tbuckley/cabot-search huggingface dataset:
Phase II study of caphosol oral rinse for prevention of oral mucositis (OM) in sarcoma patients (pts) receiving multicycle doxorubicin-based chemotherapy (CT): Randomized study with cross-over to palifermin for severe OM.
Authors: Saroj Vadhan-Raj, Dejka M. Araujo, Jonathan C. Trent, Xiao Zhou, Joseph A. Ludwig, Vinod Ravi, Mark Steven Chambers, Shreyaskumar Patel, Robert S. Benjamin
Journal: Journal of Clinical Oncology (2012)

e19520 Background: Mucositis is a common complication in cancer pts receiving CT. We have shown that palifermin (recombinant Keratinocyte Growth Factor), administered as single dose prior to CT, alleviated severe mucositis in pts receiving doxorubicin-based CT (Ann Int Med 2010). Caphosol is a supersaturated electrolyte solution of calcium phosphate that has been indicated as oral rinse for xerostomia and as an adjunct to treat OM induced by radiation or high-dose CT. Purpose of the study was to evaluate the preliminary efficacy of Caphosol in pts receiving CT. Methods: Pts were randomized 1:1 to Caphosol vs. baking soda (control) as an oral rinse five times daily from initiation of CT. All pts received doxorubicin (75 or 90 mg/m 2 by continuous infusion over 3 days) with ifosfamide (10 gm/m 2 ) or cisplatin (120 mg/m 2 ). Pts that experienced Grade (Gr) &gt; 3 mucositis received palifermin (180 mcg/kg) iv 3 days before CT in subsequent cycles. Results: 28 of 30 pts received treatment and were evaluble; 15 men and 13 women, with median age 51 (range, 20-65 yrs). Incidence of Gr &gt; 2 OM was 57% (8 of 14 pts) for Caphosol vs. 86% (12 of 14) for control (P=0.21). Incidence of Gr &gt; 3 OM was 29% (4/14) for Caphosol vs. 43% (6/14) for control (P=0.43). However, the benefit was limited to oral but not other GI mucosal sites. Of 10 pts (Caphosol: 4, BS: 6,) with Gr &gt; 3 OM, 6 crossed over to palifermin (Caphosol: 3, BS: 3); the other 4 pts (Caphosol: 1, BS: 3) came off the study. All 6 pts, that received palifermin, avoided severe OM in the next cycle. The median duration of Gr &gt; 2 OM in the cycle before cross-over was 8 days (range: 5-12) vs. 0 days (0-3) in palifermin cycle (p=0.0032) and Gr &gt; 3 OM was 5 days (2-7) vs. 0 days (p=0.0015). Oral assessment and the pts-reported outcome were in substantial agreement for the OM grading (weighted kappa, 0.78, 95% CI: 0.44-0.87, p&lt;0.0001). No serious adverse event related to the study drug was observed. Conclusions: There was a trend for less severe OM with Caphosol vs. control. Secondary prophylaxis with palifermin alleviated severe mucositis in all pts who previously experienced severe mucositis during multi-cycle CT.
Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice
Authors: Malgorzata Kasztan, Brandon M. Fox, Joshua S. Speed, Carmen De Miguel, Eman Y. Gohar, Tim M. Townes, Abdullah Kutlar, Jennifer S. Pollock, David M. Pollock
Journal: Journal of the American Society of Nephrology (2017)

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.
Feasibility of tumor genome sequencing: single center experience.
Authors: Natraj Reddy Ammakkanavar, Patrick J. Kiel, Erin Niland, Meagan E Ferguson, Stacy Marie Nance, Milan Radovich, Paul R. Helft, Bryan P. Schneider
Journal: Journal of Clinical Oncology (2015)

