tbuckley/cabot-search huggingface dataset:
Overcoming the barriers to the use of short course radiation therapy in locally advanced rectal cancer: A phase 1 study of short course radiotherapy concurrent with 5-fluorouracil.
Authors: Emma Charlotte Fields, Brian J. Kaplan, Jeremy Karlin, Jennifer Lynn Myers, Nitai Mukhopadhyay, Steven R. Grossman, Khalid Matin
Journal: Journal of Clinical Oncology (2018)

e15673 Background: Short course (SC) RT is equivalent to long course (LC) RT for local control, disease free survival (DFS) and overall survival with similar rates of sphincter preservation and late toxicity in randomized studies. However, SC RT has not been adopted in the US for several reasons including: no opportunity for a synergistic effect of chemoRT, delay to systemic therapy, less time for down-staging, and risk of increased late effects. This study aims to overcome these perceived barriers to the use of SC RT by determining a safe dose of continuous infusion (CI) 5-FU combined with SC RT, 4 cycles FOLFOX, total mesorectal excision (TME) and 6 cycles of adjuvant FOLFOX. Methods: Primary objective was to determine the MTD of CI 5-FU given concurrently with 5Gy x 5 fractions. Using the continual reassessment method, CI 5-FU was escalated from 100-200mg/m2/day. Secondary objectives included rate of clinical complete response, pathologic complete response, toxicity, 3 yr local control and DFS (not yet reportable). Pts ≥ 18 years with cT3-4 or N+ rectal adenocarcinoma were included. In an effort to mitigate the potential added toxicity IMRT was used. Results: 14 pts were enrolled from 2014-2017. All pts completed the study treatment of CI 5-FU and SC RT and the dose of 5-FU was safely escalated to 200mg/m2/day with no DLT. 93% completed the neoadjuvant mFOLFOX. Clinical response was 22% complete, 64% partial, 14% stable disease and no progression. 3 pts with cCR had negative biopsies and did not have TME. Pathologic response was 21.4% complete, 64.3% partial, 14.3% stable disease and 0 had progression. Grade 4 toxicity was reported in 1 patient (cytopenia), grade 3 in 8.6% and grade 1-2 in 91%. Conclusions: The preliminary results of this study show that SC RT can be safely and feasibly given with concurrent CI 5-FU and adds to the growing body of literature showing that SC RT is not only equivalent to LC RT, but may provide additional benefits in terms of allowing for a transition of full dose systemic therapy to the neoadjuvant setting, for selective organ preservation in complete responders, and providing a more convenient and cost-effect way of delivering pelvic RT. Clinical trial information: NCT02270606.
Prospective feasibility study of a predictive blood assay to identify patients at high risk of chemotherapy-induced nausea.
Authors: Yue Wang, Erik Zeger, Zonera A. Ali, Paul Gilman, Margaretha Wallon
Journal: Journal of Clinical Oncology (2016)

6586 Background: Chemotherapy-induced nausea and vomiting (CINV) is a highly feared side effect in patients, possibly affecting nutritional habits, ability to work and motivation to complete regimens. Even with modern interventions, some patients experience moderate to severe nausea. The aim for this study was to identify an objective assessment tool, identifying patients in need of more effective prevention/management of nausea. We hypothesized that a patient’s risk of CINV may reflect individual variations in the efficiency to scavenge free radicals, generated by chemo-induced cell damage in the small intestine, which trigger serotonin release and activates 5-hydroxytryptamine3 (5-HT3) receptors. In considering this hypothesis, we focused our attention on redox homeostasis as maintained by glutathione (GSH), a major antioxidant and free radical scavenger. Methods: Chemotherapy naïve patients diagnosed with lung or colorectal cancers were asked to participate in this IRB-approved study. Consented patients donated a tube of blood (K2 EDTA) and filled out the Rotterdam Symptom Checklist (RSCL) prior to each platinum-based treatment cycle. A commercial kit was used to measure GSH recycling capacity (OxPhos, Rockland Inc.). This assay uses a novel indirect indictor of glutathione-dependent recycling involving conversion of GSH→GSSG→GSH, which releases mercaptoethanol (ME), quantified with dithiobisnitrobenzoic acid (DNTB). Results: Values obtained from the OxPhos assay were normalized to total red blood cell count and compared to self-reported outcomes on the RSCL. Using standard methods we calculated a cut-off for nausea-associated recycling capacity to 1.0, so that < 1.0 indicated development of moderate-to-severe nausea while values > 1.0 were predicted no or mild nausea. Conclusions: Through this approach, we correctly identified 85.7% of patients with an overall sensitivity of 66.7% and specificity of 90.9%. Female patients or patients < 55 years had higher incidence of nausea and were correctly identified in 89% and 73.3% of the cases, respectively. This could be the first objective method to identify patients at high risk of difficult to prevent/manage nausea.
Comparison of incidence and average cost per toxicity in patients treated with nivolumab and pembrolizumab.
Authors: Neil Thomas Mason, Scott Joseph Antonia, Nikhil I. Khushalani, Howard L. McLeod
Journal: Journal of Clinical Oncology (2017)

