tbuckley/cabot-search huggingface dataset:
Impact of genomic profiling on treatment decisions for patients with melanoma and colorectal cancer cohorts.
Authors: Eman Biltaji, Trang H. Au, Keith Gligorich, Mary P. Bronner, David D. Stenehjem, Diana I. Brixner
Journal: Journal of Clinical Oncology (2017)

66 Background: Clinical guidelines recommend RAS testing and BRAF testing in CRC and melanoma, respectively, to guide treatment (tx) decisions. However, there are limited data to support routine multi-gene profiling. This study evaluated the impact of multi-gene profiling on genomically-guided tx decisions in patients with CRC or melanoma. Methods: A retrospective cohort study using combined data from UUHC Electronic Warehouse, Huntsman Cancer Institute (HCI) tumor registry, ARUP laboratories, and Foundation Medicine. Included patients were treated at HCI for CRC or melanoma and had genomic profiling (2012-2016). The index date was date of first genomic profiling result and impact on practice was measured by rate of genomically-guided therapy use. Results: Among 127 genomically-profiled patients with CRC, 66 (52%) received therapy. Patients were predominantly male (64%), aged 57 years (median) at diagnosis, had advanced disease (52%), received three tx lines (mean) at baseline, and had three mutations (mean) detected. Actionable mutations, other than RAS,occurred in 43.9% of tested patients; and only 10.1% of these patients received genetically-guided tx. In the CRC cohort 55% are still receiving standard of care tx, and may benefit from testing results in the future. Among 186 genomically-profiled patients with melanoma, 123 (66.1%) received therapy. Patients were predominantly male (63%), aged 60 years (median) at diagnosis, diagnosed at earlier stages (68%), received two tx lines (mean) at baseline, and had two mutations (mean) detected. Actionable mutations, other than BRAF V600E/K, occurred in 14.6 % of tested patients; and only 5.6% of these patients received genetically-guided tx. In the Melanoma cohort 77% are still receiving standard tx. Actionable mutations and genomically guided tx decisions will be presented. Conclusions: Genomic profiling lead to modest increase in genetically-guided therapy. The incremental clinical and economic benefit of guideline-recommended testing needs further investigation by cancer type.
Improving consistency of high quality diagnosis, staging, and treatment using measurement.
Authors: Shaheena Mukhi, John Srigley, Corinne Daly, Mary Agent-Katwala
Journal: Journal of Clinical Oncology (2017)

217 Background: To improve variability in diagnosing and treating cancer resection cases, six Canadian provinces implemented standardized pathology checklists to transition from narrative to synoptic reporting. In clinical practice, pathologists are electronically capturing data on the resected cancer specimens synoptically for breast, colorectal, lung, prostate, and endometrial cases. Though data were collected in a standardized format, consensus based indicators were unavailable to coordinate action across Canada. Objectives: We aimed to develop indicators to measure consistency of high quality cancer diagnosis, staging, prognosis and treatment, and coordinate action. Methods: A literature review was conducted with the input of clinical experts to inform the development of indicators. 50 clinicians from x jurisdictions reviewed, selected and ranked 33 indicators, initially drafted. Clinicians also provided input on the clinical validity of the indicators and set targets based on evidence. Clinicians reviewed the baseline data, confirmed the clinical usefulness of indicators, and assigned indicators into three pioneered domains. Results: 47 indicators were developed and categorized into one of three domains: descriptive, which provide data on intrinsic measures of a patient’s tumour, such as stage or tumour type; process, which measure the quality of data completeness, timeliness and compliance; and clinico-pathologic outcome, which examine surgeon or pathologist effect on the diagnostic pathway, such as margin positivity rates or adequacy of lymph node removal. Examples of indicators are: margin status; lymph node examined, involved and retrieval; histologic type and grade distribution; lympho-vascular invasion; pT3 margin positivity rate. Conclusions: The indicators have set a framework for: measuring consistency and inconsistency in diagnosing and staging cancer; for organizing conversations and multidisciplinary group discussions; and establishing the culture of quality improvement.
Genotyping upper gastrointestinal cancer in daily clinical care.
Authors: Thomas Zander, Michael Kloth, Shahram Zoghi, Laura Groneck, Birgit Cremer, Roland Schnell, Marcel Reiser, Jutta Benz, Tom Luedde, Achim Rothe, Yon-Dschun Ko, Andreas Draube, Stefan Paul Moenig, Juergen Wolf, Arnulf H Hölscher, Reinhard Buettner
Journal: Journal of Clinical Oncology (2014)

