tbuckley/cabot-search huggingface dataset:
Prevention of chemo-induced cardiotoxicity with ACE inhibitors and angiotensin receptor blockers.
Authors: Purva Sharma, Stephanie Hakimian, Yash Jobanputra, Shachar Peles, Beth Byron
Journal: Journal of Clinical Oncology (2018)

e14513 Background: Chemotherapeutic agents, specifically anthracyclines and trastuzumab are known to cause dose dependent cardiotoxicity ranging from subclinical changes in myocardial strain to overt left ventricular systolic dysfunction and heart failure. We conducted a meta- analysis of randomized controlled trials comparing the use of Angiotensin Converting Enzyme inhibitors (ACEI)/Angiotensin receptor blockers (ARB) and placebo in the prevention of chemo-induced cardiac toxicity. Methods: A comprehensive and systematic literature search was performed on PUBMED/Medline, EMBASE and Scopus. We found 6 RCTs that studied the effect of either an ACE inhibitor or an angiotensin receptor blocker (ARB) compared to a placebo in the prevention of cardiotoxicity in patients receiving chemotherapy. Among the 6 RCTs, 3 studies used Enalapril, 2 studies used to Candesartan and one used Perindopril. The mean difference in ejection fraction (EF%), left ventricular end-systolic volume (LVESV) and left ventricular end diastolic volume (LVEDV) were calculated using fixed and random effects model and statistical heterogeneity was evaluated using a forest plot. Results: A total of 327 patients in 6 RCTs were included in the meta-analysis. The patients receiving the ACEI/ARB were compared to placebo control group in each of the 6 studies. The mean difference (MD) in 6-months follow-up in EF was 3.02 95% CI [2.41; 3.63] using the fixed effect model. In three RCTs, the LVESV and the LVEDV were also studied. For LVESV, the mean difference in 3 RCTs among a total of 121 patients was -2.79 with 95% CI [-5.13; -0.45] using the fixed effect model. Also, for LVEDV the mean difference in a total of 121patients was 1.41 with 95% CI [-3.35; 6.18].To note, the heterogeneity was elevated and can be explained by the variability in baseline characteristics of the studied populations, such as predisposing factors to the development of cardiomyopathy independent of chemotherapy use, genetics; in addition to the use of different ACEIs and ARBs. Conclusions: The benefit of the use of pre-chemotherapy ACEI and ARBs for prevention of chemo-induced cardiotoxicity remains unclear though promising. More studies are required to validate the above findings.
Clinical outcomes with cumulative tumor suppressor gene (TSG) alterations in castration sensitive (CSPC) and resistant (CRPC) prostate cancer.
Authors: Anis Hamid, Kathryn P. Gray, Grace Shaw, Laura E MacConaill, Carolyn Evan, Brandon David Bernard, Massimo Loda, Atish Dipankar Choudhury, Christopher Sweeney
Journal: Journal of Clinical Oncology (2018)

5055 Background: Alterations (alt) in TP53, PTEN and RB1 TSGs have been identified in some prostate cancers. Preclinical data suggest that cooperative loss of 2 or more TSGs drives development of more aggressive disease. Methods: We identified men who underwent targeted exome sequencing (DFCI PROFILE) of CSPC (localized [L] and M1 presentation) and CRPC tissue samples. Biomarker(BM)-positive(+) was defined as copy number loss or deleterious mutation of ≥1 TSG (TP53, PTEN or RB1). For pts presenting with L-CSPC, Kaplan-Meier method estimated time from biopsy to PSA relapse/metastasis/death (EFS), CRPC, and death (OS). Cox model assessed association of BM status and outcomes, adjusted for age, stage and Gleason score in multivariate analyses (MVA). Time from ADT start for M1-CSPC to CRPC and death was also estimated. For M1-CRPC, duration on 1st line CRPC therapy and time from CRPC to death was estimated, adjusting for age, volume and location of metastasis in MVA. Association of cumulative BM+ hits (0 vs 1 vs 2 vs 3) and outcomes was assessed. Results: For BM+ frequencies see table. L-CSPC with BM+ had a shorter EFS (median 2.6 years, HR 1.95, 95% CI 1.22-3.13) and time to CRPC (HR 3.36, 95% CI 1.01-11.16). MVA confirmed association with EFS (HR 1.84, p = 0.029). More gene hits lead to greater risk of relapse (MVA; 1 vs 0 hit: HR 1.75, p = 0.05; 2/3 vs 0: HR 2.74, p = 0.04). None of the 43 M1-CSPC pts who were BM-neg had died with median follow-up of 3.3 yrs; BM+ 4-year OS was 64%. Only 4 (8%) of the CRPC cohort (n = 48) were BM-neg and with a median follow-up 4.1 years, only 1 had died (5.2 yrs). Cumulative TSG loss was associated with shorter duration on 1st line therapy in MVA (3 vs 0/1 hit: HR 2.86, p = 0.013). Conclusions: Deleterious TP53, PTEN and RB1 variants are associated with increased risk of relapse (M0) and death (M1) in CSPC and shorter duration on 1st line therapy in CRPC. BM-neg in CRPC is rare but may represent a subset of pts with very good prognosis. Poorer outcomes are seen with cumulative gene hits across cohorts. Cohort N Median follow-up (yrs) 1 or more TSG-alt 2 or more TSG-alt L-CSPC 205 3.1 39% 8% M1-CSPC 43 3.3 63% 18% M1-CRPC 48 4.1 92% 63%
