tbuckley/cabot-search huggingface dataset:
Recognition of tumor lysis syndrome (TLS) risk and appropriateness of prophylaxis before and after adoption of a web broswer based risk assessment tool.
Authors: Jean Kerins, Roisin O Sullivan, Kate Murphy, Gul Ahmed, Raimundas Galiauskas, Brian Richard Bird, Conleth G. Murphy
Journal: Journal of Clinical Oncology (2016)

e18194 Background: TLS is a potentially fatal oncologic emergency featuring a sudden breakdown of tumor cells, with the release of intracellular metabolites. It can lead to renal failure, arrhythmias and death. International expert consensus panels have published risk classification models which enable patients to be assigned to TLS risk groups and managed with appropriate prophylaxis. We developed a web-based application (Lysassist) based on these guidelines to assist with TLS risk assessment. We assessed the accuracy of TLS risk assignment and the appropriateness of prophylaxis among patients starting therapy for advanced malignancies before and after implementation of this tool at our institution. Methods: 30 patients were assessed in each treatment period before (June-Dec 2014) and after (June-Dec 2015) implementing Lysassist (10 advanced solid tumors, 10 lymphomas and 10 other hematologic malignancies). We recorded the cancer type, bulk of disease, chemotherapy received and pre-treatment laboratory parameters. Based on these results and according to international guidelines patients were assigned into low (LR), intermediate (IR) or high risk (HR) groups. The medical records were reviewed to see if TLS risk had been correctly identified, and whether it was managed appropriately for their risk group. Results: Patients in the pre- and post-Lysassist periods were LR in 60% and 63% respectively, IR in 20% and 14% and HR in 20% and 3%. Correct prophylaxis was assigned in 27% in the initial period and 53% post intervention (χ2 P = 0.035). Prophylaxis was below the recommended level for risk group in 50% and 20% (χ2 P = 0.015), and above the recommended level in 23% and 27% respectively (ns). Among IR and HR patients, inadequate prophylaxis was used in 100% prior to the introduction of Lysassist, and 55% afterwards (χ2 P = 0.008). Conclusions: Implementation of a user-friendly web based tool to assess TLS risk and assign prophylaxis increases the likelihood of patients receiving prophylaxis appropriate to their risk group. In particular the likelihood of inadequate prophylaxis is reduced. We plan to make this tool available for free download to assist with patient management.
Quality of life and cancer worry in a follow-up cohort of patients with asymptomatic monoclonal gammopathies.
Authors: Michelle Ann Theobald Hildebrandt, Rashida A. Callender, Alem A. Belachew, Catherine Classen, Hans Chulhee Lee, Krina K. Patel, Tiffany Ann Richards, Sheeba K. Thomas, Donna M. Weber, Robert Z. Orlowski, Elisabet Esteve Manasanch
Journal: Journal of Clinical Oncology (2018)

8049 Background: Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are monoclonal gammopathies that precede multiple myeloma (MM). Although considered asymptomatic, patients diagnosed with these conditions are at greatly increased risk of developing MM. There is currently limited to no information on quality of life (QOL) or cancer worry/anxiety burden for patients with MGUS and SMM. Methods: We implemented a longitudinal QOL and cancer-related worry assessment in an observational cohort study of MGUS and SMM patients at MD Anderson Cancer Center (expected total enrollment of N = 200). Questionnaires included the QLQ-C30 cancer QOL tool and the MY20 myeloma-specific module, as well as questions to measure cancer worry. In this preliminary data analysis, a total of 46 patients completed the baseline questionnaires (MGUS = 17; SMM = 29). Results: Overall, individuals with MGUS have a worse QOL compared to SMM patients with MGUS patients reporting a > 12 point lower Global QOL score (71.6 vs 83.9; P = 0.035). Significant differences were also observed for Physical Functioning (P = 0.012), Nausea/Vomiting (P = 0.045), and Pain (P = 0.027). For myeloma-specific QOL and symptoms, MGUS patients again reported higher levels of Back Pain (P = 0.017), Burning/Sore Eyes (P = 0.021), Restlessness/Agitation (P = 0.026), and Tingling in Hands/Feet (P = 0.031) compared to SMM patients. This increase in reported QOL burden corresponded to MGUS patients less feeling in control of their MM risk compared to SMM patients (P = 0.0038). Conclusions: Patients with MGUS self-reported a high QOL burden that was often greater than SMM patients and more closely in line with MM-specific or overall cancer reference values. Further, a sense of loss of control of their MM risk is heightened in MGUS patients. Together, even though MGUS is considered clinically asymptomatic, patients diagnosed with this condition are experiencing reduced QOL is impacting their overall well-being. These results suggest potential opportunities for interventional strategies to improve the lives of patients with monoclonal gammopathies. This work was supported in part by MD Anderson's Cancer Center Support Grant P30 CA016672.