e15004 Background: Cancer is driven by somatic genetic alterations. Recently molecular subtypes have been identified in a number of different cancer types such as lung cancer, melanoma or GIST. Little is known on the distribution of genetic subtypes of upper gastrointestinal cancer in daily routine. Methods: We build up a molecular diagnostics platform for patients with incurable upper gastrointestinal tumors starting Q1/13 at our center for GI cancer in Cologne. In addition, several participating private practices and non-academic hostpitals are offered a comprehensive panel of molecular diagnostic (FGFR1, FGFR2, MET, ERBB2, KRAS, NRAS, BRAF, PIK3CA, TP53, MSI). Pathological reports are send back including a treatment recommendation. Results: Molecular diagnostics on the first 156 consecutive patients (Oesophageal cancer 108, gastric cancer 47) are presented. In squamous cell esophageal cancer the following frequencies of genetic alterations were observed: TP53 mut 89%, NFE2L2 25%, KEAP1 17%, PIK3CA 14%, FGFR1 amp 22% without significant difference in frequency to 328 squamous cell lung tumors. In adenocarcinoma of upper GI we found amplifications of FGFR2 (6%), MET (12%), EGFR (8%), ERBB2 (10%). TP53 (75%) and PIK3CA (3%) were mutated in lower frequency compared to squamous cell esophageal carcinoma. Conclusions: Comprehensive molecular screening on a daily routine is feasible for patients with upper GI tumors. More than 30% of patients harbour potentially targetable genetic alterations amenable to clinical trials. Squamous cell esophageal cancer genetically highly resembles squamous cell lung cancer. Updated data on survival will be presented.
Serial assessment of regulatory T cells (Tregs) in pediatric AML: A prospective study.
Authors: Anuj Kumar Bansal, Surender Kumar Sharawat, Ritu Gupta, Vishnu kumar Sreenivas, Sameer Bakhshi
Journal: Journal of Clinical Oncology (2012)

9549 Background: Data of Tregs in pediatric AML is lacking. The study objectives were determining Tregs in pediatric AML at diagnosis and follow up; and correlating with outcome. Methods: From Nov 2010-May 2011, 30 consecutive AML patients ≤ 18 years were prospectively enrolled with 6 healthy controls. All patients received daunorubicin / cytarabine induction and 3 courses of cytarabine. Tregs (CD4+CD25+FoxP3+) were assessed at diagnosis, post-induction, post-consolidation, 3 and 6 months follow up and relapse. Results: 30 cases with median age 9.5 years; male/female ratio 14:16 had significantly higher baseline Tregs than healthy controls (12.36±4.65% vs 3.16±1.49%; p=0.0001). Patients with high Tregs frequency were females (p=0.044), WBC&gt;50,000/mm 3 (p=0.023), hypoalbuminemia (p=0.002), absence of lymphadenopathy (p=0.04) and linear correlation with peripheral blood blast% (r=0.55, p=0.0014). CR rate was 83.3% (25/30); EFS 38% and OS 73% at 14 months follow up. When Tregs were categorized as high and low based on median value, CR rate (86.6% vs 80%, p=NS), EFS [17% vs 60%, HR 1.46 (0.51-4.14) p=0.46] and OS (66% vs 80%, HR 0.58 (0.13-2.44) p=0.45) were not different. Amongst those who achieved CR, there were 7/13 relapses in those with high Tregs versus 3/12 in those with low Tregs (p=0.226).Tregs reduced post-induction (12.1±4.6 vs 6.32±2.8, p&lt;0.000) from baseline. Using generalized estimating equation regression model, average Tregs reduction from post-induction till 3 month follow up was 0.785 units/visit (p&lt;0.005) in those with continuous CR(n=15) and 1.25 units/visit (p&lt;0.001) in those whom relapsed (n=10). Difference between these two groups was not significant. Tregs significantly increased at relapse as compared to post consolidation value (15.3±5.2 vs 4.5±1.9, p=0.003). Conclusions: This first study in pediatric AML demonstrates that Tregs is increased at diagnosis and is significantly associated with females, high WBC count, hypooalbuminemia, absence of lymphadenopathy and high peripheral blood blast%. Tregs significantly reduced post-induction on follow up; however, it increased at relapse. Baseline Tregs did not predict CR, EFS, or OS. However, there were more relapses in those with high baseline Tregs.
Three quarters of physician aided deaths in Oregon are in patients with cancer
Authors: Jacqui Wise
Journal: BMJ (2017)

Three quarters of patients who died with doctors’ help in the US state of Oregon had cancer, says an analysis of data from the state since it became the first to legalise physician aid in dying.

