tbuckley/cabot-search huggingface dataset:
LGR5 rs17109924 to predict chemoresistance to 5FU-based chemotherapy in adjuvant colon cancer.
Authors: Armin Gerger, Sereina Herzog, Joanna Szkandera, Martin Pichler, Michael Stotz, Renate Schaberl-Moser, Hellmut Samonigg, Sigurd Lax, Gerhard Leitner, Wilfried Renner, Andrea Berghold, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

3580 Background: We recently investigated 25 germline polymorphisms in a comprehensive panel of genes that have been previously associated with colon cancer stem cell genes to predict tumor recurrence in patients with stage III and high-risk stage II colon cancer treated with 5-FU based chemotherapy. We found the minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A and LGR5 rs17109924 T>C being significantly associated with increased time to recurrence (TTR). In this study we validated these molecular biomarkers in a large and independent study cohort to clarify their predictive and/or prognostic role. Methods: A total of 599 consecutively collected patients with stage II and III colon cancer were included in this validation study. Genomic DNA was analyzed for CD44 rs8193, ALCAM rs1157, and LGR5 rs17109924 by TaqMan 5'-exonuclease assays. Results: The mean age at time of diagnosis was 64 years (std 11), with a median follow-up time of 4.2 years (range 0.1-16.6). Tumor recurrence was observed in 185 (30.9%) patients with a stage III and stage II dependent probability of three-year recurrence of 37.1% (std 2.5) and 16.5% (std 2.3), respectively. Adjuvant chemotherapy was received by 393 (65.6%) of the patients. The tested gene variants CD44 rs8193 and ALCAM rs1157 did not show a statistically significant association with TTR in the analyses. However, patients carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared to patients carrying the homozygous T/T (HR 0.60, 95%CI 0.37-0.98; P=0.043). Stratified by adjuvant chemotherapy, LGR5 rs17109924 was highly significant for patients receiving adjuvant chemotherapy (P=0.007) whereas no association was found for patients without adjuvant chemotherapy (P=0.633). Also after adjusting for sex, age, stage, number of resected lymph nodes, lymphovascular, vascular, and perineural invasion in the multivariate Cox analysis LGR5 rs17109924 remained significant (HR 0.38, 95%CI 0.19-0.79; P=0.009) for patients with adjuvant chemotherapy. Conclusions: We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive molecular biomarker for 5-FU based adjuvant chemotherapy in patients with colon cancer.
Carfilzomib for metastatic castration-resistant prostate cancer (mCRPC) following chemotherapy and androgen pathway inhibitors.
Authors: Guru Sonpavde, Frederick M. Schnell, Christopher G Wang, David James Mooney, Gurudatta Naik, Alan Cantor, Edward P Acosta, Isam-Eldin Eltoum, Graeme Bolger, Mollie DeShazo, Mansoor N. Saleh
Journal: Journal of Clinical Oncology (2014)

TPS5101 Background: mCRPC is an incurable disease despite increments in outcomes with new agents. Proteasome inhibitors are promising agents for the therapy of mCRPC. In a phase I trial of bortezomib in 47 men with mCRPC, 4% had > 50% PSA decline, 25% had stable PSA; 9.5% had objective partial responses among 21 men with measurable disease. Dose-dependent inhibition of whole-blood 20S proteasome activity was seen. Carfilzomib is a second-generation epoxyketone proteasome inhibitor that binds selectively and irreversibly with its target. In vitro studies demonstrated potent pro-apoptotic activity across a broad panel of bortezomib-resistant tumor cell lines. The pharmacodynamic half-life of carfilzomib activity was ≥ 24 hours and doses of 15 to 36 mg/m2 lead to 77% to 86% proteasome inhibition in whole blood 1 hour after dosing. The dose-limiting toxicity (DLT) in clinical trials was hematologic. Fatigue, nausea and diarrhea and neurotoxicity were manageable. Carfilzomib is approved for relapsed/refractory myeloma where the starting dose is 20 mg/m2 over 2-10 minutes on days 1,2, 8,9,15,16 over 28 days in cycle 1, and the target dose is 27 mg/m2 in subsequent cycles. With 30-minute infusions of carfilzomib, the MTD was 56 mg/m2. Methods: A non-randomized proof-of-concept phase II trial (NCT02047253) was designed to evaluate carfilzomib for mCRPC following docetaxel and abiraterone acetate and/or enzalutamide. A 6-month PFS ≥30% is considered important, while PFS<10% is not; 28 patients are accrued to account for 10% inevaluable patients. Carfilzomib is administered on days 1,2,8,9,15,16 every 28 days. The starting dose is 20 mg/m2 over 30 minutes during the first week followed by a target dose of 56 mg/m2 if no DLTs occur. Daily oral acyclovir is administered for herpes zoster prophylaxis. Therapy will continue until progression or severe toxicities. PFS is the primary endpoint based on radiographic and symptomatic criteria (not PSA). Secondary endpoints are PSA declines, present pain index change, measurable tumor response, CTC (circulating tumor cell) declines and overall survival. Whole blood is collected at baseline for 20S proteasome activity. Clinical trial information: NCT02047253.
A randomized phase II study of paclitaxel-carboplatin-bevacizumab (PCB) with or without nitroglycerin patches (NTG) in patients (pts) with stage IV nonsquamous non-small cell lung cancer (NSCLC): Nvalt 12 (NCT01171170).
Authors: Anne-Marie C. Dingemans, Harry J.M. Groen, Judith Herder, Jos Stigt, Egbert F. Smit, Idris Bahce, Otilia Dalesio, Sjaak A. Burgers, Henk Codrington, BEN VAN Den Borne, Bonne Biesma, Andrew D. Vincent, Vincent van de Noort, Joachim Aerts
Journal: Journal of Clinical Oncology (2014)