e18292 Background: PD-1 inhibitors such as nivolumab and pembrolizumab have demonstrated efficacy in numerous metastatic cancers. However, these drugs are also some of the most expensive and can have severe adverse side effects. However, most available data comes from clinical trials rather than patients treated in clinical practice as standard-of-care. This study reports the incidence of severe toxicities in a number of cancer types and estimates the per patient cost of managing these toxicities. Methods: All patients treated with nivolumab or pembrolizumab between January 1, 2014 through April 30, 2016 were identified at Moffitt Cancer Center (nivolumab N=74, pembrolizumab N=134). Toxicities occurring during or within 2 months of stopping treatment were identified and graded using the CTCAE 4.0 criteria. A cost of care analysis was performed comparing patients with Grade 3-5 toxicities to patients with Grade 0-2 toxicities. Results: The most common severe toxicities were anemia, dyspnea, dermatitis, hepatitis, and renal failure (Table 1). The average cost of care for patients experiencing Grade 3-5 toxicities was $640 and $4,784 higher than those without toxicity in nivolumab and pembrolizumab, respectively. Conclusions: Primary cost drivers differed between the two drugs with outpatient visits and additional pharmacy costs driving nivolumab cost while inpatient stays and radiation therapy drove costs with pembrolizumab. The large difference between the toxicity cost of each group could be due to the heterogeneity of cancer types treated with nivolumab versus primarily melanoma in the case of pembrolizumab or the smaller sample size of nivolumab patients. [Table: see text]
Nivolumab (Nivo) maintenance (maint) in high-risk (HR) acute myeloid leukemia (AML) patients.
Authors: Tapan M. Kadia, Jorge E. Cortes, Ahmad Ghorab, Farhad Ravandi, Elias Jabbour, Naval Guastad Daver, Yesid Alvarado, Maro Ohanian, Marina Konopleva, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2018)

7014 Background: Frontline AML induction produces 60-70% complete remission (CR) rates but relapse is a major source of failure. Beside stem cell transplant (SCT), few options exist for post-CR maint in HR pts. Prior maint studies of cytotoxics were unsuccessful. Post SCT immune surveillance via tumor-specific cytotoxic T-cells may be important in suppressing AML relapse. Immune checkpoint inhibitors may restore host immune surveillance in post-CR maint. Methods: This is a pilot phase II study of nivo maint in HR AML pts in CR, ineligible for SCT. Pts ≥ 18 yrs with a HR feature in 1st CR (CR1) or any pt in 2nd CR (CR2) who received induction & ≥ 1 consolidation cycle & were within 12 months (mos) of CR were eligible. Treatment was: nivo 3mg/kg IV Q2 weeks for 6 mos, then Q4 weeks until 12 mos on study, & then Q3 mos until relapse. All pts had baseline cytogenetic (CG) & molecular testing, & minimal residual disease (MRD) assessment by flow cytometry. Blood & marrow samples were collected for immune correlatives. CR duration (CRd) is compared to a similar historical cohort with median (med) of 8 mos. Results: 14 pts (med age 56 yrs): 11 pts were in CR, CRp (1), & CRi (2) at enrollment; 11 pts (79%) were in CR1, 2 pts (14%) in CR2, & 1 pt (7%) in CR4 was treated. Baseline mutations: TP53 (n = 3), DNMT3a (2), IDH2 (2), NPM1 (2), TET2 (3). HR features: 5 (36%) persistent MRD, 4 (29%) adverse CG, 1 (7%) adverse mutation alone, 1 t-AML (7%) & 3 pts (21%) in ≥ CR2. Pts received a med of 4 (1-17) cycles of therapy. At med F/U of 11 mos (1.4 – 26), med CRd was not reached. 6- & 12-mo rates of CRd were 79% & 71%, respectively. The 12- & 18-mo estimated OS were 86% & 67%, respectively. Therapy was well tolerated; 5 pts had grade 3/4 immune-related events. 1 pt had thyroiditis, treated with steroids & hormone replacement; 1 pt with transaminitis responded to dose interruption; 2 pts had pneumonitis treated with steroids & dose interruption. All 4 pts resumed rx after interruption. 1 pt had autoimmune hemolytic anemia & came off study. Most pts have detectable MRD while on therapy & in CR; 1 pt cleared MRD & 1 pt normalized CG. Conclusions: Maint nivo is safe & feasible in HR AML. The study continues to surpass expected rate of 6-mo CRd of HR pts. Correlatives profiling the immune repertoire are being analyzed. Clinical trial information: NCT02532231.
PREDMED®, a normalized expression signature of drug targets versus reference tissues aiming at generalizing treatment personalization
Authors: L. Verlingue, M. Baranger, C. Gianesini, J. Fritz, M. Schaeffer, D. Malka, C. Jouffroy, B. Loubaton, D. Bagnard
Journal: Annals of Oncology (2018)