The analysis, published in JAMA Oncology ,1 showed that the number of physician aided dying prescriptions written in Oregon has increased each year since the Death with Dignity Act became law in 1997.

A total of 1545 prescriptions were written from 1998 to 2015, and 991 …
Vulnerable populations and overconfidence in cancer screening.
Authors: François Eisinger, Jean-François Morère, Chantal Touboul, Jérôme Viguier, Jean-Yves Blay, Yvan Coscas, Christine Lhomel, Xavier B. Pivot
Journal: Journal of Clinical Oncology (2014)

1574 Background: The EDIFICE surveys have been conducted every 3 years since 2005. The aim is to characterize behavior related to recommended, organized screening services (breast and colorectal). However, we recently focused on levels of confidence in screening efficacy for cancer locations for which only opportunistic screening is available. Results from vulnerable and non-vulnerable populations were compared. Methods: Phone interviews were conducted among a representative sample of 1,600 individuals (age 40-75 years), using the method of quotas. Opinions on efficacy of cancer screening were assessed for 8 anatomical locations. Data were analyzed according to a validated vulnerability score. Results: For cancer locations with no organized screening services, the level of confidence in screening efficacy is surprisingly high, and significantly higher in vulnerable than in non-vulnerable populations; in decreasing order: lung cancer, 85% vs. 78% (P<0.05), leukemia, 69% vs. 60% (P<0.05), gastric cancer, 67% vs. 56% (P<0.05), liver cancer, 63% vs. 48% (P<0.05), esophageal cancer, 59% vs.52% (P<0.05), and central nervous system cancer, 34% vs. 27% (P<0.05), respectively. In contrast, organized screening programs inspire very similar high levels of confidence in both populations: breast cancer, 95% vs. 96% (NS) and colorectal cancer, 92% vs. 94% (NS), respectively. Risk factors for cancer are more prevalent in vulnerable populations: higher BMI, more active smokers and less frequent sports activities. Conclusions: Our results demonstrate an excess of confidence in the efficacy of cancer screening, particularly by vulnerable populations. We have put forward two opposing mechanisms to potentially explain the paradoxical coexistence of overconfidence in cancer screening and greater exposure to cancer risk factors. Firstly, individuals may (wrongly) feel protected within the safe net of screening and therefore allow themselves greater exposure to known risk factors. This has been termed the “Moral Hazard”. On the other hand, although they realize they have a high risk of being affected by cancer, they ignore the facts and adopt an attitude of wishful thinking.
Theranostic biomarkers involved in immunomodulation and the PI3KCA signal transduction pathway in HPV-induced cervical, oropharyngeal, and anal carcinoma.
Authors: Nooshin Hashemi Sadraei, Rebecca Feldman, Zoran Gatalica, Sandeep K. Reddy, Patrick McKay Boland, Krishnansu Sujata Tewari
Journal: Journal of Clinical Oncology (2015)

