bluuebunny/crossref_metadata_2025 huggingface dataset:
Volatile Constituents of the Leaves of Kalanchoe pinnata From the Venezuelan Andes
Authors: Obregón-Díaz Ysbelia , Pérez-Colmenares Alida , Obregón-Alarcón Karelys , Aparicio-Zambrano Rosa , Rojas-Fermín Luis , Usubillaga Alfredo , Carmona Juan
Published: May 2019

The essential oil from the leaves of Kalanchoe pinnata (Lam.) Pers. (Crassulaceae), collected in the Venezuelan Andes, was obtained by hydrodistillation and its composition determined by gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). Nineteen compounds were identified, representing 95.2% of the oil. The most abundant components were α-curcumene (44.7%), 1-octen-3-ol (18.1%), β-curcumene (4.9%), and β-caryophyllene (3.7%).
Integrated X-Ray, NMR, ECD, and Computational Approaches to Assign the Stereochemistry of Nortriterpenoids
Authors: Wang Xiaojuan , Hamann Mark T.
Published: May 2019

Highly oxygenated nortriterpenoids are the principle bioactive chemical constituents isolated from plants of the genera Schisandra and Kadsura. The stereochemistry of these molecules remains a highly challenging problem to solve. To establish the stereochemistry and develop a general nuclear magnetic resonance-electric circular dichroism-computational approach to solve these complex metabolites, we reviewed the published methods to solve the stereochemistry of these triterpenoids. A key goal of this review is to provide a protocol to solve the problems hampering the assignment of the relative absolute configurations of other members of this natural product class.
Dissolution of aluminium from metakaolin with oxalic, citric and lactic acids
Authors: Karbalaei Saleh Danyal , Abdollahi Hadi , Noaparast Mohammad , Fallah Nosratabad Alireza
Published: May 2019

This study examines the leaching of aluminium from calcined kaolin (metakaolin) with citric, oxalic and lactic acid and binary combinations of these organic acids. The investigated parameters were the pulp density, acid concentration, pH, agitation speed, temperature and contact time. The kinetics of aluminium dissolution from metakaolin in binary organic acid mixtures were determined and scanning electron microscopy examination and energy-dispersive spectrometry mapping of Si and Al of untreated kaolin and residual solids were also carried out. Aluminium dissolution increased with temperature, time, acid concentration, pulp density and acidity. At maximum dissolution, citric–oxalic (1:4 w/w) and lactic–oxalic (1:4 w/w) mixtures dissolved 77% and 78% aluminium, respectively, from metakaolin in 11 h. The activation energy ranged from 57.8 to 74.6 kJ/mol. The most effective parameter in the dissolution of aluminium was the temperature, indicating that the reaction was not diffusion-controlled. It was concluded on the basis of the activation energy values and the sensitivity of the reaction to temperature that the dissolution was under chemical-reaction control.
RETRACTED ARTICLE: Comparison of minimally invasive Ivor Lewis esophagectomy and left transthoracic esophagectomy in esophageal squamous cell carcinoma patients: a propensity score-matched analysis
Authors: Wang Qi , Wu Zixiang , Zhan Tianwei , Fang Shuai , Zhang Sai , Shen Gang , Wu Ming
Published: May 2019

Background

To investigate the long-term efficacy of the minimally invasive Ivor Lewis esophagectomy (MIILE) in esophageal squamous cell carcinoma (ESCC) patients, a retrospective comparison of the quality of life (QOL) and survival between patients who underwent MIILE and left transthoracic esophagectomy (Sweet approach) was conducted.

Methods

A detailed database search identified 614 patients who underwent MIILE and 243 patients who underwent Sweet esophagectomy between January 2011 and December 2017. After propensity score matching, 216 paired cases were selected for statistical analysis. Survival was evaluated with Kaplan-Meier curves or Cox models.

Results

MIILE was associated with a longer duration, less blood loss and more lymph node dissected than Sweet esophagectomy. MIILE patients suffered from less pain, less frequently developed pneumonia, and had fewer postoperative complications. Additionally, MIILE patients began oral intake earlier and had a shorter postoperative hospital stay, and enhanced recovery of QOL. There was no significant difference between the approaches regarding the recurrence pattern, 2-year and 5-year overall survival (OS) or disease-free survival (DFS), except that patients with tumor-node-metastasis (TNM) stage I in the MIILE group demonstrated superior OS and DFS. Pathological TNM stage and postoperative complications were determined to be independent prognostic factors based on the multivariate analysis.

Conclusion

MIILE is a safe and feasible approach for treating ESCC patients. MIILE approach may provide more postoperative advantages, enhanced QOL improvement, and more favorable long-term survival in early stage patients than the Sweet procedure.
Lithium for suicide and readmission prevention after electroconvulsive therapy for unipolar depression: population-based register study
Authors: Brus Ole , Cao Yang , Hammar Åsa , Landén Mikael , Lundberg Johan , Nordanskog Pia , Nordenskjöld Axel
Published: May 2019

Background

Electroconvulsive therapy (ECT) is effective for unipolar depression but relapse and suicide are significant challenges. Lithium could potentially lower these risks, but is used only in a minority of patients.

Aims

This study quantifies the effect of lithium on risk of suicide and readmission and identifies factors that are associate with readmission and suicide.

Method

This population-based register study used data from the Swedish National Quality Register for ECT and other Swedish national registers. Patients who have received ECT for unipolar depression as in-patients between 2011 and 2016 were followed until death, readmission to hospital or the termination of the study at the end of 2016. Cox regression was used to estimate hazard ratios (HR) of readmission and suicide in adjusted models.