e22131 Background: Genome analysis is becoming an important tool to guide cancer management. Prior data on this approach have been largely confined to highly focused settings. Data on feasibility across multiple tumor types and settings is limited. We did a retrospective study to analyze our experience at Indiana University. Methods: 171 patients (pts) seen in our ‘Precision Genomics Clinic’ from Apr 2014- Dec 2014 had genomic testing (PCDx from Paradigm) and were discussed in the genomic tumor board. Complete analysis meant all components of the test were feasible. Demographics, disease variables, and testing outcomes were analyzed. Fisher’s exact test was used for analysis. Results: 171 pts with 22 different cancer types were evaluated. Median age was 60 years. Median number of systemic treatments was 2. 107 (62%) pts had fresh tumor tissue biopsy. 13 (12%) pts failed tissue biopsy. 34 pts had liver biopsy, 21 had lung/mediastinal biopsy, 27 had soft tissue biopsy, 17 had non-liver intra-abdominal tumor biopsy and 12 had lymph node biopsy. Tissue was sufficient for complete analysis in 70%. Successful genomic testing occurred at higher rate in tissues from liver biopsy compared to other sites (85% vs. 64%, p = 0.024). Failure rate was highest for non-liver intra-abdominal biopsies (41%). 4 pts (3.7%) had severe complications, all from lung biopsy. Median time from biopsy to tumor board discussion was 14 days (range 8- 24). Of the 171 pts, 163 (95%) were able to have genomic analysis performed and 138 (81%) had sufficient tissue for complete analysis. 109 (67%) pts received a therapeutic recommendation from the tumor board derived from the unique genomic finding. The likelihood of making a genomic based therapeutic recommendation was higher for pts with complete analysis when compared with partial analysis due to insufficient tissue (71% vs. 42%, p = 0.008). Conclusions: Our data demonstrates that genomic testing is feasible in a broad spectrum of tumor types and settings. Liver biopsy is safe and the most useful for genome sequencing. Biopsy related complications were mostly from lung biopsy. Significant number of patients had therapeutic recommendations made from the genomic findings and this was augmented when adequate tissue was available for complete analysis.
Antenatal corticosteroids for women at risk of preterm delivery
Authors: Sarah D McDonald
Journal: BMJ (2017)

Timing is critical to maximising benefits for very premature babies

The administration of antenatal corticosteroids to women at risk of early preterm birth has been one of the most effective interventions to improve premature infants’ outcomes, reducing death and serious morbidities in randomised trials and meta-analyses. For women at risk of delivery before 34 weeks gestational age, clinical practice guidelines advocate injection of 12 mg of betamethasone followed by a repeat injection 24 hours later.1 Recent guidelines also recommended antenatal steroids for women at risk of delivering a 23 week infant, when resuscitation is desired.23

In their large retrospective observational study (doi:10.1136/bmj.j1039), Travers and colleagues studied an American cohort of neonates born between 23 and 34 weeks of gestation.4 Slightly more than 60% of 23 week infants received antenatal steroids, and the proportions increased to approximately 80% between 24 and 32 weeks, before decreasing to …
A novel polymer-coated nanoparticle (NP) for urothelium penetration and drug delivery.
Authors: Christopher J. Hoimes, Darryl T Martin, Hristos K Kaimakliotis, Christopher J Cheng, William Kevin Kelly, Gregory N Tew, Marcia Wheeler, Robert M Weiss, W. Mark Saltzman
Journal: Journal of Clinical Oncology (2013)

e15543 Background: Up to 40% of patients with non-invasive bladder cancer (BC) will develop invasive disease progression despite locally-directed therapy. Overcoming the urothelial barrier is a challenge for intravesical drug delivery. We designed a biodegradable poly(lactide-co-glycolide) (PLGA) NP coated with a novel cell penetrating polymer, poly (guanidinium oxanorbornene) (PGON) for testing against BC in vitro and in vivo. We chose to deliver the HDAC inhibitor belinostat (bel) for its BC cell cytotoxicity and inhibition of invasion &amp; migration pathways; key mechanisms that enable progression of BC. Methods: Fluorophore (C6) or bel was encapsulated in PLGA using an oil/water nanoemulsion method, and surface coated with PGON, and then characterized for morphology, size, and loading. BC cell lines UM-UC-3 and T24 were treated with belinostat or NP-bel-PGON vs controls for assessment of cytotoxicity and acetyl-H4 histone expression over time. In vivo murine bladder and ex vivo human ureter were treated with NP-C6-PGON, and compared to NPs coated with chitosan or PEG for urothelial penetration using FACS analysis, tissue extraction, and fluorescence microscopy. UM-UC-3 murine flank xenografts were treated locally biweekly with NP-bel-PGON or controls and assessed for tumor size and acetyl-H4 expression. Results: C6 extraction of intravesically treated mouse bladder and ex-vivo human ureter showed uptake improved ten-fold in NP-C6-PGON compared to other NPs and corroborated by fluorescent microscopy. In vitro, NP-bel-PGON and bel had similar IC50 of ~2.0 μM in UM-UC-3 &amp; T24 lines, and no effect from PGON. Significantly, the NP-bel-PGON treated groups retained 30% of max H4 hyperacetylation whereas bel groups declined to basal at 12hr post wash, which supports a mechanism of intracellular NP release and activity. In vivo, xenografts treated with NP-bel-PGON showed tumor volume reduced 70% and had 2.5 fold higher intratumoral acetyl-H4 expression compared to vehicle three days post final treatment. Conclusions: NP-bel-PGON penetrates the urothelium, is taken up by BC cells, sustains HDAC inhibition, and causes tumor regression. These data demonstrate the potential for NP-bel-PGON as an intravesical nanotherapy of BC.
Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial
Authors: Christopher R Heery, Geraldine O'Sullivan-Coyne, Ravi A Madan, Lisa Cordes, Arun Rajan, Myrna Rauckhorst, Elizabeth Lamping, Israel Oyelakin, Jennifer L Marté, Lauren M Lepone, Renee N Donahue, Italia Grenga, Jean-Marie Cuillerot, Berend Neuteboom, Anja von Heydebreck, Kevin Chin, Jeffrey Schlom, James L Gulley
Journal: The Lancet Oncology (2017)
Outcome of localized blastemal-type nephroblastoma patients treated according to intensified treatment in the SIOP 2001 protocol: A report of the SIOP-RTSG.
Authors: Marry M van den Heuvel-Eibrink, Harm van Tinteren, Christophe Bergeron, Aurore Coulomb-Hermine, Beatriz De Camargo, Ivo Leuschner, Bengt Sandstedt, Tomas Acha Garcia, Saskia L Gooskens, Jan De Kraker, Gordan M Vujanic, Kathy Pritchard-Jones, Norbert Graf
Journal: Journal of Clinical Oncology (2014)