Association between pap abnormalities and HPV infection in participants in HPV vaccine clinical trials.
Authors: Evan Meyers, Alain Luxembourg, Alfred Saah, Christine Velicer
Journal: Journal of Clinical Oncology (2018)

5530 Background: Few studies have reported the burden of Pap abnormalities associated with the specific HPV types targeted by HPV vaccines. The purpose of this analysis is to estimate prevalence of HPV anogenital infection, by baseline Pap results, in participants of 3 worldwide trials of the quadrivalent HPV vaccine (placebo and vaccine groups, FUTURE I, II, III), and to estimate incidence of Pap abnormalities by HPV infection status at enrollment (placebo only, FUTURE I, III). Methods: Among 16,949 young women (YW) age 15-26 years (FUTURE I, II) and 3,674 adult women (AW) age 24-45 (FUTURE III), HPV prevalence (measured with PCR for 14 HPV types) was estimated at enrollment for women with: atypical squamous cells of undetermined significance (ASC-US) (n = 781 YW, 115 AW), low-grade squamous intraepithelial lesion (LSIL) (n = 993 YW, 115 AW), and high-grade squamous intraepithelial lesion or atypical squamous cells- cannot exclude HSIL (HSIL/ASC-H) (n = 157 YW, 30 AW). Cumulative incidence of high-grade Pap abnormalities (HSIL/ASC-H) over 4 years (placebo only), by baseline HPV status, was estimated for 1,481 (YW) and 1,701 (AW). Results: Prevalence of any 9-valent (9v) vaccine type (6/11/16/18/31/33/45/52/58) among women with ASC-US, LSIL, or ASC-H/HSIL at enrollment was 47%, 67%, and 89%, respectively (YM), and 29%, 55%, and 93%, respectively (AW). Prevalence of any non-vaccine type (35/39/51/56/59) among women with ASC-US, LSIL, or ASC-H/HSIL was 32%, 64%, and 47%, respectively (YM), and 24%, 54%, 38%, respectively (AW). Over 48 months, cumulative incidence of high-grade Pap abnormalities (HSIL/ASC-H) among women with any high-risk 9v HPV type at enrollment was 8% (YW) and 6% (AW); cumulative incidence among women with no measured HPV infection at enrollment was 2% (YW) and 0.4% (AW). Conclusions: While the 9-valent vaccine will substantially reduce Pap abnormalities associated with HPV types that cause 90% of cervical cancers, non-vaccine HPV types also contribute to Pap abnormalities. These findings underscore the need for vaccination to protect against 9 HPV types, as well as the ongoing need for cervical cancer screening. Clinical trial information: NCT00090220.
Chemoimmunotherapy combination after PD-1 inhibitor failure to improve clinical outcomes in metastatic melanoma patients.