P05.14 Optimising trial recruitment in a meningioma trial using qualitative research methods: results from the ROAM / EORTC 1308 information study
Authors: M D Jenkinson, F C Sherratt, B J Haylock, D C Weber, B Young
Journal: Neuro-Oncology (2018)

ROAM/1308 is an international randomised controlled phase III trial comparing radiation to observation following complete surgical resection of atypical meningioma. We embedded a qualitative sub-study within ROAM/1308 with the aim of optimising patient recruitment. Patients approached to participate in the ROAM trial and recruiting clinicians were enrolled into the sub-study in 11 UK sites. Audio-recorded recruitment consultation (n=30), and semi-structured interviews with clinicians (n=17) and patients (n=23), including decliners and consenters. Analysis of transcribed audio-recordings was informed by content and thematic analysis. Ethics approval was granted for the study. Analysis identified areas where communication was problematic. Giving patients their pathology results immediately before discussing ROAM left them overwhelmed and unable to absorb trial information. Clinicians’ presentation of the trial arms often lacked balance with a tendency to emphasise the negative aspects of radiotherapy whilst neglecting to discuss that radiotherapy may confer better disease control. Conversely the positive aspects of active monitoring (i.e. no additional treatment) were emphasised and the negative aspects of tumour recurrence were rarely discussed. Patients exhibited bias against radiotherapy citing concerns about side effects and this perception was rarely challenged by recruiting clinicians. Several patients viewed the prospect of radiotherapy as illogical, in part, due to earlier conversations with neurosurgeons who indicated further treatment was unnecessary following resection. Embedded qualitative studies can address barriers to recruitment in meningioma trials. We have amended the patient information leaflet and provided workshops and a webinar for healthcare professionals (surgeons, oncologists research nurses) to enhance communication about ROAM/1308. Subsequent recruitment consultations had a more balanced discussion of ROAM and clinicians felt more confident approaching patients about ROAM/1308. On going support will be provided to sites to assist them in implementing and maintaining changes in the recruitment consultation.
Optimizing measurement when lymph nodes merge on serial CT in clinical trials.
Authors: Ahmad Shafiei, Mohammadhadi Bagheri, Faraz Farhadi, Nathan Lay, Jianhua Yao, Les R. Folio, Elizabeth C. Jones, Ronald M. Summers
Journal: Journal of Clinical Oncology (2018)

e18590 Background: To investigate the size change of merging target lymph nodes (Merged LN), and to compare with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 on these nodes. Methods: We retrospectively assessed size change of metastatic target lymph nodes (short axis diameter ≥ 1.5 cm) that merged on serial CT exams of chest, abdomen, and pelvis in 182 patients with various cancers. Short axis changes of three other well-circumscribed lymph nodes were recorded to represent Surrogate Lesions and their mean percentage change was considered as the ground truth. As only up to two nodes can be selected as Target Lesion in RECIST, two possibilities were considered: 1- One target node had merged with other nodes. 2- Two neighboring target nodes had merged. Then based on orientation of merging, we subdivided group 1 into 1-A: Linear and 1-B: Non-Linear RECIST was compared to the Surrogate and a mean correction factor was calculated in each group. Applied correction factor was considered as an alternative method. Results: We identified 20 cases with 1 merged target lesion and 9 with 2 merged target lesions. Mean percent size change of Surrogate Lesions in groups 1-A, 1-B, and 2 was +52, +44, +45 respectively, while RECIST showed +56, +118, -5. Mean size change in RECIST was similar to Surrogate in group 1-A, but a significant difference was noted between RECIST and Surrogates in groups 1-B (P < 0.001) and 2 (P < 0.001). While in all cases the Surrogates indicated an increase in size, in 77% of cases with 2 target lesions RECIST showed a decrease in size. Calculated Correction factor was 1, 0.75, 1.5 for groups 1-A, 1-B, and 2 resulted in mean size change of +56, +64, +42 respectively. Conclusions: Applying a correction factor of 0.75 when 1 target node Non-Linearly merges to the others and 1.5 when 2 target nodes merge, can improve RECIST measurement in clinical trials. Our proposed correction factors may improve RECIST assessments in clinical trials when 1 target lymph node non-linearly merge with other nodes, or 2 neighboring target nodes merge. Table 1: Mean % size change by RECIST 1.1, Surrogate Lesions and applied correction factor in Merged LN % Size Change Group 1-A Group 1-B Group 2 RECIST 1.1 +56 +118 -5 Surrogate Lesions +52 +44 +45 Applied Correction Factor +56 +64 +42
Minimally invasive image guided thermal ablation for recurrent renal cell carcinoma (RCC) after ipsilateral partial nephrectomy.