10002 Background: From previous pre-surgery chemotherapy based SIOP protocols, blastemal type Wilms tumor (BT-WT) has been identified as a poor prognostic subgroup. Therefore in SIOP 2001, post-operative treatment for BT-WT was prolonged and intensified (VCR/Act/Dox in stage I, VP16/Carbo/Cyclo/Dox in stage II-IV) aiming to improve survival. Here, we present characteristics and outcome of BT-WT patients treated on intensified regimen in SIOP 2001. Methods: Response and survival analysis of unilateral BT-WT (n = 238) patients treated from 2001-2012 (SIOP 2001) were compared with SIOP 93-01 (n = 113). Results: In SIOP 93-01 and SIOP 2001 trials, among 4061 unilateral non-metastatic Wilms tumor patients registered, 351 (8.6%) were BT-WT. Median age at diagnosis was 43 months (IQR 24-68). Stages were: I (n = 140, 40%), II (n = 106, 30%), III (n = 105, 30%). Pre-surgery chemotherapy reduced tumor volume from median 359 ml (IQR 174-611) to 123 ml (IQR 41-291). BT-WT were older, higher staged and showed less markedly volume decrease after pre-surgery chemotherapy. Univariate analysis of localised unilateral BT-WT cases in SIOP 2001 showed a 5-year event-free survival (EFS) of 80% (95% CI 75-86%) (67% in SIOP 93-01 (95% CI 59-76; p = 0.006)) and an overall survival (OS) of 88% (95% CI 83-93) (84% (95% CI 77-91; p = 0.4) in SIOP 93-01). Treatment protocol, volume at surgery, age and stage were prognostic variables for EFS in uni- and multivariate Cox regression analysis. Independent prognosticators for OS were stage, age and tumor volume at surgery. The most significant benefit of intensified treatment was found in Stage I BT-WT with 96% EFS in SIOP 2001 (OS 100%), compared to 71% EFS in SIOP 93-01 (OS 96%). Conclusions: BT-WT, defined after pre-operative chemotherapy, benefits from more intensive chemotherapy as reflected by reduction of relapse risk. However, OS mainly seems to be enhanced in stage I BT-WT patients underscoring the value of doxorubicin for relapse prevention in these tumors.
Phase II study of refametinib (BAY 86-9766), an allosteric dual MEK 1/2 inhibitor, and gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
Authors: Jean-Luc Van Laethem, Jacek Jassem, Volker Heinemann, Colin D. Weekes, John A. Bridgewater, Stefano Cascinu, Bohuslav Melichar, Marc Peeters, Paul J. Ross, Piotr Saramak, Marius Giurescu, Vittorio Luigi Garosi, Katrin Roth, Anke Schulz, Michael Teufel, Barrett H. Childs, Hanno Riess
Journal: Journal of Clinical Oncology (2014)