Authors: Jesus Vera Aguilera, Jonas Paludo, Anagha Bangalore, Jarrett Failing, Robert R. McWilliams, Lisa A. Kottschade, Matthew Stephen Block, Svetomir Markovic, Roxana Stefania Dronca, Yiyi Yan
Journal: Journal of Clinical Oncology (2018)

9558 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains a challenge and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients (pts). Our pre-clinical study has shown that in MM pts who have failed PD-1 blockade, the addition of chemotherapy can reshape a subset of tumor-reactive CD8+ T cells, resulting in enhanced anti-tumor immune responses. We conducted a retrospective study comparing the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We retrospectively reviewed MM pts seen at Mayo Clinic, Rochester between Jan, 2012 and Jun, 2017 who had failed anti-PD1 therapy. We identified 48 pts who received subsequent CIT (carboplatin/paclitaxel n = 22; temazolomide n = 1, nab-paclitaxel n = 1), or immune checkpoint inhibitors (ICI) or chemotherapy alone. The overall survival (OS), objective response rate (ORR), time-to-next therapy (TTNT), and toxicities were assessed between these groups. Results: Among the 48 pts, 24 received CIT after disease progression on PD-1 blockade. At median follow up of 3.9 years, pts who received CIT had a median OS of 5 years (95% CI: 2-NR) versus 1.8 years (95% CI: 0.9-2; p = 0.002) for those who received either ICI (n = 9) or chemotherapy alone (n = 15), with ORR of 61% versus 17% (p = 0.001), respectively. The median TTNT was 8 months (95% CI: 6-15) for CIT cohort versus 3.4 months (95% CI: 2.8-4; p = 0.004) for those who received ICI or chemotherapy alone. Conclusions: In MM pts who have failed anti-PD-1 therapy, the chemo-immunotherapy combination showed favorable clinical outcomes and acceptable toxicity profile. This regimen should be considered for MM pts in this setting who have limited treatment options. CIT (n = 24) ICI or Chemotherapy Alone (n = 24) p value Age, median (range) 54 (30-77) 57 (21-77) 0.73 Male sex, n (%) 15 (62) 14 (58) 0.76 BRAF mutation, n (%) 10 (41) 9 (37) 0.76 Brain metastasis, n (%) 9 (37) 8 (33) 0.76 ORR, n (%) 14 (61) 4 (17) 0.001 Response, n (%) - CR 5 (22) 3 (12) - PR 9 (39) 1 (4) - SD 1 (4) 2 (8) - PD 8 (35) 18 (75) Grade ≥ 3 AE, n (%) 5 (20) 5 (20) 0.71
Phase II study of the combination of bevacizumab plus irinotecan and temozolomide for relapsed or refractory neuroblastoma (NB).
Authors: Shakeel Modak, Brian H. Kushner, Kim Kramer, Samantha Leyco, Ellen M. Basu, Stephen S. Roberts, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2016)

10554 Background: The rationale for studying the combination of bevacizumab+irinotecan and temozolomide (BIT) in NB is based on: (a) VEGF expression is associated with aggressive phenotype in NB. (b) Anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts. (c) Irinotecan+temozolomide (IT) is standard salvage chemotherapy for NB. (d) Bevacizumab safety was established in pediatric phase I studies. Methods: We completed a phase II study to evaluate tumor responses to BIT in patients with measurable/evaluable refractory or relapsed high-risk NB. Each cycle consisted of bevacizumab (15mg/kg IV) (days 1 and 15) plus irinotecan (50mg/m2/day IV) and temozolomide (150mg/m2/day orally) (days 4-8). Patients could have previously received but not relapsed on IT. Patients were monitored for toxicity and response assessed after every 2 cycles; cycles could be repeated every 4 weeks after reversal of toxicities, and if progressive disease (PD) was not observed. An early stopping rule for efficacy mandated continuation of study only if > 5/27 evaluable patients achieved partial (PR) or complete response (CR) based on INRC after 4 cycles. Results: 33 heavily-pretreated (25 previously received IT) patients (9 primary refractory; 24 relapsed) received 1 (n = 7 patients), 2 (n = 7), 3 (n = 1), 4 (n = 10), 5 (n = 1), 6 (n = 5), 7 (n = 1) or 8 (n = 1) cycles respectively. All toxicities were expected and transient. Grade 4 toxicities were neutropenia (n = 11;30%), thrombocytopenia (n = 8;24%) and proteinuria (n = 2;6%). Grade 3 toxicities included hepatic transaminitis (n = 5;15%) and diarrhea (n = 1;3%). Overall responses were: 3CR (all in prior IT-treated patients with relapsed NB), 12PD and 18 no response. Only 1/23 patients evaluable for early stopping rule achieved CR/PR. Median progression-free and overall survival post-BIT was 7.7±1.7 and 31.5±5.6 months respectively; all patients received further anti-NB therapy post-BIT. Conclusions: Although BIT was well tolerated, addition of bevacizumab did not significantly increase response rates in relapsed or refractory NB compared to historical data for IT. The study was terminated due to lack of efficacy of the combination. Clinical trial information: NCT01114555.