8089 Background: NTG increases tumor blood flow and thereby may augment drug delivery to the tumor and inhibits HIF-1a, a major regulator of hypoxia. In mouse models addition of HIF-1α inhibitors to B significantly impairs tumor growth. A randomized phase II study has shown improved clinical outcome when NTG patches were added to vinorelbine/cisplatin in pts with advanced NSCLC (Yasuda, 2006). We hypothesized that adding NTG to PCB improves progression free survival (PFS), response rate (RR) and overall survival (OS) in pts with stage IV non-squamous NSCLC. Methods: This open-label multicenter phase II trial randomized chemo-naive pts with stage IV non-squamous NSCLC 1:1 to PCB with or without NTG. Main other inclusion criteria: performance score 0-2; measurable disease (RECIST 1.1); adequate bone marrow, liver and renal function; written informed consent; no clinical significant cardiovascular disorders; no significant bleeding. Pts were treated with P 200 mg/m2 day (d) 1-C AUC 6 d1-B 15 mg/kg d1 every 3 weeks (wks) without (Arm A) or with (Arm B) NTG 15 mg/24 h for 5 d (d -2 to +3) every cycle for 4 cycles and B and NTG until progression. Tumor measurements were assessed every 2 cycles. The study was powered (80%) to detect a decrease in the hazard of progression of 33% in arm B at α = 0.05 with a two-sided log rank test when 222 pts were enrolled and followed until 195 events were observed. Results: Between 01-2011 and 01-2013 223 pts were randomized; 112 arm A and 111 arm B; 50% males; median (range) age 62 years (39-81); 85% adenocarcinoma. Pts characteristics were balanced between both arms. RR was 45% in arm A and 30% in arm B. Median (95% CI) PFS in arm A was 6.8 months (m) (5.6-7.3) and 5.0 m (4.2-5.8) in arm B, HR 1.22 (95% CI 0.91-1.63). OS was 11.6 m (8.7-14) in arm A and 9.5 m (7.8-11.9) in arm B, HR 1.12 (95% CI 0.76-1.67). In arm B no additional toxicity was observed except headache (14% arm A and 57% arm B). Conclusions: Adding NTG to first line PCB does not improve PFS and OS in pts with stage IV non-squamous NSCLC. No further study with this regimen is warranted. Clinical trial information: NCT01171170.
TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK
Authors: Edina Schweighoffer, Josquin Nys, Lesley Vanes, Nicholas Smithers, Victor L.J. Tybulewicz
Journal: The Journal of Experimental Medicine (2017)

Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB.
Survivorship care plan: Use of the ‘Oncology History’ (OncHx) feature of the Epic electronic health record (EHR).
Authors: Kelly Bugos, Jessica Foran, Janis M. Petree, Katrina Pose Sabati, Mary Bruels, Marta Cook, Pooja Mishra, Hamed Barahimi, Andrew Cook, Douglas W. Blayney
Journal: Journal of Clinical Oncology (2017)