Results

Out of 7350 patients, 56 died by suicide and 4203 were readmitted. Lithium was prescribed to 638 (9%) patients. Mean follow-up was 1.4 years. Lithium was significantly associated with lower risk of suicide (P= 0.014) and readmission (HR 0.84 95% CI 0.75–0.93). The number needed to be treated with lithium to prevent one readmission was 16. In addition, the following factors were statistically associated with suicide: male gender, being a widow, substance use disorder and a history of suicide attempts. Readmission was associated with young age, being divorced or unemployed, comorbid anxiety disorder, nonpsychotic depression, more severe symptoms before ECT, no improvement with ECT, not receiving continuation ECT or antidepressants, usage of antipsychotics, anxiolytics or benzodiazepines, severity of medication resistance and number of previous admissions.

Conclusions

More patients could benefit from lithium treatment.

Declaration of interest

None.
Prognostic Factors in the Assessment of Male Transsexuals for Sex Reassignment
Authors: Wålinder Jan , Lundström Bengt , Thuwe Inga
Published: May 2019

To bring to light the particular circumstances which from the outset weigh against the prospect of a successful result of sex reassignment the authors describe five male cases of transsexualism all of whom subsequently regretted the measure taken for sex reassignment. The number of factors suspected to be prognostically unfavourable was to a statistically significant degree more common among five ‘repentant’ cases than among nine cases with favourable outcome. It was also evident that the patients with unfavourable outcome were considerably older when they first sought help with the aim of obtaining sex reassignment. The results suggest that the more of such factors there are present in a particular case the stronger are the reasons for restraint in embarking upon a course of active intervention.
Studies Relating to the Clinical Significance of Urinary 3-Methoxy-4-Hydroxyphenylethylene Glycol
Authors: Howlett D. R. , Jenner F. A.
Published: May 2019

It has been suggested that cerebral noradrenaline turnover in patients can be assessed from the excretion in urine of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG). Studies were therefore made on the effects of mild exercise on the excretion of the conjugates of MOPEG as this might complicate interpretation. Changes are produced, but there are individual differences between subjects.

Physical fitness was also studied and, although it could not be shown to be the factor explaining differences between different patients, nevertheless it is probably a factor influencing the levels of MOPEG excreted.

The study of the distribution of free MOPEG and its sulphate conjugate in a human brain also raised doubts about the proportions which could have a cerebral origin.

The observations suggest the need for caution in using MOPEG excretion to detect abnormal amine changes in brain. They do not, however, conclusively refute the hypothesis that MOPEG sulphate in urine significantly reflects cerebral noradrenaline activity.
Victims of Indecent Exposure
Authors: Gittleson N. L. , Eacott S. E. , Mehta B. M.
Published: May 2019

One-hundred female nurses at a psychiatric hospital were interviewed in an attempt to assess the overall frequency of having been the victim of indecent exposure and to describe it as experienced by the victim.

Forty-four of the subjects had been victims of indecent exposure, one-third of these on two or more occasions.

The attitudes of those who had been victims were no different from the attitudes of those who had not. One-third of all incidents had not been disclosed to anyone. In over one-fifth of the episodes the reaction of the family and friends in whom the victim confided had been more distressing to the victim than the episode itself.
The Patient's Primary Group
Authors: Henderson Scott , Duncan-Jones Paul , McAuley Helen , Ritchie Karen
Published: May 2019

The size and utilization of the primary group (those with whom one has interaction and commitment) was examined in 50 patients with non-psychotic psychiatric disorder and 50 matched controls. The hypotheses tested were that the patients would have a smaller size of primary group, less contact with its members and an inferior affective quality of interaction with it; and that this deficiency would be most marked in transactions with the principal attachment figure. Patients were found to spend the same amount of time as normals with their primary group, but proportionately more of that time was affectively unpleasant. They had fewer good friends and fewer contacts with persons outside the household. They had fewer attachment figures, almost one half of them reporting that either they had only one, or that they had had no recent contact with those alternatives that did exist. The majority of patients considered that their principal attachment figures gave them insufficient support. The complexity of interpreting these data is discussed.
Inheritance of Alcoholism in Adoptees
Authors: Cadoret Remi J. , Gath Ann
Published: May 2019

Among 84 adoptees, 18 years of age and older, separated at birth from their biological parents and without further contact with them, alcoholism was found more frequently in those whose relatives included an individual with alcoholism or in whom heavy drinking had been noted. Adoptee alcoholism did not correlate with any other diagnosis in a biological parent.

Childhood socialized conduct disorder was significantly higher in those adoptees who later received a diagnosis of alcoholism or suspected alcoholism, and was positively, but not significantly, related to heavy drinking or alcoholism in parents.