Authors: Tessa N. Hudspeth, Mohamed E. Abdelsalam, Sharjeel H Sabir, Samuel B. Kusin, Surena F. Matin, Christopher G. Wood, Jose A. Karam, Kamran Ahrar
Journal: Journal of Clinical Oncology (2018)

e16557 Background: To evaluate the technical success, safety, pathological, and local oncologic outcomes of image guided thermal ablation of recurrent renal cell carcinoma (RCC) after ipsilateral partial nephrectomy. Methods: We reviewed our institutional database for patients who underwent renal ablation for local recurrence in the ipsilateral kidney following partial nephrectomy between January 2005 and December 2014. We describe the tumor characteristics, procedure details, pathological and local oncologic outcome Results: Out of 282 renal ablations during the study period , a total of 28 patients (17 Males and 11 females) with a median age of 66 years met our inclusion criteria. Thirteen patients had a solitary kidney. Thirty six procedures were performed for 37 lesions with average size of 2.3 cm (range 0.8 – 3.7cm). Four lesions were at the surgical margin. Pathology report revealed negative tumor margin in 3 patients, the fourth patient had surgery at another institution with no pathology report available. Of the 36 procedures, 32 were performed under CT and 4 were performed under MRI guidance. Of the 37 lesions, 30 were treated with RFA and 7 were treated with cryoablation. Hydrodissection and pyeloperfusion were performed in 7 and 2 cases respectively. Technical success was obtained in 100% of cases. Complications were recorded for seven procedures (19 %). Three patients developed Clavien Grade III complications. Of the 30 biopsied lesions, 27 samples were diagnostic (18 clear cell and 9 papillary). Fuhrman grading was obtained in 24 lesions (Grade 1 = 2, Grade II = 18, Grade III = 4).Median follow up imaging was 3.8 years (0.9 – 11.5 years).Three lesions (8%) had residual/recurrence at the ablation site detected at 5.7, 6.6 and 7.3 months after ablation Conclusions: Image guided thermal ablation is technically feasible and effective in treatment of recurrent RCC after ipsilateral partial nephrectomy. Intermediate term follow up data reveals adequate local oncologic control in those patients.
Analysis of admissions due to Schistosoma mansoni influence over colorectal cancer admissions and mortality.