51 Background: Survivorship care plans, including a cancer treatment summary, are a standard of cancer survivorship care. At Stanford Health Care (SHC), OncHx, a component of the Beacon module in Epic version 2012, became available May 2, 2013. The OncHx, linked to the problem list and visible to all SHC users, can be inserted in all encounter documentation and provides a chronological treatment summary. OncHx can be updated at any time. Events are categorized as: diagnosis, surgery, chemotherapy, radiation, blood and marrow transplant, anti-hormone therapy, clinical research, disease status, procedures, hospital admissions and adverse reactions. Each event is auto-sorted by date. We measured OncHx use at SHC between 5/1/13-5/1/16. Aim: Our objective is to measure the frequency OncHx is populated as a treatment summary. Methods: Our cohort was unique cancer diagnosis in the problem list and &gt;1 visit to SHC during the analytical period. Cohort patients with &gt;1 event recorded in OncHx at analytic period end was counted as having a populated OncHx. Results: The number of documented cancer diagnoses in the problem list increased over time. The frequency of populated OncHx increased from 5.6 to 16.5% reached a steady state of 15%. Five survivorship APPs populated 12% of all OncHx (#653). Nurses have edit privileges and populated &lt; 1% of all OncHx events. Conclusions: The OncHx contains an organized, date ordered and refreshable treatment summary and is useful in generation of the survivorship care plan. Initial adoption by SHC advanced practice providers (APPs) and physicians has been slow, except Survivorship APPs. Use increased after more providers were given edit privileges in May, 2014. Near future enhancements are auto-population of chemotherapy administered and report of OncHx usage in Epic generated survivorship care plan template. There is an opportunity for nurses to populate OncHx and use it for their documentation.
Four-fraction carbon ion radiotherapy for hepatocellular carcinoma: results of a phase II clinical trial
Authors: H. Kato, S. Yamada, S. Yasuda, K. Yamaguchi, I. Ohno, M. Ohto, T. Kamada, J. Mizoe, H. Tsujii
Journal: Journal of Clinical Oncology (2004)

4090 Background: Both radicality and minimal invasiveness are essential for the treatment of hepatocellular carcinoma (HCC), because in 85% of all patients the condition is associated with liver cirrhosis. Carbon ion radiotherapy is expected to potentially have both the natures because of its excellent dose distribution and its high cytocidal effect resulting from biologically unique characteristics. Methods: Forty-four patients with histologically documented HCC were treated with 4-fraction carbon ion radiotherapy of 52.8 GyE total dose from April 2001 to February 2003. In this report, thirty-six patients with 36 lesions, whose follow-up periods were longer than one year, were the subjects. Fifteen had recurrent tumors (locally: 9, regionally: 6). Six were at Stage I of the disease, 20 at Stage II and 10 at Stage IIIA according to the UICC criteria (Sixth Edition). Child-Pugh grade was A in 28 and B in 8 patients. Mean maximum tumor size was 4.0 (1.2–7.5) cm in diameter. Anti-tumor effect was evaluated by the best tumor response based on the WHO criteria, cumulative local control rate and overall survival rate calculated by Kaplan-Meier method. NCI-Common Toxicity Criteria (CTC) modified by the Liver Cancer Working Group and RTOG/EORTC criteria were used for evaluation of toxicity. Results: During a median follow-up of 23 (15–31) months, no severe adverse effects and no treatment-related deaths have occurred. As to the best tumor response, the ratio of the number of CR and PR to that of all the lesions was 28/36 (78%). Local control rates were 97% and 89% at 1 and 2 year, respectively. Overall survival rates were 92% and 85% at 1 and 2 year, respectively. Within 3 months after the start of therapy, Grade 3 hepatic reaction according to the modified CTC was observed in 3% out of the subjects. Within 3 to 12 months after the start of therapy, no Grade 3 or more hepatic reaction was observed. None of the subjects died of hepatic failure within 1 year after the start of therapy. Conclusions: Four-fraction carbon ion radiotherapy using 52.8 GyE total dose preliminarily proved to be safe and effective for patients with HCC associated with chronic liver disease. No significant financial relationships to disclose.
Paradoxes and personalised medicine: from preseason to post-diagnosis
Authors: Jane S Thornton
Journal: British Journal of Sports Medicine (2017)

In this Canadian Academy of Sport and Exercise Medicine (CASEM)-led issue, we highlight the myriad benefits of physical activity. Evidence continues to emerge for the role of chronic workload in sport injury prevention, this time in rugby league players.195973 Just as an optimal training stimulus will enhance performance and decrease injury in elite sport, it appears similar principles may apply to patients with cancer or chronic disease.