Age of adoptee, time spent in foster care, age of biological mother at the time of the birth, socio-economic status of adoptive home, psychopathology other than alcoholism in the biological background, and psychiatric or behavioural problems in the adoptive family (parents or sibs) were all unrelated to adult alcoholism in the adoptee.
Monthly Variation of Suicidal, Accidental and Undetermined Poisoning Deaths
Authors: Barraclough B. M. , White Susan J.
Published: May 2019

Undetermined and accidental poisoning deaths in England and Wales between 1968 and 1974 did not show the same pattern of seasonal variation as suicides by poisoning.
The Applicability of the Foulds and Bedford Hierarchy Model to Mania and Hypomania
Authors: Bagshaw V. E. , McPherson F. M.
Published: May 2019

A group of 30 manic and hypomanic patients was assessed on the Delusions-Symptoms-States Inventory and did not appear to conform well to Foulds' and Bedford's hierarchy model. Failure to fit the hierarchy was caused by lack of scores in the Neurotic Symptom Class. The relationship between delusions of Grandeur and state of Elation, which was found to be inclusive and non-reflexive, did, however, support the hierarchy model.
Randomized phase 2 trial of the combination of vincristine and irinotecan with or without temozolomide, in children and adults with refractory or relapsed rhabdomyosarcoma (RMS).
Authors: Defachelles Anne Sophie , Bogart Emilie , Casanova Michela , Merks Hans , Bisogno Gianni , Calareso Giuseppina , Gallego Melcon Soledad , Gatz Susanne , Le Deley Marie-Cecile , McHugh Kieran , Probst Alicia , Rocourt Nathalie , van Rijn Rick R. , Wheatley Keith , Minard-Colin Veronique , Chisholm Julia
Published: May 2019

10000

Background: Vincristine with Irinotecan (VI) is effective in patients with relapsed RMS but outcomes remain poor. The addition of temozolomide to VI (VIT) is attractive owing to different resistance mechanisms and distinct toxicity profiles. Methods: The VIT-0910 trial, an EpSSG-ITCC randomized phase 2 trial, evaluated efficacy and safety of VI and VIT in patients (pts) aged 0.5-50 years with relapsed/refractory RMS. Pts received Vincristine 1.5 mg/m2 d1, d8, Irinotecan 50mg/m2 d1-d5 +/- Temozolomide 125 mg/m² d1-d5 (150 mg/m² from cycle 2 if no toxicity > grade 2); 21-day cycles were given until progression/unacceptable toxicity. The primary endpoint was centrally reviewed objective response rate (ORR) after 2 cycles (primary lesion, WHO response criteria: metastatic sites, RECIST 1.1 ). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events (NCI-CTCAE v4). Initially a Simon 2-stage design was used to analyse separately 40 pts/arm. After amendment, the trial sample size was increased to 120, and a comparison between arms, adjusted for confounding factors, was added to the statistical plan. Results: 120 pts (60 VIT, 60 VI) were recruited in 37 European centers from 03/2012-04/2018. Median age was 11 years (0.75-46), 89% pts relapsed RMS. ORR was 24/55 (44%) for VIT vs 18/58 (31%) for VI; adjusted odds ratio =0.50, 95%CI, 0.22-1.12, p=0.09. The VIT arm achieved significantly better PFS (adjusted Hazard Ratio (HR)=0.65, 95%Cl, 0.43-0.97, p=0.036) and OS (HR=0.53, 95%CI, 0.33-0.83, p=0.005) compared to VI. PFS and OS results were similar when only relapsed patients were included. Adverse events ≥ grade 3 were more frequent in VIT compared to VI, but only hematological toxicity was significantly increased (81% for VIT, 59% for VI, odds ratio=1.36, 95%CI, 1.06-1.76, P=0.02). Conclusions: The addition of temozolomide to VI improves PFS and OS of pts with relapsed/refractory RMS. VIT is now standard treatment for relapsed RMS in Europe. Clinical trial information: NCT01355445.
Impact of asparaginase discontinuation on outcome in childhood ALL: A report from the Children’s Oncology Group (COG).
Authors: Gupta Sumit , Wang Cindy , Raetz Elizabeth A. , Schore Reuven J. , Salzer Wanda L. , Larsen Eric , Maloney Kelly W. , Mattano Leonard A. , Carroll William L. , Winick Naomi J. , Hunger Stephen , Loh Mignon L. , Devidas Meenakshi
Published: May 2019

10005

Background: Asparaginase (ASP) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued due to toxicity. For allergic reactions, but not other toxicities, Erwinia Asparaginase (EA) is often substituted. The majority of treatment protocols use discrete, discontinuous periods of asparagine depletion. In the context of such protocols, the impact of EA substitution or complete ASP discontinuation is unknown. Methods: Patients age 1-30.99 years enrolled on frontline COG trials for B-ALL [standard risk (NCI SR): AALL0331; high risk (NCI HR) AALL0232] were included. The number of prescribed pegaspargase (PEG) doses varied by trial, risk strata, and randomization (Table). Maintenance therapy did not contain ASP. Landmark analyses starting at Maintenance compared event free survival (EFS) between those receiving all prescribed doses of PEG vs. those switched to EA but receiving all doses vs. those not receiving all ASP doses. Results: This study included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG discontinuation was 12.2±4.6% on AALL0331 and 25.4%±0.8% on AALL0232. In multivariable analyses adjusted for patient and disease variables, NCI HR patients who did not receive all prescribed ASP doses had inferior EFS [hazard ratio (HR) 1.5, 95% confidence interval (95CI) 1.2-1.9; p=0.002] compared to those receiving all prescribed PEG doses. Patients with EA substitution who completed their courses were not at increased risk (HR 1.1, 95CI 0.7-1.6; p=0.69). Sensitivity analyses excluding patients discontinuing ASP due to pancreatitis or thrombosis yielded similar results. NCI SR patients who discontinued ASP were not at elevated risk (HR 1.2, 95CI 0.9-1.6; p=0.23), except when analyses were restricted to NCI SR patients with slow early response (HR 1.7, 95CI 1.1-2.7; p=0.03). Conclusions: Discontinuation of ASP doses is associated with significantly inferior EFS and must be balanced against the risks of ASP re-challenge. Our results also illustrate the potentially severe consequences of EA shortages. Prescribed pegasparagase doses. [Table: see text]
Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial.
Authors: Parsons Donald Williams , Janeway Katherine A. , Patton David , Coffey Brent , Williams Paul M. , Hamilton Stanley R. , Purkayastha Anjan , Tsongalis Gregory J. , Routbort Mark , Gastier-Foster Julie M , Saguilig Lauren , Piao Jin , Alonzo Todd Allen , Berg Stacey L. , Fox Elizabeth , Adamson Peter C. , Mooney Margaret M. , Takebe Naoko , Tricoli James V. , Seibel Nita ,   NCI-COG Pediatric MATCH Team
Published: May 2019