4025 Background: Refametinib is a potent oral allosteric MEK 1/2 inhibitor with single-agent and synergistic activities in combination with gemcitabine in preclinical pancreatic cancer (PC) models. We report the results of a single-arm, open-label, phase 2a study combining refametinib and gemcitabine in advanced PC. Methods: Eligibility criteria included: ECOG PS ≤ 2; locally advanced, unresectable or metastatic pancreatic adenocarcinoma; and no prior systemic therapy. Refametinib was administered 50 mg bid po in combination with gemcitabine (1000 mg/m2 IV weekly for 7 of 8 weeks in C1; 3 of 4 weeks in subsequent cycles). The primary objective was overall response rate (ORR); secondary objectives were duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS) and safety. All responses were confirmed by central independent radiological review. Genetic biomarker analysis was conducted on circulating tumor DNA from plasma samples (BEAMing). Results: Sixty patients were treated: median age 63 yrs, 53% male, 40% PS 0. KRAS mutations were detected in 39 patients (65%). Best overall response was PR in 35% [median DOR 3.8 mo (117 days; 95% CI: 83-265)]; SD in 38%, PD in 10%, and not evaluable in 17% The DCR was 73%. Median TTP was 7.4 mo (224 days; 95% CI: 188, UL ND); median PFS 6.2 mo (190 days; 95% CI: 112-225); OS 8.9 mo (270 days; 95% CI: 200-355). In the KRAS subgroups (mut/WT respectively) the ORR, mPFS and OS were 28%/48% (p=0.136), 4.6/9.0 mo (HR 0.26) and 6.6/18.2 mo (HR 0.27). Full biomarker analysis is being reported separately (Riess et al, this meeting). The most common grade 3-4 TEAEs were neutropenia (43%), thrombocytopenia (22%) anemia (12%), elevations of AST (12%) or ALT (13%), DVT (10%), hypertension (12%), fatigue (15%) and rash acneiform (10%). Conclusions: The combination of refametinib and gemcitabine in advanced PC is active, with an acceptable safety profile. The reported high prevalence of KRAS mutations in PC patients was confirmed by BEAMing. A trend towards improved outcomes (ORR, PFS and OS) in patients with KRAS wild type PC was observed. Clinical trial information: NCT01251640.
CD34+ Selection Avoids Methotrexate and Reduces the Severity of Oral Mucositis in TBI-Based Allogeneic Stem Cell Transplantation
Authors: Ankit Anand, Prathima Anandi, Jain A. Natasha, Kit Lu, Neil Dunavin, Christopher S. Hourigan, Robert Q. Le, Puja D. Chokshi, Sawa Ito, David F. Stroncek, Marianna Sabatino, John Barrett, Minoo Battiwalla
Journal: Blood (2014)
BC2001 long-term outcomes: A phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer.
Authors: Emma Hall, Syed A. Hussain, Nuria Porta, Malcolm Crundwell, Peter Jenkins, Christine Lisa Rawlings, Jean Tremlett, Charlotte Friend, Clive Stubbs, Rebecca Lewis, Nicholas D. James, Robert Anthony Huddart
Journal: Journal of Clinical Oncology (2017)

280 Background: BC2001 showed that adding chemotherapy (5FU+MMC) to radiotherapy significantly improved rates of muscle invasive bladder cancer (MIBC) locoregional control (LRC) [James 2012] but that reduced high dose volume RT rather than standard RT did not significantly reduce late side effects [Huddart 2013]. Here we present an update of the time to event outcomes after a median 10 years follow up. Methods: Under the 2x2 partial factorial design, 458 pts were randomised to RT (178) or cRT (182) (CT comparison) and/or to stRT (108) or RHDVRT (111) (RT comparison). Primary endpoint was LRC, secondary endpoints included overall survival (OS), bladder-cancer specific survival (BCSS), metastasis free survival (MFS) and salvage cystectomy rates. Results: Median follow up was 118 months (95%CI: 112-122). LRC and invasive LRC (ILRC) were improved with cRT (Table 1). Though no statistically significant differences between groups were found in OS, cRT exhibited a trend towards improvement in BCSS, significant when adjusted by known prognostic factors. Similar trend was found for MFS. Salvage cystectomy rate was lower for cRT (2-year rate, cRT:11% vs RT:17%, p=0.03). No differences between stRT and RHDVRT were found for any trial endpoint. Conclusions: With extended follow-up, an improvement in LRC and a reduced salvage cystectomy rate is confirmed with cRT. After adjustment for known prognostic factors this results in an improvement in BCSS. This updated data supports the use of cRT with 5FU/MMC and confirms this should be a standard of care for this patient population. Clinical trial information: ISRCTN68324339. [Table: see text]
Does the EPIC-26 measure five domains in English and Spanish speakers?
Authors: Maria Carmen Mir, Marisa Perera, Olatz Garin, Montserrat Ferrer, Lluis Fumadó, Sanoj Punnen, Raymond R Balise, Ashly Westrick
Journal: Journal of Clinical Oncology (2017)