The emergence of paradoxes extends to both sports and exercise medicine. Higher chronic match and training workloads, once thought to cause injuries, are now being reconsidered as a protective ‘vaccine’.2 Where we used to treat cancer and chronic disease with kid gloves, now we are setting new guidelines for higher activity levels. In recent years, this counterintuitive thinking has led to studies regarding high-intensity interval training in disease …
Biological and clinical prognostic factors in patients with advanced non-small-cell cancer (NSCLC) treated by erlotinib: Preliminary results of the ERMETIC cohort
Authors: J. Cadranel, M. Beau-Faller, A. Mauguen, S. Lizard, J. Madelaine, A. Lansiaux, J. Prétet, A. Madroszyk, C. Chouaid, F. Morin
Journal: Journal of Clinical Oncology (2009)

8079 Background: Although it has been suggested that results of EGFR-IHC, EGFR-FISH and EGFR and KRAS mutations are predictive of EGFR-TKIs efficacy, they are not used in clinical practice. ERMETIC is a French NCI granted prospective study aiming to facilitate implementation of these biomarkers in France. Methods: After a preliminary phase of validation in 16 French centers, these biomarkers were studied in available tumor specimens collected from all consecutive NSCLC patients (pts) treated by erlotinib, for the first time. Patients were followed-up until progression or death. Demographic, clinical, pathological characteristics and biomarkers were studied by Cox model as predictors of progression free survival (PFS) and overall survival (OS). Results: 493 of the 530 enrolled pts between 02/07 and 03/08 are included in this analysis, among whom at least 357 (72%) tumor specimens were collected. 88% were Caucasians, 32% females; median age was 62 (33–93); 15% were never smoker, 67% former and 15% active. 18% were PS0, 51% PS1 and 31% PS2–3. 92% pts were metastatic and 66% had adenocarcinoma (ADC). Erlotinib (150 mg in 98% of pts) was given as first-, second- and third-or-more-line in 10, 45, 42% of pts, respectively. 94% of pts had received previous platin-based chemotherapy. With a 11.5 months (mo.) median of follow-up, PFS was 2.4 mo. and OS 5.6 mo., with a 30% 1-year OS. Clinical factors independently associated with shorter OS were: PS1 and PS2–3 (HR=1.79 and 4.3, p&lt;.0001); histology other than ADC and squamous cell (HR=1.44 and 1.03, p=.05); 2 sites of metastasis and more (HR=1.60 and 1.82, p&lt;.0001) and former and active smoking (HR=1.49 and 2.12, p=.002). In multivariate analysis, line of treatment was not prognostic. Conclusions: The study confirmed in a large cohort of advanced NSCLC treated by erlotinib the independent value of several prognostic factors. Prognostic values of EGFR-IHC, EGFR-FISH and EGFR and KRAS mutations will be reported at the meeting. [Table: see text]
Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): A phase I/II study.
Authors: Paul Gerard Guy Richardson, Jesus G. Berdeja, Ruben Niesvizky, Sagar Lonial, Vivek Roy, Parameswaran Hari, Deborah Berg, Guohui Liu, Neeraj Gupta, Alessandra Di Bacco, Ai-Min Hui, Shaji Kumar
Journal: Journal of Clinical Oncology (2012)

8033 Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m 2 ) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m 2 and the RP2D as 2.23 mg/m 2 ; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.
A personalized medicine approach to identifying dysregulated epigenetic enzymes in the development of castrate-resistant prostate cancer.
Authors: David Frazier Jarrard, Jin-Hee Lee, Melissa Boersma, Bing Yang, Nathan Alan Damaschke, Eva Corey, John M Denu
Journal: Journal of Clinical Oncology (2017)

237 Background: Recent advances in proteomic and chromatin immunoprecipitation tools have been crucial in studying cancer epigenetics but the ability to measure directly the enzyme activities of dysregulated histone-modifiers is lacking. We utilize a novel approach to identify altered histone-modifying enzymes in the progression from hormone sensitive (HS) to castrate-resistant prostate cancer (CRPC) progression. Methods: We developed, validated and utilized a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in tumor lysates. Functional assays, novel HS and CRPC human tumor arrays and xenografts were utilized to confirm these findings. Results: This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant CR cell line compared to its hormone-sensitive (HS) isogenic counterpart. NAD + -dependent deacetylation assays revealed down-regulated Sirtuin activity in validated CR lines. Levels of acetyltransferases GCN5, PCAF, CBP and p300 were unchanged between matched HS and CR cell lines. However, auto-acetylation of p300 at K1499, a modification known to enhance HAT activity and a target of deacetylation by SIRT2, was highly elevated in CR cells. Among all 7 Sirtuins, only SIRT2 and SIRT3 protein levels were reduced in CR lines. Interrogation of HS and matched CR xenograft lines reveals that H3K18 hyperacetylation, increased p300 activity, and decreased SIRT2 expression are associated with progression to CR in 8/12 (66%). Tissue microarray analysis revealed that hyperacetylation of H3K18 is a feature of CRPC. Inhibition of p300 results in lower H3K18ac levels and increased expression of androgen receptor. Conclusions: This novel microarray approach provides a method to identify commonly dysregulated chromatin enzymes during progression providing a personalized therapeutic strategy to direct available drugs to target enzymes. Reduced SIRT2 expression and increased p300 activity lead to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18)