10011

Background: The screening protocol for the NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial detects tumor alterations that are used to assign patients with treatment-refractory or recurrent cancers to phase 2 treatment arms of molecularly-targeted therapies. Methods: Patients age 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at U.S. based COG sites are eligible. DNA and RNA extracted from FFPE tumor samples are sequenced using an Oncomine cancer gene panel for detection of mutations, amplifications, and fusions. Loss of SMARCB1, SMARCA4, and PTEN expression is detected by immunohistochemistry. Lists of actionable mutations (aMOIs) based upon available clinical and pre-clinical data are used a priori to determine eligibility for treatment arms. Results: Between 7/24/17 and 12/31/18, 422 patients with a median age of 13 years (range 1-21) were enrolled from 93 COG sites. Solid tumors comprised 71% (n = 300) of diagnoses, CNS tumors 24% (n = 101) and lymphomas/histiocytoses 5% (n = 21). A tumor sample was submitted for 390 patients, sequencing was attempted for 370 (95%), and results were confirmed for 357 (92%). Median turn-around time was 15 days. An aMOI for at least one of the 10 current treatment arms was identified in 112 patients (29%, 95% CI 24%-33%); 95 patients (24%, 95% CI 20%-29%) were assigned to a treatment arm with 39 patients (10%, 95% CI 7%-13%) enrolled to date. The aMOI rate was similar in patients less than 12 years of age (35%) compared to patients 12 years and older (25%). Actionable MAPK pathway alterations were found in 11% of patients (n = 41), most often HRAS/ KRAS/ NRAS mutations (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11). Other genes with recurrent aMOIs included SMARCB1 (n = 14), ALK (n = 8), CDK4 (n = 8), PIK3CA (n = 7), PTEN (n = 7), FGFR1 (n = 5), and BRCA1/BRCA2 (n = 5). Conclusions: Approximately one-quarter of patients with tumor submitted for Pediatric MATCH screening have been assigned to an investigational therapy, facilitating the evaluation of molecularly-targeted agents in biomarker-positive pediatric cohorts through a collaborative nationwide study. Clinical trial information: NCT03155620.
Risk prediction of anthracycline-related cardiomyopathy (AC) in childhood cancer survivors (CCS): A COG-ALTE03N1 and CCSS report.
Authors: Wang Xuexia , Chen Yanjun , Hageman Lindsey , Singh Purnima , Landier Wendy , Blanco Javier G. , Hawkins Douglas S. , Ritchey A. Kim , Ginsberg Jill P. , Winick Naomi J. , Sapkota Yadav , Yasui Yutaka , Morton Lindsay M. , Armstrong Gregory T. , Oeffinger Kevin C. , Hudson Melissa M. , Chow Eric Jessen , Robison Leslie L. , Relling Mary V. , Bhatia Smita
Published: May 2019

10015

Background: CCS treated with anthracyclines are at risk for AC. While risk increases with dose, significant inter-patient variability in AC risk suggests a role for genetic predisposition in moderating the risk and provides an opportunity to identify patients at high or low risk. Methods: We curated candidate single nucleotide polymorphisms (SNPs) associated with AC from previous publications and used these to develop a risk prediction model, drawing upon COG-ALTE03N1 (CCS with AC [155 cases] matched with CCS without AC [256 controls]). Final Model (clinical + genetic) was obtained using backward variable selection guided by effect on area under receiver operating characteristic curve (AUC). Bootstrapping corrected for optimism of AUC. Regression coefficient estimates from Final Model were used to calculate risk scores, which were used to create risk groups. We validated the model in an independent sample from CCSS (229 cases; 5,360 controls). Results: Previously-published SNPs (rs1786814 [ CELF4], rs11864374 [ ABCC1], rs1800566 [ NQO1], rs4673 [ CYBA], rs2232228 [ HAS3]) were verified in COG-ALTE03N1 and were included, along with GxE interaction of rs1786814, rs4673, rs2232228 in a Final Model containing age at cancer, sex, race, cumulative anthracyclines (mg/m2), chest radiation, diabetes, hypertension, dyslipidemia. This yielded an optimism-corrected AUC = 0.8138, which was superior ( P= 0.0002) to the Clinical Model (corrected AUC = 0.7677). The sensitivity/specificity of the prediction model were 73.7%/ 81.3%. The prediction model was successfully replicated in CCSS (Final Model performed significantly better than the Clinical Model, P= 0.02). Conclusions: It is possible to identify CCS at high or low risk for AC on the basis of genetic and clinical information. This information can be used to inform interventions in CCS. [Table: see text]
Can pediatric and adolescent patients with recurrent tumors benefit from a precision medicine program? The European MAPPYACTS experience.
Authors: Berlanga Pablo , Pierron Gaëlle , Lacroix Ludovic , Adam de Beaumais Tiphaine , Bernard Virginie , Cotteret Sophie , Andre Nicolas , Corradini Nadege , Thebaud Estelle , Abbou Samuel , Casanova Michela , Owens Cormac , Michiels Stefan , Delattre Olivier , Vassal Gilles , Schleiermacher Gudrun , Geoerger Birgit
Published: May 2019

