were noted in pathways involving FGFR, and WNT. Mutations were noted in a number of tumor suppressor genes including TP53, APC, and EPHA3. In each case, plausible drug options were identified to target these pathways. Conclusions: WGS is a useful tool to interrogate tumor biology, and can reveal abnormalities in signaling transduction in patients with mCRC. This information may guide therapeutic strategies beyond what is yielded from standard mutation panels.
Efficacy and tolerability of trabectedin in heavily pretreated soft tissue sarcomas (STS).
Authors: Teresa Alonso, Pablo Gajate, Antonio Casado, Eduardo Raul Segura Gonzalez, Luis Ortega, Juan Luis Cebrian, Pablo Talavera, Jon Zugazagoitia, Daniel Acosta, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2012)

e20513 Background: Advanced STS have a dismal prognosis with a median overall survival of 1 year, reported in most phase III clinical trials. Although newer targeted therapies are currently being evaluated, chemotherapy continues to be the mainstay of treatment. However, due to the limited activity of current treatments, new therapies are needed. Trabectedin, an alkylating agent to the minor groove of DNA, has demonstrated significant activity after failure of anthracyclines and ifosfamide. Methods: This is a retrospective analysis of 22 patients diagnosed with advanced, heavily pretreated STS, treated with trabectedin in a single institution. From 06/ 2000 to 06/ 2011, trabectedin was administered as a 3-hour infusion every 21 days at a dose of 1.1-1.5mg/m2 with steroid premedication. No patients were excluded from this analysis. Results: Median age was 53 years (range 21-82). The most frequent histologic subtypes were: 27% liposarcomas, 18% leiomyosarcomas, 13% malignant fibrous histiocytomas and 9% synovial sarcomas. One third of patients had received 3 or more prior therapy lines. Overall response rate was 8.33% and stable disease (more than 16 weeks) was achieved in 36.3% of patients (75% of liposarcomas and 50% of leiomiosarcomas). The median duration of response was 11 weeks (range 4-22). Dose reduction was required in two patients, but no patient discontinued treatment due to drug-related toxicity. There were no treatment-related deaths. The most relevant toxicity was grade 3/4 neutropenia in 25% of patients (one case of febrile neutropenia). Grade 3/4 transaminitis was observed in the only patient who received trabectedin with doxorubicin for one cycle, and continued with trabectedin monotherapy without further liver function test disturbances. A case of transient rhabdomyolysis was observed; the patient had mild renal dysfunction and liver metastases, but recovered completely. Grade 1/2 nausea, vomiting and asthenia were reported in 8.33%, 4.17% and 45.83% of patients, respectively. Conclusions: Trabectedin achieves significant clinical benefit in heavily pretreated advanced STS patients. Trabectedin was well tolerated with reversible and manageable toxicity, demonstrating an acceptable safety profile.