Background: The genomic landscape of tumors is highly heterogeneous. We aim at developing a tumor-agnostic and treatments-specific gene expression signature that could facilitate treatment personalization in the context of massive drug development. Methods: To this end, we developed PREDMED®, a tumor gene expression signature composed of multiple drug targets normalized with gene expression from reference tissues. For the clinical evaluation, the relation between the score of each drug targets in the signature and the effect of the targeted therapies, has been evaluated in different cohorts of patients. Bayesian statistics have been used in these studies to compute the probability of the relation between drug targets scores and outcome values. Results: In a pilot retrospective cohort of 11 patients with clear cell renal carcinomas (CCRCC) treated in first line with sunitinib (anti-VEGFR2) (UroCCR), VEGFR2 scores were positively associated to response (5 complete or partial responses, 6 progressions) under sunitinib with a probability of 98% (Bayesian logistic regression). In a second retrospective cohort of 37 patients with metastatic colorectal cancers (mCRC) treated in first line with bevacizumab (anti-VEGFA) associated to standard chemotherapy (Indivumed), VEGFA scores were positively associated to Progression-Free Survival with a probability of 94% (Bayesian logistic regression). In both studies, no relation between drug target expression and outcome values was found without PREDMED® (probability of a positive association: 50 % for CCRCC and 51% for mCRC) or with a partial normalization method (probability of a positive association: 36 % for CCRCC and 65% for mCRC), suggesting an advantage of using the PREDMED® normalization method. Conclusions: These two preliminary studies of different tumor types for patients treated with anti-angiogenics, give encouraging signals for the use of a treatments-specific gene expression signature. We aim at further evaluating the generalizability of PREDMED® on other tumor types and targeted therapies, including immunotherapies. Legal entity responsible for the study: Adaptherapy. Funding: Adaptherapy. Disclosure: Personal fees from Amgen, Celgene, Teva, Boehringer-Ingelheim, Menarini, Bayer, Lilly, MSD, outside the submitted work. L. Verlingue: Consulting for Adaptherapy. D. Malka: Personal fees and non-financial support from Roche, Sanofi-Aventis, Merck Serono; D. Bagnard: Scientific advisor for Adaptherapy, shareholder. All other authors have declared no conflicts of interest.
Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study
Authors: Gary T. Ferguson, Alberto Papi, Antonio Anzueto, Edward M. Kerwin, Christy Cappelletti, Elizabeth A. Duncan, Jack Nyberg, Paul Dorinsky
Journal: European Respiratory Journal (2018)

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history. In this phase III, double-blind, parallel-group, 24-week study ( NCT02766608 ), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) and FEV 1 area under the curve from 0–4 h (AUC 0–4 ). Time to first and rate of moderate/severe exacerbations were assessed. BFF MDI 320/10 µg improved pre-dose trough FEV 1 versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV 1 AUC 0–4 versus BD MDI (LSM 173 mL and 157 mL, respectively; both p&lt;0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5–1.4%. BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.
Maintenance immunotherapy in patients with metastatic breast cancer (MBC) who have a clinical benefit with chemotherapy. Long-term follow-up of a phase II study.
Authors: Francesco Recchia
Journal: Journal of Clinical Oncology (2018)