10018

Background: The international prospective precision medicine trial MAPPYACTS (NCT02613962) aims to define the molecular profile in recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. Methods: Patients < 18 years-old at the time of initial diagnosis underwent on-purpose tumor biopsy/surgery of their recurrent/refractory malignancy for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years. 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients did not undergo intervention procedure (10 screening failures, 1 consent withdrawal). Molecular profiling was performed on samples in 433 patients and was contributive for 390 patients. For 271/390 patients (70%), there was at least one genetic alteration that could represent a potential therapeutic target and 8% had alterations considered as “ready for use” for treatment at relapse. Among them, 19 (7%) died before the CMTB. With follow-up censored in January 2019, 72 patients (27%) were treated with at least one matched targeted agent, 57 of them in a clinical trial, mostly the proof-of concept AcSé-ESMART trial (NCT02813135). Of the 166 patients (61%) that did not receive the matched treatment recommended by CMTB (80 still on follow-up), main reasons were: response/stable disease under previous therapy (50), another treatment (48), rapid disease progression/death (30) and legal representative refusal (12). Conclusions: MAPPYACTS profiling allowed tailored targeted treatment, mainly through early clinical trials, in patients with recurrent pediatric cancer. Since most detected molecular findings are within the investigational or hypothetical evidence level, therapeutic proof-of-concept trials that are exploring targeted therapies in molecularly enriched patient populations are crucial to improve knowledge and potentially outcome. Clinical trial information: NCT02613962.
Impact of protein supplementation on lean muscle mass in adult survivors of childhood cancer engaged in resistance training.
Authors: Krull Matthew R , Howell Carrie R. , Partin, MS Robyn , Carney Ginger , Mulrooney Daniel A. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K.
Published: May 2019

10027

Background: Muscle weakness, low lean muscle mass and poor physical performance are prevalent among adult survivors of childhood cancer. We evaluated the effects of resistance training with and without protein supplementation on lean muscle mass, and muscle strength among childhood cancer survivors. Methods: This double-blind placebo-controlled trial enrolled survivors aged ≥18 to < 45 years. Participants were randomized to resistance training with daily protein supplement (21g protein/day, 90kcal) (RT+S) or resistance training with placebo (sucrose, 90kcal) (RT+P). Both groups received educational materials, access to a local fitness center and a tailored resistance training program with tapered supervision. Lean muscle mass and muscle strength were assessed at baseline and 24 weeks, using dual x-ray absorptiometry and dynamometer testing respectively. Mean changes were compared within and between groups. Results: Of 93 participants randomized, 57 completed the 24-week intervention (24 in RT+S, 33 in RT+P). The mean age was 33.1 (SD 7.0), 67% were white and 47% female. The RT+S group had a significant increase in lean body mass (1.05 kg [SD 2.34], p = 0.04), while the RT+P group did not (0.13 kg [SD 2.19], p = 0.74). Mean change in handgrip strength also improved in the RT+S group (1.98 [SD 4.30], p = 0.03); change approached significance in the RT+P group (1.49 [SD 4.60], p = 0.07). All survivors significantly improved their strength over time (Table) as measured by one max repetition test at baseline and follow-up. Conclusions: Preliminary findings indicate that a supervised resistance training program among adult survivors of childhood cancer that includes protein supplementation is feasible and may increase total lean body mass and muscle strength. Clinical trial information: NCT02501460. [Table: see text]
IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Schmid Peter , Adams Sylvia , Rugo Hope S. , Schneeweiss Andreas , Barrios Carlos H. , Iwata Hiroji , Dieras Veronique , Henschel Volkmar , Molinero Luciana , Chui Stephen Y. , Husain Amreen , Winer Eric P. , Loi Sherene , Emens Leisha A.
Published: May 2019

1003

Background: IMpassion130 evaluated atezo (anti–PD-L1) + nP vs placebo + nP in 1L mTNBC. The primary PFS analysis found that atezo + nP significantly improved PFS in intent-to-treat (ITT) and PD-L1+ pts vs placebo + nP, with efficacy driven by the PD-L1+ population. At that time, the 1st interim OS analysis was conducted (Schmid, NEJM 2018). Here we report the 2nd interim OS analysis. Methods: Eligible pts had histologically documented locally advanced or mTNBC, ECOG PS 0-1 and tumor tissue for PD-L1 testing. Pts were randomized 1:1 to IV atezo 840 mg or placebo on d1 and d15 + nP 100 mg/m2 on d1, d8 and d15 of each 28-d cycle until progression (stratification factors: prior taxanes, liver metastases, PD-L1 on tumor-infiltrating immune cells [IC]). RECIST 1.1 PFS (in ITT and PD-L1+ pts) and OS (tested in ITT and, if significant, PD-L1+ pts) were co-primary endpoints. Results: OS data are shown (Table). As of data cutoff (Jan 2, 2019), 9% of pts in the atezo + nP arm and 3% in the placebo + nP arm were still on treatment. Statistical significance was not demonstrated in ITT pts, but a 7.0-month improvement in median OS was observed in PD-L1+ pts with atezo + nP (25.0 mo) vs placebo + nP (18.0 mo; HR, 0.71 [95% CI: 0.54, 0.93]). A 4.5-mo safety update (Schneeweiss, ASCO 2019, submitted) showed that atezo + nP remained tolerable. Conclusions: The 2nd IMpassion130 interim OS analysis was consistent with the 1st analysis, confirming clinically meaningful OS benefit with atezo + nP in previously untreated PD-L1+ mTNBC. Clinical trial information: NCT02425891. [Table: see text]
A novel association between GSTM1 null variant and anthracycline-induced cardiac dysfunction (ACD) in childhood cancer survivors (CCS): A COG ALTE03N1 report.
Authors: Singh Purnima , Wang Xuexia , Hageman Lindsey , Chen Yanjun , Magdy Tarek , Landier Wendy , Ginsberg Jill P. , Neglia Joseph Philip , Sklar Charles A. , Castellino Sharon M. , Dreyer ZoAnn Eckert , Hudson Melissa M. , Robison Leslie L. , Blanco Javier G. , Relling Mary V. , Burridge Paul , Bhatia Smita
Published: May 2019