Authors: Gustavo Fernandes Godoy Almeida, Mauricio Assuero Lima de Freitas, Lais Neares, Maxwell Moura, Evandro Lopes de Barros Filho, Lauro Vinicius Machado da Silva, Mariana M M Lira, Ana Lucia Coutinho Domingues, Luiz Alberto Reis Mattos
Journal: Journal of Clinical Oncology (2018)

e13602 Background: literature suggests a link between intestinal schistosomiasis and colorectal cancer. However, carcinogenesis promotion needs to be proven. This study aims to compare the incidence and mortality rates of colorectal cancer in cities with (Schistosoma + cancer cities - SCC) or without (cancer only cities – COC) diagnosis of schistosomiasis in Pernambuco (Northeast Brazil). Methods: DATASUS was used as database (Brazilian Ministry of Health) where hospital admissions, their diagnosis and mortality rates information is available. Odds ratio and relative risk were performed to test the null hypothesis that there were no difference between SCC and COC. Search was performed from January 2008 until November 2017. Results: In this period, there were 2444 admissions due to schistosomiasis in Brazil, 54.05% of them in the Northeast region. The state of Pernambuco registered 586 admissions, which correspond to 24.10% of the country and 44.45% of the region. In Brazil, a 39% decrease in the rate of hospitalizations due to schistosomiasis was observed from 2008 (2.20) in comparison to 2017 (1.33). In the same period, Pernambuco registered 10,524 admissions due to colorectal cancer (ADTCC) with an increase of 175% and an average growth of 9.93% per year from 2008 (4,78) to 2017 (12.32). One hundred one cities were categorized as SCC and 79 as COC. The mean rate of ADTCC in SCC was 94.55, with a variability of 366%, while in COC it was 11.06, with a variability of 88%. At a significance level of 5%, variance test rejected the hypothesis that the number of SCC and COC were similar (p-value, 0.0000), as well as ADTCC (p-value 0.0167) between SCC and COC. Data variability did not permit reliable conclusions about mortality. Conclusions: Despite the reduction in admissions due to schistosomiasis in Brazil in the last 10 years, the average rate of ADTCC in SCC were higher than in COC. This suggests that schistosomiasis may be a causal factor.
Targeting quiescent leukemic stem cells using second generation autophagy inhibitors
Authors: Pablo Baquero, Amy Dawson, Arunima Mukhopadhyay, Elodie M. Kuntz, Rebecca Mitchell, Orianne Olivares, Angela Ianniciello, Mary T. Scott, Karen Dunn, Michael C. Nicastri, Jeffrey D. Winkler, Alison M. Michie, Kevin M. Ryan, Christina Halsey, Eyal Gottlieb, Erin P. Keaney, Leon O. Murphy, Ravi K. Amaravadi, Tessa L. Holyoake, G. Vignir Helgason
Journal: Leukemia (2018)
Multipeptide immunotherapy plus immunogenic chemotherapy in refractory cancer.
Authors: Juan Pablo Marquez-Manriquez, Alejandro Camacho-Hernandez, jose Antonio Matute, Mark Verburg, Salvador Icedo-Zamora, Pedro Alejandro Lucero-Diaz
Journal: Journal of Clinical Oncology (2018)

e15159 Background: Refractory tumors are a challenge. Tumor adaptive immune infiltration in several tumors, even when refractory, is not uncommon. It is clear that the future of oncology treatments is the combination of therapies to revert chemoresistance. We treat in a pilot study 25 patients with refractory tumors using 22 peptides from biological and relevant proteins in combination with oxaliplatin and doxorubicin as immunogenic chemotherapy. After the end of the treatment, we observed an effective clinical response in 100% of the cases. Methods: After approval by the local ethics committee, we treated patients such as high-grade serous ovarian cancer (n = 8), soft sarcomas (n = 5), pancreatic cancer (n = 2) and triple negative breast cancer (n = 10). Blood was drawn before, during and after treatment to monitor the adaptive immune response by granzyme B and interferon-gamma ELISPOT. Also, we collected serum for ELISA. DTH was performed before and after treatment in leg and primary tumor area. 22 peptides were administrated subcutaneously (S.C.) every week for 4 weeks in the axillary and inguinal lymph nodes. Afterwards, the peptides were administrated S.C. in the areas with tumor activity according with CT and/or PET scan. Doxorubicin and oxaliplatin were administered at low dose (immunogenic chemotherapy) four times every two weeks. Results: The treatment was well tolerated in 100% of the patients with minimal local dermatological reactions in the peptide administration site. 100% of the subjects entered remission according with the CT SCAN. Importantly, the clinical remission correlated with the infiltration of CD8 cells in the DTH site. Also, all the patients had a statistically significant CD8 immune response against all the peptides. This was especially remarkable for fascin (p = 0.0001), Ape-1 (p = 0.0001), Bcl-2 (p = 0.001) and VCP (p = 0.005) peptides. Conclusions: Combination therapy with multipeptide antigen specific active immunotherapy with immunogenic chemotherapy is feasible and demonstrated remarkable clinical results, as remission were reached even in refractory patients. We observed multiple lymphadenopathies in the CT scans that correlate with the clinical and the granzyme immune response.
Effect of a short self-reflection intervention on clear communication in prostate cancer screening discussions.