e13068 Background: In a phase I study we have shown, that a combination of 13-cis retinoic acid (RA) and interleukin-2 (IL-2) was feasible and was able to improve the immune function of cancer patients who had had a clinical benefit with chemotherapy (Clin Cancer Res 2001;7:1251). Methods: With the aim of prolonging progression free survival (PFS) and overall survival (OS), through immune-mediated mechanisms, patients with hormone resistant MBC who had not progressed with chemotherapy, received the following maintenance immunotherapy regimen: IL-2, (1.8 M UI ), and oral RA (0.5 mg/kg), 5 days/week, 3 weeks/month for 1 year. Therapy was continued, with intermittent schedule until progression. Primary endpoints were the count of lymphocyte, NK, and the CD4+/CD8+ratio. Secondary endpoints were PFS, OS and toxicity. Results: From 12/1996 to 04/2009, 74 patients with MBC were entered into the study. Median age was 55 years (range 31-75); 30% of patients were pre-menopausal; 60% were ER+and had progressed after 2 or more lines of hormonal therapy. The 74 patients had received 368 courses of chemotherapy regimens (median of 6 courses each patient). Thirty-six patients had received, also, high-dose chemotherapy with peripheral blood progenitor cell transplantation. Disease sites were as follows: soft tissue 45%, viscera 35%, and bones 20%. After a median follow-up of 100 months (range 96-200), each patient had received a median of 8 courses of immunotherapy (total of 924 courses delivered). No WHO grade 3 or 4 toxicity was observed; grade 2 cutaneous toxicity and autoimmune reactions occurred in 19% and 16% of patients, respectively. Statistically significant improvements were observed in the number of lymphocytes (p < 0.001), NKs (p < 0.001), and the CD4+/CD8+ratio (p < 0.01). 10-year PFS and OS were 25% and 31%, respectively. Conclusions: MI with IL-2 and RA in MBC patients, who have a clinical benefit from chemotherapy, is feasible, is well tolerated, is able to give statistically significant improvements in lymphocyte, NK count, CD4+/CD8+ ratio, and a statistically significant delay in disease recurrence with respect to historical controls.
Intramuscular versus intravenous oxytocin to prevent postpartum haemorrhage at vaginal delivery: randomised controlled trial
Authors: Nita Adnan, Rebecca Conlan-Trant, Ciara McCormick, Fiona Boland, Deirdre J Murphy
Journal: BMJ (2018)

To determine whether intravenous oxytocin is more effective than intramuscular oxytocin at preventing postpartum haemorrhage at vaginal delivery.Double blind placebo controlled randomised trial.University affiliated maternity unit in the Republic of Ireland.1075 women aged 18 years or older, at term with a singleton pregnancy who were aiming for a vaginal delivery with an actively managed third stage of labour.Women were allocated to an intravenous bolus of oxytocin (10 IU in 1 mL given slowly over one minute) and placebo intramuscular injection (1 mL 0.9% saline) or an intramuscular bolus of oxytocin (10 IU in 1 mL) and placebo intravenous injection (1 mL 0.9% saline given slowly over one minute) at vaginal delivery. Allocation was by a secure web based randomisation service with masking of participants and clinicians to the trial intervention.The primary outcome was postpartum haemorrhage (PPH, measured blood loss ≥500 mL). Secondary outcomes were severe PPH (measured blood loss ≥1000 mL), need for blood transfusion, admission to a high dependency unit, and side effects to oxytocin.Between 4 January 2016 and 13 December 2017, 1075 women were randomised and 1035 (96.3%) included in the primary and secondary analyses (517 in the intravenous oxytocin group and 518 in the intramuscular oxytocin group). The incidence of PPH was not significantly lower in the intravenous group (18.8%, 97/517) compared with intramuscular group (23.2%, 120/518): adjusted odds ratio 0.75 (95% confidence interval 0.55 to 1.03). The incidence of severe PPH, however, was significantly lower in the intravenous group (4.6%, 24/517) compared with intramuscular group (8.1%, 42/518): 0.54 (0.32 to 0.91) as was the need for blood transfusion (1.5% v 4.4%, 0.31, 0.13 to 0.70) and admission to a high dependency unit (1.7% v 3.7%, 0.44, 0.20 to 0.98). The number needed to treat to prevent one case of severe PPH was 29 (95% confidence interval 16 to 201) and to prevent one case of blood transfusion was 35 (20 to 121). The incidence of side effects to oxytocin was not increased in the intravenous group compared with intramuscular group (4.1% v 5.2%, 0.75, 0.42 to 1.35).Intravenous oxytocin for the third stage of labour results in less frequent severe PPH, blood transfusion, and admission to a high dependency unit than intramuscular oxytocin, and without excess side effects.Current Controlled Trials ISRCTN14718882.
Deficient necroptosis pathway as a negative prognostic factor in acute myeloid leukemia.
Authors: Silvia Lo Monaco, Giovanni Marconi, Maria Chiara Fontana, Cristina Papayannidis, Eugenio Fonzi, Carmen Baldazzi, Nicoletta Testoni, Emanuela Ottaviani, Eugenia Franchini, Anna Ferrari, Giorgia Simonetti, Antonella Padella, Andrea Ghelli Luserna di Rorà, Valentina Robustelli, Stefania Paolini, Maria Chiara Abbenante, Sarah Parisi, Jacopo Nanni, Luca Bertamini, Giovanni Martinelli
Journal: Journal of Clinical Oncology (2017)