10030

Background: ACD is a leading cause of mortality in CCS. Previous studies have identified genomic variants that moderate the ACD risk. An agnostic evaluation of differential gene expression between those with and without ACD has not been explored, and could provide insights into the mechanism of cardiotoxicity. Methods: Gene expression profiles in leukocyte RNA from anthracycline-exposed non-Hispanic white (NHW) CCS (20 with ACD [cases]; 20 without ACD [controls]) used Illumina HumanHT-12 v4.0 Expression Beadchips. Gene expression profiles in h uman iPSC-derived cardiomyocytes (hiPSC-CMs – Day 30) from 6 childhood cancer patients (3 each with and without CD) treated with 1μM doxorubicin or vehicle for 24 h, used RNA-seq. Genotyping in leukocyte DNA from anthracycline-exposed NHW CCS (65 cases; 76 controls) to determine if the differentially-expressed genes mapped to genetic variants that modified ACD risk, used conditional logistic regression analysis adjusted for sex, age at cancer diagnosis, chest radiation and anthracycline dose. Patient characteristics are in Table. Results: Gene-expression in survivors:Glutathione S transferase mu 1 ( GSTM1) was differentially-expressed; RT q-PCR showed significant downregulation of GSTM1 in cases (0.67±0.57 vs. 1.33±1.33, p=0.049). hiPSC-CMs gene expression: GSTM1 was downregulated in patients with ACD (logFC = -1.4). Genotyping: Using PCR for GSTM1 null, we observed a significant association between CD risk and GSTM1 null genotype (OR=3.0; 95%CI, 1.4-6.2, p=0.003). Conclusions: We report an association between GSTM1 null genotype and ACD, previously unreported likely because GWAS studies did not examined gene deletions. GSTM1 is involved in detoxification of anthracyclines. This finding could facilitate identification of childhood cancer survivors at increased risk of ACD. [Table: see text]
Gene expression signature associated with in vitro dexamethasone resistance and post-induction minimal residual disease in pediatric T-cell acute lymphoblastic leukemia.
Authors: Meyer Lauren K. , Delgado-Martin Cristina , Roy Ritu , Huang Benjamin J. , Vincent Tiffaney , Olshen Adam , Wood Brent L. , Liu Yu , Zhang Jinghui , Mullighan Charles Grenfell , Horton Terzah M. , Loh Mignon L. , Devidas Meenakshi , Raetz Elizabeth A. , Hayashi Robert J. , Winter Stuart , Dunsmore Kimberly P. , Hunger Stephen , Teachey David T. , Hermiston Michelle L.
Published: May 2019

10033

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, which has largely precluded the use of genetic mutations for risk stratification. We hypothesized that despite this heterogeneity, diverse T-ALLs may have functional similarities that underlie patterns of chemotherapy sensitivity. Methods: We used flow cytometry to evaluate in vitro dexamethasone (DEX) sensitivity and baseline expression of signal transduction effectors and BCL2-family proteins in 68 fresh diagnostic T-ALL samples from patients enrolled on the Children’s Oncology Group (COG) trial AALL1231. We also performed RNA-sequencing (RNA-seq) on 40 AALL1231 samples and used hierarchical clustering and linear regression to analyze these and published T-ALL RNA-seq data from COG AALL0434. Comparisons between groups were made using t-tests and Fisher’s exact tests. Results: Of the proteins analyzed, only high BCL2 expression was significantly associated with increased in vitro DEX resistance (p = 0.002). Hierarchical clustering of the AALL1231 RNA-seq data identified two distinct clusters. Cluster 1 was associated with significantly higher BCL2 transcript expression (p = 0.0002) and in vitro DEX resistance (p = 0.04) relative to cluster 2. We defined a gene set consisting of the top 210 differentially expressed genes between these clusters and applied this gene set to the COG AALL0434 cohort. In this analysis, the early T-cell precursor (ETP) and near-ETP samples clustered together (p < 0.0001) in cluster 1 along with 39 of 146 non-ETP samples. Not only did these cluster 1 non-ETP samples have significantly higher BCL2 transcript expression relative to the non-ETP samples in cluster 2 (p < 0.0001), but 54% of these non-ETP samples were minimal residual disease (MRD) positive (≥0.01%) at the end of induction, as opposed to only 16% of the non-ETP samples in cluster 2 (p < 0.0001). Conclusions: Gene expression profiling identifies non-ETP T-ALLs that cluster with ETP/near-ETP T-ALLs and have significantly higher BCL2 expression and increased rates of post-induction MRD.
Vincristine, irinotecan, and temozolomide as a salvage regimen for relapsed or refractory sarcoma in children and young adults.
Authors: Park Byung-Kiu , Ju Hee Young , Park Meerim , Park Hyeon Jin
Published: May 2019