Abstract 13874: Thrombin Activatable Fibrinolysis Inhibitor Promotes Development of Chronic Thromboembolic Pulmonary Hypertension -A Possible Novel Therapeutic Target
Authors: Taijyu Satoh, Kimio Satoh, Nobuhiro Yaoita, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Shinichiro Sunamura, Masamichi Nogi, Tomohiro Otsuki, Kazuhiko Numano, Md. Elias Al-Mamun, Mohammad Abdul Hai Siddique, Shunsuke Tatebe, Tatsuo Aoki, Koichiro Sugimura, John Morser, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) still remains elusive. Methods and Results: CTEPH patients had higher plasma levels of and prevalence of SNPs of thrombin activatable fibrinolysis inhibitor (TAFI). Plasma levels of activated TAFI (aTAFI) were significantly increased in CTEPH patients (n=32) compared with controls (n=13) (8.7-fold, P&lt;0.01). Immunostaining showed that TAFI and its linker protein thrombomodulin (TM) were strongly expressed in the distal pulmonary arteries (PA) in CTEPH patients. TAFI-deficient mice (TAFI –/– ) exposed to hypoxia showed significantly reduced right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P&lt;0.05, n=10 each). In contrast, TAFI-overexpressing mice (TAFI-Tg) exposed to hypoxia showed significantly augmented RVSP, RV hypertrophy and PA remodeling compared with controls (all P&lt;0.01, n=19 each). Importantly, systemic TAFI-Tg mice (n=19) showed a significantly reduced survival under hypoxia compared with controls (n=22) (63% vs. 95%, P&lt;0.01). Bone marrow transplantation demonstrated that the increased plasma levels of aTAFI, but not those in the bone marrow, promoted hypoxia-induced PA thrombus formation and PH (all P&lt;0.01, n=10 each). Interestingly, liver-specific TAFI overexpression exacerbated hypoxia-induced PH compared with controls (all P&lt;0.01, n=12 each). Plasma levels of TAFI were increased by hypoxia and were correlated with clot lysis time and the severity of PH. Morphological analysis using 3 dimensional-CT showed multiple obstruction of PAs in TAFI-Tg mice after hypoxic exposure (P&lt;0.01, n=10 each). Mechanistic experiments demonstrated that treatment with human TAFI (300 nM) increased permeability of PA endothelial cells and proliferation of PA smooth muscle cells compared with vehicle controls (n=10 each, both P&lt;0.01). Finally, a PPARα agonist, WY14643, significantly reduced plasma levels of TAFI, ameliorated hypoxia-induced PH and significantly improved mortality (-70%) in TAFI-Tg mice compared with controls (P&lt;0.01, n=12 each). Conclusions: TAFI promotes PA thrombus formation and the development of PH and could be a novel biomarker and therapeutic target for the disorder.
First-line PD-1/PD-L1 inhibitor followed by carboplatin (carbo)-based chemotherapy (chemo) or the reverse sequence in cisplatin-ineligible metastatic urothelial cancer (mUC) patients (pts).
Authors: Xiao X. Wei, Kevin Lundgren, Min Yuen Teo, Jonathan E. Rosenberg, Vadim S. Koshkin, Petros Grivas, Lucia Carril, Daniel E. Castellano, Pedro Velho, Noah M. Hahn, Rana R. McKay, Daniele Raggi, Andrea Necchi, Ravi Kanesvaran, Parissa Alerasool, Jacob Gaines, Laura Morrison, Thomas Powles, Joaquim Bellmunt, Guru Sonpavde
Journal: Journal of Clinical Oncology (2018)

e16517 Background: PD-1/PD-L1 inhibitors or carbo-based chemo are both reasonable therapeutic options in the first-line setting for cisplatin-ineligible mUC pts. However, optimal first-line therapy and sequencing of these regimens is unclear. Methods: We conducted a multicenter retrospective analysis of cisplatin-ineligible mUC pts treated with first-line PD-1/PD-L1 monotherapy followed by carbo-based chemo (P- > C) or the reverse order (C- > P). Perioperative cisplatin-based chemo was allowed if the interval between its completion and starting first-line mUC therapy was > 1 year. A multivariate analysis (MVA) examined the association of sequence of therapy with overall survival (OS) adjusted for baseline Hb ( < 10 vs. ≥10 g/dl), ECOG PS (0-1 vs. 2-3), and site of metastasis (LN/soft tissue only vs. non-liver vs. liver). Results: 115 pts (P- > C n = 33, C- > P n = 82) with median age 71, 74% men, and 85% ECOG PS 0-1 were included. Most pts (94.8%) had not received prior perioperative cisplatin-based chemo, and 16.5% pts had liver metastasis. Baseline characteristics were balanced except a higher proportion of men in the P- > C group (91% vs. 67%, p = 0.009). The rates of partial response (PR)/complete response (CR) to PD-1/PD-L1 inhibitor in P- > C and C- > P were 9%/0% and 22%/4%, respectively. The rates of PR/CR to carbo-based chemo in P- > C and C- > P were 49%/0% and 40%/4%, respectively. MVA demonstrated that sequence of therapy was not significantly associated with OS when adjusted for Hb, ECOG PS and site of metastasis (HR 1.14, p = 0.68). The site of metastasis was associated with OS (p < 0.0001). Limitations of a retrospective analysis apply. Conclusions: In this hypothesis-generating retrospective study of a selected cohort of cisplatin-ineligible mUC pts sequentially receiving PD-1/PD-L1 inhibitors followed by carbo-based chemo or the reverse sequence, both sequences appeared to confer similar OS despite higher PR/CR with carbo-based chemo. Further biomarker-driven prospective investigation is warranted, and ongoing phase III randomized trials may inform optimal sequencing.