Authors: Jia Luo, Maria Peila, Katherine Iossi, Carol Sprague
Journal: Journal of Clinical Oncology (2016)

e18166 Background: The average health literacy in the United States is at an eighth grade level. Studies have shown that physicians use up to two medical jargon words a minute, half left unexplained. Awareness of jargon use can improve communication, but helpful interventions are unknown. We present an exercise in self-reflection demonstrating improved resident communication over four weeks. Methods: Resident physicians at an academic teaching hospital were asked to pair up and record a simulated patient-physician shared-decision-making roleplay about prostate cancer screening. They were then asked listen to, transcribe and identify words they would consider “medical jargon” in their conversation. They were also supplied with a “clear communication strategies” handout and asked to reflect on utilizing these recommendations in future discussions. The roleplay was repeated four weeks later. Flesch-Kincaid, the most commonly used calculator for literacy, was used to calculate grade level of the transcription. Results are expressed in mean (standard deviation) format. Wilcoxon rank-sum 2-tailed tests were used to compare paired results. Results: Twenty-two residents completed the study. Over 50 unique jargon terms were identified. Unique jargon use decreased from 6.4 (SD = 2.4) to 4.0 (SD = 1.6) words per discussion after four weeks (p = 0.0003). After the four weeks, residents explained the definition of jargon terms more frequently 14% vs 31% (SD = 19% and SD = 23%, respectively; p = 0.001), and asked more clarifying questions 1.2 vs 1.9 questions (SD = 1.0 and 1.1, respectively; p = 0.015). Grade level analysis showed improvement in grade level information was conveyed from 8.5 (SD = 2.0) to 7.2 (SD = 1.9) (p = 0.0012). Conclusions: Residents use significant amounts of jargon communicating with patients. Residents in our study identified fewer jargon terms in their own conversations than were present, suggesting overestimation of communication clarity. This study highlights the need for communication training in medical education, and future studies will be needed to identify the ideal curriculum for long-term awareness of health literacy and clear communication that can be sustained past residency.
THU0085 Cr6086, a novel ep4 antagonist with immunomodulatory properties, decreases bone loss in the rat collagen-induced arthritis (CIA) model: a microtomography (MICROCT) study
Authors: M. Lanza, G. Caselli, F. Ferrari, A. Grotti, R. Cavagnoli, M. Perrella, F. Daubine, V. Ayer, L.C. Rovati
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> CR6086 is a novel PGE2 EP4 receptor antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and an anti-inflammatory activity targeted to immune-mediated diseases and distinct from that of NSAIDs. Besides its role in controlling T cells, PGE2 is implicated in the aggressive bone erosion of rheumatoid arthritis (RA). <h3>Objectives</h3> To characterise CR6086 activity on the bone compartment mostly affected by erosion in the CIA model in rats. <h3>Methods</h3> 15 male Lewis rats were immunised by intradermal injection with collagen II in CFA. 5 naïve animals were the sham group. 3 days after boost, oedema was assessed and rats assigned to treatment with vehicle or CR6086 (3 or 10 mg/kg qd). Oedema was measured again on days 7 and 14, and hindlimb joints were blindly scored for clinical signs of arthritis (scale 0–4; from normal=0 to maximally inflamed limb with involvement of multiple joints=4). At sacrifice, hindlimb calcaneus underwent high-resolution X-ray microCT (total and cancellous bone), a sensitive method that allows the reduction of experimental animals in compliance with the 3R rule. Parameters were expressed as the mean of left and right paw. Joints were then scored for histological features. Statistics were performed by ANOVA, correlations by Spearman analysis. <h3>Results</h3> CR6086 significantly reduced bone loss in CIA rats (table 1), even at the low dose of 3 mg/kg. The effect on cancellous bone plateaued already at 3 mg/kg, confirming the sensitivity of the metabolically more active districts of bone to the action of EP4 antagonists. There was a strict correlation between clinical score and bone parameters (BMD; figure 1 inset), confirming that bone erosion in CIA is closely associated with arthritis severity. <h3>Conclusions</h3> CR6086 is an EP4 antagonist in clinical development for RA (NCT03163966). Besides its immunomodulatory activity, CR6086 effectively decreases the aggressive bone erosion that characterises both the CIA model and the early phases of human RA. <h3>Disclosure of Interest</h3> M. Lanza Employee of: Rottapharm Biotech, G. Caselli Employee of: Rottapharm Biotech, F. Ferrari Employee of: Rottapharm Biotech, A. Grotti Employee of: Rottapharm Biotech, R. Cavagnoli Employee of: Rottapharm Biotech, M. Perrella: None declared, F. Daubine Employee of: Atlantic Bone Screen, V. Ayer Employee of: Rottapharm Biotech, L. Rovati Employee of: Rottapharm Biotech