e557 Background: Despite being widely used in many countries to assess health-related quality of life for patients undergoing treatment for localized prostate cancer(PC), seldom research has been done to investigate the five domain scores generated by 26 question short form of the Expanded Prostate Cancer Index Composite Short (EPIC-26). We conducted exploratory and confirmatory factor analyses searching for evidence of five unique domains of dysfunction in men being treated for PC in the US and Spain.Methods: Using two-year post treatment information, data from 400 men who were part of the original EPIC (OE) validation cohort [T1 or T2, 87% Radical Prostatectomy (RP), 10% External Beam Radiation (EBR), 3% Brachytherapy (BR)] and 450 men who were treated for prostate cancer at Institut Hospital del Mar d'Investigacions Mèdiques in Spain [33% RP, 33% EBR, 33% BR], were subjected to exploratory (EFA) and confirmatory factor analysis (CFA).Results: EFA analyses on both the OE and Spanish cohorts provides support for three, four or five factor models (accounting for approximately 83, 91 or 97% of variance in either cohort) to describe the EPIC-26 variables and weak evidence for the hormonal domain. There is evidence of separate urinary, sexual and bowel factors, but limited evidence of a separate hormonal domain. With the exception of the questions which could be described as assessing depression (lack of energy and depression and in some models weight gain), items within the hormonal domain frequently failed to consistently load onto a single factor (orthogonal communalities ranging from .22 to .27 in the OE cohort and .10 to .21 in the Spanish for hot flashes, breast tenderness and weight gain). CFA looking for the published five domain solution in the Spanish data provides mediocre support for a five factor solution (Standardized RMR = .0624, RMSEA Estimate = .07, Bentler Comparative Fit Index = .91). Conclusions: While all questions asked on the EPIC-26 are of clinical value, there is limited evidence to continue to treat the hormonal domain as a single entity. Urologists should consider looking at the questions linked to depression separately from the other hormonal questions
Role of PARL-PINK1-Parkin pathway in adipocyte differentiation
Authors: Ming-Yuh Shiau, Pin-Shen Lee, Ying-Jyun Huang, Ching-Ping Yang, Chiao-Wan Hsiao, Kai-Yun Chang, Huan-Wen Chen, Yih-Hsin Chang
Journal: Metabolism (2017)
Comparison of yoga versus relaxation on chemotherapy-induced nausea and vomiting (CINV) outcomes a mechanism of action study.
Authors: Rao M. Raghavendra, Malur R. Usharani, Mahesh Kavya, S Aishvarrya, Pkl Nandini, Shekhar Patil, Diwakar B Ravi, H P Shashidhara, C T Satheesh, Nayak Radheshyam, Basavalinga S Ajaikumar
Journal: Journal of Clinical Oncology (2013)

6624 Background: Chemotherapy induced nausea and vomiting is a common distressing symptom. In this study we evaluated the effects of Yoga vs. Jacobson’s relaxation training on CINV outcomes in chemotherapy naive patients undergoing moderately to highly emetogenic chemotherapy. Methods: One hundred and twenty patients who satisfied the selection criteria and gave written consent to participate were randomized to receive Yoga or Jacobson’s relaxation or serve as waitlist controls for first 4 cycles of chemotherapy. Assessments for nausea and emesis including functional living index emesis, nausea diary and cardiac autonomic function and electrogastrogram were carried out at baseline, six days after 1 st cycle, after 2 nd and 3 rd cycle of chemotherapy. Assessments for mood states such as anxiety and depression using HADS, and perceived stress were carried out at baseline and after 3 rd cycle of chemotherapy. Both interventions were for a duration of 25 minutes imparted by a trained instructor. Data were analysed using repeated measures ANOVA with post hoc Bonferroni tests. Results: There was a significant decrease in acute and delayed nausea severity in Yoga compared to control group (p=0.001) and Jacobson’s group (p=0.004) after 1 st cycle of chemotherapy. There was a significant decrease in self reported anxiety and depression in Yoga (p=0.03) and Jacobson’s relaxation (p=0.004) compared to control group following 3 rd cycle of chemotherapy.There was significant decrease in LF/HF ratio in Yoga group compared to control group (p=0.06) after 3 rd cycle of chemotherapy. There was a significant decrease in bradygastria (p=0.002) and tachygastria percentage (p=0.03) in Yoga group compared to Jacobson’s and control group becoming more evident after 3 rd cycle of chemotherapy. Conclusions: Both Yoga and Jacobson’s intervention conferred beneficial effects in reducing chemotherapy induced nausea and vomiting. Yoga helps normalise gastric motility and enhances cardiac and gastric parasympathetic activity in subjects undergoing chemotherapy. Clinical trial information: NCT01387841.