GENE-13. AN INTEGRATED GENOMIC ANALYSIS OF ANAPLASTIC MENINGIOMA IDENTIFIES PROGNOSTIC MOLECULAR SIGNATURES
Authors: Grace Collord, Patrick Tarpey, Kieren Allinson, Rasheed Zakaria, Oliver Hanemann, Colin Watts, Jemma Dunn, Michael McDermott, Stephen Price, Zvi Ram, Sam Behjati, Manuel Castro, Imran Noorani, Sebastian Moran, Manel Esteller, Gabriele Schackert, Peter Collins, George Vassiliou, Chris Mcmurran, Adam Young, Danita Pearson, Tibor Nagy, Matthew Young, Michael Jenkinson, Ramez Kirollos, Matthias Kirsch, Ultan McDermott, Thomas Santarius
Journal: Neuro-Oncology (2017)

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of two distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Our analyses discern two biologically distinct variants of anaplastic meningioma with potential prognostic and therapeutic significance.
Staging the tumour and staging the host in primary operable colorectal cancer: East and West.
Authors: James Hugh Park, Mitsuru Ishizuka, Keiichi Kubota, Hitoshi Nagata, Kazutoshi Takagi, Yoshimi Iwasaki, Norisuke Shibuya, Paul G. Horgan, Donald C McMillan
Journal: Journal of Clinical Oncology (2016)

e15107 Background: The systemic inflammatory response (SIR) is a stage-independent predictor of survival in patients with cancer. Of measures of the SIR, the most widely validated is the modified Glasgow Prognostic Score (mGPS). The present study aims to examine the clinical utility of the combination of TNM stage and mGPS in patients undergoing primary resection of stage I-III colorectal cancer (CRC) in two centres in Scotland and Japan. Methods: 882 patients from Glasgow Royal Infirmary (GRI), Scotland, and 611 patients from Dokkyo Medical University (DMU), Japan, who underwent resection of stage I-III CRC were included. The pre-operative mGPS was calculated (0- CRP ≤ 10mg/L, 1- CRP > 10mg/L and albumin ≥ 35g/L, 2—CRP > 10 mg/L and albumin < 35 g/L) and its relationship with five-year overall survival (OS) examined. Results: Patients from GRI were more likely to be female, have a higher ASA grade and undergo emergency surgery, but were less likely to receive adjuvant therapy compared to patients from DMU (all P< 0.001). GRI patients were more likely to have a higher TNM stage (P< 0.05), serosal involvement (P< 0.001), and margin involvement (P< 0.05) but less likely to have venous invasion (P< 0.001). 29% of patients had an elevated SIR (mGPS ≥ 1); more patients from GRI had an elevated mGPS (39% vs. 16%, P< 0.001); after controlling for patient and pathological characteristics, GRI patients were more likely to have an elevated mGPS Five-year OS of patients from GRI and DMU was 64% (standard error 2) and 85% (2) respectively. The combination of TNM and mGPS stratified five-year OS of GRI patients from 87% (4) (TNM I, mGPS 0, n= 116) to 40% (4) (TNM III, mGPS ≥ 1, n= 135) and five-year OS of DMU patients from 94% (3) (TNM I, mGPS 0, n= 118) to 63% (15) (TNM III, mGPS ≥ 1, n= 29). Conclusions: The present study suggests that patients undergoing resection of CRC from Europe and Japan differ not only with respect to clinicopathological characteristics but also the SIR. Despite this, the combination of TNM stage and mGPS showed similar prognostic value in both populations. Routine staging of the SIR in addition to the tumour may allow for more direct worldwide comparison of patients with cancer, and their prognosis, in clinical trials as well as routine clinical practice.