11107 Background: Several distinct cancers are caused by human papillomavirus (HPV)- including squamous cell carcinomas of the cervix (CSCC), anal canal (ASCC), and oropharynx (OSCC). Importantly, platinum based chemoradiation protocols are similarly effective in these entities. We assessed CSCC, ASCC, and OSCC for additional evidence of shared characteristics which could be used to identify potential molecular targets across the spectrum of HPV induced cancers. Methods: 201 ASCC, 321 CSC and 358 OSCC tumors underwent molecular profiling with a multiplatform approach (Caris Life Sciences). TP53 wild type status was used as a surrogate for HPV. Testing included sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). The 2-tail Fisher’s exact test (p≤0.05), JMPv10.0 (SAS Institute Inc., Cary, NC) was utilized for statistical analysis. Results: Excluding TP53-mutated patients, 197 ASCC, 317 CSCC and 317 OSCC were included in the study. Multiplatform profiling reveals marked similarities among the HPV-induced cancers. None of the frequencies observed displayed statistically significant differences. Selected results appear below. Conclusions: Unlike the genomic instability observed in many solid tumors, HPV-induced carcinogenesis yields a more homogenous phenotype. These data support previous work identifying the PIK3CA-AKT-mTOR pathway as a potential target. Given the phenomenon of HPV E6 & E7-induced oncogene addiction following viral integration, the need to explore PD1/PDL1 inhibition in these cancers is implicit. Frequency (positivity, underexpression#, amplified or mutated): Greyed boxes indicate Rx is NCCN-endorsed Rx Association Anal Cervical Oropharyngeal PGP IHC Taxanes 9% 3% 3% TLE3 IHC 32% 31% 37% TUBB3# IHC 89% 75% 83% ERCC1# IHC Platinums 51% 60% 67% BRCA1 NGS 10% 15% 7% BRCA2 NGS 10% 30% 10% EGFR IHC Anti-EGFR 92% 70% 92% EGFR_ISH 7% 17% 18% HER2 Anti-HER2 0% 4% 2% HER2_ISH 2% 6% 3% PTEN# IHC PAM pathway inhibitors 55% 47% 50% PIK3CA NGS 29% 34% 18% PTEN NGS 4% 2% 5% AKT NGS 2% 2% 4% PD1 IHC Immuno-modulatory 50% 78% 81% PDL1 IHC 0% 18% 9% FBXW7 NGS mTOR inhibitors 14% 6% 6% KRAS NGS MEK inhibitors 1% 3% 4%
Networking for ovarian rare tumors: a significant breakthrough improving disease management
Authors: N. Chiannilkulchai, P. Pautier, C. Genestie, A.S. Bats, M.C. Vacher-Lavenu, M. Devouassoux-Shisheboran, I. Treilleux, A. Floquet, S. Croce, G. Ferron, E. Mery, C. Pomel, F. Penault-Llorca, C. Lefeuvre-Plesse, S. Henno, E. Leblanc, A.S. Lemaire, G. Averous, J.E. Kurtz, I. Ray-Coquard
Journal: Annals of Oncology (2017)
Multifactorial prospective study of tumoral factors related to disease-free survival (DFS) in colorectal cancer patients
Authors: G. Milano, M. Francoual, A. Bourgeon, D. Benchimol, M. Chazal, P. Laurent-Puig, T. André, C. Letoublon, F. N. Gilly, M. C. Etienne-Grimaldi
Journal: Journal of Clinical Oncology (2006)

3604 Background: There is still a need to identify faithful biological prognostic factors in colorectal cancer, particularly in stage 2, so as to decide upon adjuvant treatment. We thus conducted a prospective multicentric multifactorial study to this end. Methods: Primary colorectal tumors (30 stage 1, 119 stage 2, 107 stage 3) were prospectively collected in 256 patients undergoing total tumor resection (152 men, 104 women ; mean age 69, extremes 29–90). Adjuvant 5FU-based chemotherapy was administered in 92 patients. Median follow-up was 54 months (53 patients developed metastasis or recurrence). Tumors were analyzed for thymidylate synthase (TS), thymidine phosphorylase and dihydropyrimidine dehydrogenase expression (RT-PCR), TS activity (radioenzymatic assay), EGFR level (ligand-binding assay), VEGF (Elisa), DNA content and cell cycle (flow cytometry), p53 mutations (exon 4 to 8), microsatellite instability (bat 25, bat 26), EGFR genotype (CA repeats in intron 1 and -216G&gt;T), TS genotype in 3’ (6 bp deletion) and 5’ (28 bp repeats including the G&gt;C mutation), and methylenetetrahydrofolate reductase genotype (677C&gt;T and 1298A&gt;C). Results: With the exception of tumor TS expression (p = 0.034, the higher the expression, the better the DFS), none of the analyzed parameters were linked to DFS. In multivariate Cox analysis, tumor staging (p = 0.001) and TS expression (p = 0.062) were the sole factors associated to DFS. Focus on tumoral EGFR revealed large inter-patient variability (from 1 to 510 fmol/mg prot) with a significant influence of tumor localisation (p = 0.009, higher in proximal colon) and differentiation status (p = 0.01, higher in poorly differentiated tumors). EGFR within the tumors was 30 % lower than in adjacent normal mucosa (p&lt;0.001). The longer the intron 1 CA repeats, the higher the tumor EGFR (p = 0.044). EGFR -216G&gt;T polymorphism was linked to intron 1 polymorphism, although -216G&gt;T did not influence EGFR levels. Conclusions: The present results underline the major impact of TS expression as a prognostic factor and provide new insights in the knowledge of EGFR in colorectal cancer. No significant financial relationships to disclose.
Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue
Authors: Yi-Ju Ho, Chih-Kuang Yeh
Journal: Theranostics (2017)