10040

Background: No standard salvage regimen is available for recurrent or refractory sarcoma. Only a few studies using vincristine (V), irinotecan (I), and temozolomide (T) for rhabdomyosarcoma or Ewing sarcoma have been conducted mostly in pediatric age. We investigated the efficacy and toxicity of VIT regimen for several relapsed or refractory sarcomas in children and young adults. Methods: We retrospectively reviewed the relapsed or refractory sarcoma patients who were treated at the Center for Pediatric Cancer of the National Cancer Center, Korea between 2012 and 2018. VIT regimen given every 3 week schedule was as follows; V, 1.5mg/m2 i.v. on day 1, I, 50mg/m2 i.v. on days 1-5, and T, 100mg/m2 p.o. on days 1-5. Cefixime prophylaxis at 4mg/kg/day p.o. was administered to reduce irinotecan-induced diarrhea. Results: Total 26 patients (12 males) were treated with VIT during the study period. Patients were diagnosed with rhabdomyosarcoma ( n= 8), osteosarcoma ( n= 7), Ewing sarcoma ( n= 3), synovial sarcoma ( n= 3), alveolar soft part sarcoma ( n= 2), and mixed rhabdomyosarcoma and liposarcoma, hemangiopericytoma and desmoplastic small round cell tumor, one for each. Median age at the start of VIT was 18.5 years (range 2.0-39.9). VIT was delivered as the 2nd to 7th line of treatment, with the 4th line most common (9/26, 34.6%). Number of administered courses were 1-18, with two courses most common (6/26, 23.1%). Of the 25 evaluable patients, we had 2 partial response (PR), 13 stable disease (SD), and 11 progressive disease (PD) with an overall control rate (CR + PR + SD) of 60.0% as assessed by RECIST 1.1. According to diagnoses, we observed 4SD and 4PD for rhabdomyosarcoma; 1PR, 2SD and 4PD for osteosarcoma; 1PR, 1SD and 1 non-evaluable for Ewing sarcoma; 2SD and 1PD for synovial sarcoma; 2SD for alveolar soft part sarcoma. With a median follow-up of 24 months, 5 patients were alive without disease; 9 were alive with disease; 12 died of PD. Progression-free survival rate at one year was 33.8%, and overall survival rate was 79.3% at one year and 45.5% at 2 years. Of the 26 patients, two patients had grade 4 neutropenia; two had grade 3 colitis and another two had grade 3 neutropenic fever; 8 had grade 2 diarrhea. Grade 4 non-hematologic toxicity or treatment-related mortality was not observed. Conclusions: VIT was effective especially for disease control and relatively safe in our cohort of sarcoma patients.
What is the best therapy for grossly resected synovial sarcoma? Experience of the CWS Study Group.
Authors: Scheer Monika , Vokuhl Christian , Stegmaier Sabine , Muenter Marc W. , von Kalle Thekla , Serwa Paulina , Sparber-Sauer Monika , Kazanowska Bernarda , Niggli Felix , Ladenstein Ruth Lydia , Ljungman Gustaf , Jahnukainen Kirsi , Bauer Sebastian , Fuchs Joerg , Bielack Stefan S. , Koscielniak Ewa , Klingebiel Thomas
Published: May 2019

10042

Background: Adjuvant therapy in patients with localized grossly resected synovial sarcoma (SS) still is a matter of debate. This analysis was performed to contribute to the clarification. Methods: SS patients of all ages with initially gross tumor resection registered in the prospective international CWS-trials 1981–2013 were evaluated. CWS-protocols currently recommend chemotherapy for all SS patients. Results: 185 patients with median age of 13.9 years (range 0.1–56.9) and median follow-up of 7.2 years (0.2-31.1) had 5-year event-free (EFS) and overall survival (OS) of 82.9%±5.7 (95%CI) and 92.5%±3.9, respectively. All but six patients received adjuvant chemotherapy. Best surgical treatment consisted of R0-resection in 107 and R1-resection in 70; no information in 7. 135 (73%) were irradiated. In the univariate analysis factors associated with EFS are tumor size and the application of chemotherapy; factors associated with OS are tumor site, size and invasiveness. In the multivariate analysis independent factors for adverse EFS are large tumor size and the application of chemotherapy, for OS tumor site and size. In the group of 58 patients with tumors < 3cm one patient suffered metastatic recurrence (2%), in those 59 patients with tumors 3-5cm 3 suffered metastatic recurrence (5%). In 42 patients with tumors 5-10cm, 4 metastatic and 2 combined recurrences were reported (14%), and in those 13 patients with tumors > 10cm 4 suffered metastatic and 1 combined relapse (38%). Conclusions: Patients with grossly resected SS treated according to the CWS recommendations have an excellent prognosis. A subgroup with very low metastatic potential probably does not need chemotherapy. Whether tumor size and surgery are sufficient criteria has still to be proven by long term results. Biological studies are needed.
Late toxicities, especially second malignancies, with GWAS analysis in hepatoblastoma cases treated in the Japanese study group for pediatric liver tumor protocol-2.
Authors: Hiyama Eiso , Watanabe Kenichiro , Mori Makiko , Ida Kohmei , Hishiki Tomoro , Yano Michihiro , Tanaka Yukichi , Yoshimura Kenichi , Hiyama Keiko
Published: May 2019