11611 Background: Necroptosis is a type of necrotic cell death involving several genes transcription and activation of molecular mechanisms as death receptors, interferon, toll-like receptors, intracellular RNA and DNA sensors.The process is leading by the family of receptor-interacting protein kinase ( RIPK3, RIPK2, RIPK1) and the MLKL substrate. Losses of RIPK3 or MLKL, as well as deficiency in apoptosis, could allow tumor cells to escape the immunomediated cells death (ICD). Methods: We performed SNP Arrays (Cytoscan HD and SNP 6.0, Affymetrix) on a cohort of 300 non-M3 AML patients at diagnosis and we analyzed the Overall Survival (OS) of our patients with deficiency on necroptosis pathways. Survival was analyzed with Kaplan-Mayer method and Log-Rank test. We further analyze the relevance of different prognostic factors by the use of COX-Hazard Ratio statistical analysis. Results: We find that 18 patients presented a loss of RIPK1 or MLKL (nobody presented losses in RIPK3/RIPK2) and 13/18 patients were older than 65 years old. The Overall Survival (OS) of patients with alterations in these genes is significantly lower than control group, with a median OS of 3 vs 6 month respectively (p&lt;.0.001). With Fisher Exact Test we further demonstrate that copy number loss of RIPK1 or MLKL are associate to loss of TP53 or FANCAgenes, complex karyotype and advanced age. COXHR model with RIPK1 or MLKL loss, BRACA1 loss, TP53 mutation, FANCA loss, secondary disease and diagnosis karyotype considered as categorical variable shows that necroptosis deficiency (HR 1.98, CI 95% 1.04-3.78), TP53mutation , and secondary AML are independent negative prognostic factors in an optimal model. Conclusions: Our study shows that losses in necroptosis pathways are an uncommon alteration in AML, prevalent in old population. Moreover, we hypothesize that the loss of genes involved in necroptosis could be a real mechanism of tumor immune-escape and could be a rational to select patients that have high probability to be resistant at chemotherapy promoting ICD mechanism. Acknowledgment: ELN,AIL,AIRC, progetto Regione-Università 2010-12, FP7 NGS-PTL project,HARMONY.
Comparison of myeloablative vs reduced intensity conditioning regimens in stem cell transplantations for acute myeloid leukemia.
Authors: Gunhan Gurman, Gozde Aydemir Guloksuz, Erden Atilla, Pinar Ataca Atilla, Sinem Civriz Bozdag, Meltem Kurt Yuksel, Selami Kocak Toprak, Pervin Topcuoglu, Muhit Ozcan, Onder Arslan, Taner Demirer, Hamdi Akan, Osman Ilhan, Meral Beksac
Journal: Journal of Clinical Oncology (2017)

e18518 Background: The development of reduced intensity conditioning (RIC) regimens enabled allogeneic hematopoietic stem cell transplantations (allo-HSCT) also for patients who had contraindications and comorbidities for myeloablative conditioning (MAC) regimens. The aim of this study is to evaluate the effects of conditioning regimens on outcomes of alllo-HSCT for patients with acute myeloid leukemia. Methods: We retrospectively analysed 362 acute myeloid leukemia patients who underwent allo-HSCT between November 1989 to November 2016. We compared the outcomes of MAC vs RIC by Fisher’s test and chi-square test. Results: Engraftment was achieved in 87% of RIC and 95% of MAC recipients (p = 0.03).Incidences of acute and chronic graft vs host disease were not statistically different in groups (41% vs 47%, p = 0.7; 32% vs 43%, p = 0.2).Relapse rate was higher in RIC group (45% vs 25%, p = 0.02).Both 1-year overall survival (OS) and 1-year relapse free survival (RFS) rate were lower in the patients treated with RIC (71% vs 35%; 55% vs 16%).The higher OS was related with patients who were transplanted in remission, received grafts from related donors as well as having acute and chronic graft vs host disease. Conclusions: In the treatment of young patients who do not have comorbidities for intense conditioning regimens, show good performance status and are high risk; the initial use of standard myeloablative conditioning regimens is feasible. However, the lower number of RIC transplants and the variations between groups in terms of patient and donor characteristics might effect the results of this study. [Table: see text]