Solid tumors with poorly perfused regions reveal some of the treatment limitations that restrict drug delivery and therapeutic efficacy.Acoustic droplet vaporization (ADV) has been applied to directly disrupt vessels and release nanodroplets, ADV-generated bubbles (ADV-Bs), and drugs into tumor tissue.In this study, we investigated the in vivo behavior of ADV-Bs stimulated by US, and evaluated the possibility of moving intertissue ADV-Bs into the poorly perfused regions of solid tumors.Intravital imaging revealed intertissue ADV-B formation, movement, and cavitation triggered by US, where the distance of intertissue ADV-B movement was 33-99 µm per pulse.When ADV-Bs were applied to tumor cells, the cell membrane was damaged, increasing cellular permeability or inducing cell death.The poorly perfused regions within solid tumors show enhancement due to ADV-B accumulation after application of US-triggered ADV-B.The intratumoral nanodroplet or ADV-B distribution around the poorly perfused regions with tumor necrosis or hypoxia were demonstrated by histological assessment.ADV-B formation, movement and cavitation could induce cell membrane damage by mechanical force providing a mechanism to overcome treatment limitations in poorly perfused regions of tumors.
Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development
Authors: Swapna Thomas-Jinu, Patricia M. Gordon, Triona Fielding, Richard Taylor, Bradley N. Smith, Victoria Snowden, Eric Blanc, Caroline Vance, Simon Topp, Chun-Hao Wong, Holger Bielen, Kelly L. Williams, Emily P. McCann, Garth A. Nicholson, Alejandro Pan-Vazquez, Archa H. Fox, Charles S. Bond, William S. Talbot, Ian P. Blair, Christopher E. Shaw, Corinne Houart
Journal: Neuron (2017)

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes to motor axons. The cytosolic version of SFPQ abolishes motor axonal defects, rescuing key transcripts, and restores motility in the paralyzed sfpq null mutants, indicating a non-nuclear processing role in motor axons. Novel variants affecting the conserved coiled-coil domain, so far exclusively found in fALS exomes, specifically affect the ability of SFPQ to localize in axons. They broadly rescue morphology and motility in the zebrafish mutant, but alter motor axon morphology, demonstrating functional requirement for axonal SFPQ. Altogether, we uncover the axonal function of the splicing factor SFPQ in motor development and highlight the importance of the coiled-coil domain in this process. VIDEO ABSTRACT.
Population based study of prognostic factors in stage II colon cancer
Authors: M. J. Morris, B. Iacopetta, C. Platell
Journal: Journal of Clinical Oncology (2006)

3619 Background: Guidelines for the use of adjuvant chemotherapy in stage II colorectal cancer state this treatment may be considered to patients whose tumours show features of poor prognosis. The aim of the current study was to evaluate the prognostic significance of commonly reported clinical and pathological features of this disease. Methods: A population-based observational study encompassing all stage II colon cancer patients diagnosed in the state of Western Australia from 1993–2003 inclusive. A total of 1306 cases treated by surgery alone were identified and had a median follow-up of 59 months (range 0–145). Results: Multivariate analysis revealed the only independent prognostic factors for disease-specific survival were T4 stage (HR=1.75, 95%CI [1.32–2.32], P&lt;0.0001) and vascular invasion (HR=1.63, 95%CI [1.15–2.30], P&lt;0.0001). In the younger patient group (≤75 yrs) who are more likely to be considered for chemotherapy, the same two features showed independent prognostic significance but with higher HR values (1.96 and 2.73 respectively). T4 and/or the presence of vascular invasion identified a “poor” prognosis group comprising 26% of younger cases and having a 5-year survival rate of 71%. The remaining “good” prognosis group showed 84% survival at 5 years follow-up. Conclusion: This study highlights the importance of accurate pathological assessment of T stage and vascular invasion for the prognostic stratification of stage II colon cancer and their subsequent consideration for adjuvant chemotherapy. No significant financial relationships to disclose.