10043

Background: This study focused on late toxicities, especially second malignancies (SMNs), experienced by patients with hepatoblastoma (HB) treated with CITA (cisplatin and pirarubicin) in the Japanese Study Group for Pediatric Liver Tumor protocol-2 (JPLT-2). Methods: In the JPLT-2, 361 children with HB were eligible for inclusion. We evaluated late effects including ototoxicity, cardiotoxicity and SMN in these patients. PRETEXT I/II patients were typically treated by initial resection at diagnosis followed by CITA. Otherwise, patients received preoperative CITA, followed by surgery and postoperative chemotherapy. Non-responders to CITA received ITEC (ifosfamide, pirarubicin, etoposide, and carboplatin) or intensified chemotherapeutic regimens. In 267 patients whose germline DNA samples were available, genotyping analysis was performed using the Illumina Human Omni Express Exome-8 v.1.3 BeadChip. Associations between single nucleotide polymorphisms (SNPs) and toxicities were assessed using logistic regression analysis. Results: Among the patients (n = 300) who survived more than 5 years, ototoxicity was detected in 61 and cardiotoxicity in 18. The presence of ototoxicity was associated with a significantly higher dose of cisplatin, and the Brock grade of ototoxicity was correlated with the total dose of cisplatin (P < 0.01). SMNs occurred in 13 patients (9 leukemia, 1 myelodysplastic disease, 1 lymphoma, 1 Ewing sarcoma and 1 thyroid tumor). The total dose of pirarubicin in SMN cases was significantly higher than those without SMNs (P = 0.035). The mean age at onset of HB was 13 months in the patients with SMNs and 23.3 months in the other patient (P = 0.12). However, two-way analysis of variance showed that SMN occurrence was significantly correlated with the age of HB onset and the total dose of pirarubicin (P < 0.0001). We identified ten inherited SNPs, including six SNPs associated with ototoxicity such as ACYP2, two SNPs associated with cardiotoxicity and two candidate SNPs associated with SMNs. Conclusions: The total dose of cisplatin was significantly associated with ototoxicity development. A low incidence of cardiotoxicity but high rates of SMTs, which were correlated with a high dose of pirarubicin and younger age at diagnosis, were found in this study. We also identified SNPs associated with SMNs in HB. Our study provides strong evidence that germline mutation may modify the effect of chemotherapy for childhood cancers on late toxicities, especially during early childhood. Clinical trial information: UMIN000001116.
ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma.
Authors: Gardner Sharon L. , Allen Jeffrey C. , Zaky Wafik Tharwat , Odia Yazmin , Daghistani Doured , Khatib Ziad , Koschmann Carl Johannes , Aguilera Dolly , MacDonald Tobey J. , Chi Andrew S. , Tarapore Rohinton , Merdinger Krystal , Oster Wolfgang , Allen Joshua E. , Khatua Soumen
Published: May 2019

10046

Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.
AcSé-ESMART: European Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors in Children and Adolescents–Arm D: Olaparib and irinotecan.
Authors: Gatz Susanne Andrea , Rubino Jonathan , Rossoni Caroline , Andre Nicolas , Aerts Isabelle , Thebaud Estelle , Nebchi Souad , Rondof Windy , Hübschmann Daniel , Mortimer Peter G. , Paoletti Xavier , Vassal Gilles , Geoerger Birgit
Published: May 2019

10047

Background: AcSé-ESMART is a proof-of-concept, phase I/II, multicenter, prospective basket trial designed to explore targeting agents in a molecularly enriched cancer population; treatment arms with targeted agents as single agent or in combination regimens are explored independently. Arm D explores the PARP inhibitor olaparib (ola) in combination with irinotecan (iri). The design is based on the hypothesis that in pediatric cancer pathogenic BRCA alterations are extremely rare and proliferative capacity is high requiring a chemotherapy sensitisation approach. Preclinical data in pediatric cancer suggest PARP inhibitor activity in other genomic alterations impairing homologous recombination (HR) and demonstrate synergy with iri. We here report the results of the Phase I part of the trial. Methods: Children and adolescents with relapsed/refractory cancer and comprehensive molecular profiling (whole exome and RNA sequencing) at relapse were eligible. Dose-escalation followed a continuous reassessment method design of pre-specified dose combinations of oral ola and iv iri. Plasma for pharmacokinetics (PK) was collected. Results: From Oct 2016 to April 2018, 27 pts (19 sarcomas, 3 brain tumors, 5 other) with a median age of 15 y (range 4;22) were enrolled over 4 dose levels. Dose limiting toxicities occurred in 7 of 24 evaluable pts (gastrointestinal (n = 4), febrile neutropenia (n = 1), thrombocytopenia (n = 2)). The RP2D was defined as ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Twenty-three pts evaluable for response received a median of 2 cycles (range 1-27+). Confirmed PRs were seen in one osteosarcoma, one pinealoblastoma and one neuroblastoma; time to progression was 22.4, 50 and 89+ weeks, respectively. Eight pts experienced disease stabilization (median 14.8 weeks, range 9;42.3). PK and biomarker analysis (ie. HR alterations, DNA and gene expression signatures) is ongoing to identify factors associated with clinical benefit and data will be presented. Conclusions: The RP2D of the combination is ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Preliminary activity led to the ongoing Phase II part of the arm. Clinical trial information: NCT02813135.