To reduce the morbidity and mortality associated with unrelated donor bone marrow (BM) transplantation and potentially extend the pool of suitable donors, cryopreserved unrelated donor umbilical cord blood was considered as an alternate source of hematopoietic stem cells for transplantation. Patients with leukemia, BM failure syndrome, or inborn error of metabolism were eligible for a phase I clinical trial designed to estimate the risk of graft failure and severe acute graft-versus- host disease after transplantation of umbilical cord blood from unrelated donors. As of December 21, 1995, unrelated donor umbilical cord blood was used to reconstitute hematopoiesis in eighteen patients aged 0.1 to 21.3 years weighing 3.3 to 78.8 kg with acquired or congenital lympho-hematopoietic disorders or metabolic disease. Patients received either HLA-matched (n = 7) or HLA-1 to 3 antigen disparate (n = 11) grafts collected and evaluated by the New York Blood Center (New York, NY). The probability of engraftment after unrelated donor umbilical cord blood transplantation was 100% with no patient having late graft failure to date. The probability of grade III-IV acute graft-versus-host disease at 100 days was 11%. With a median follow-up of 6 months (range, 1.6 to 17 months); the probability of survival at 6 months is 65% in this high risk patient population. We conclude that cryopreserved umbilical cord blood from HLA-matched and mismatched unrelated donors is a sufficient source of transplantable hematopoietic stem cells with high probability of donor derived engraftment and low risk of refractory severe acute graft-versus-host disease. Limitations with regard to recipient size and degree of donor HLA disparity remain to be determined.

BACKGROUND Fertility preservation (FP) is an important quality of life issue for cancer survivors of reproductive age. Despite the existence of broad international guidelines, the delivery of oncofertility care, particularly amongst paediatric, adolescent and young adult patients, remains a challenge for healthcare professionals (HCPs). The quality of oncofertility care is variable and the uptake and utilization of FP remains low. Available guidelines fall short in providing adequate detail on how oncofertility models of care (MOC) allow for the real-world application of guidelines by HCPs. OBJECTIVE AND RATIONALE The aim of this study was to systematically review the literature on the components of oncofertility care as defined by patient and clinician representatives, and identify the barriers, facilitators and challenges, so as to improve the implementation of oncofertility services. SEARCH METHODS A systematic scoping review was conducted on oncofertility MOC literature published in English between 2007 and 2016, relating to 10 domains of care identified through consumer research: communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, training, supportive care during treatment, reproductive care after cancer treatment, psychosocial support and ethical practice of oncofertility care. A wide range of electronic databases (CINAHL, Embase, PsycINFO, PubMed, AEIPT, Education Research Complete, ProQuest and VOCED) were searched in order to synthesize the evidence around delivery of oncofertility care. Related citations and reference lists were searched. The review was undertaken following registration (International prospective register of systematic reviews (PROSPERO) registration number CRD42017055837) and guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). OUTCOMES A total of 846 potentially relevant studies were identified after the removal of duplicates. All titles and abstracts were screened by a single reviewer and the final 147 papers were screened by two reviewers. Ten papers on established MOC were identified amongst the included papers. Data were extracted from each paper and quality scores were then summarized in the oncofertility MOC summary matrix. The results identified a number of themes for improving MOC in each domain, which included: the importance of patients receiving communication that is of a higher quality and in different formats on their fertility risk and FP options; improving provision of oncofertility care in a timely manner; improving access to age-appropriate care; defining the role and scope of practice of all HCPs; and improving communication between different HCPs. Different forms of decision aids were found useful for assisting patients to understand FP options and weigh up choices. WIDER IMPLICATIONS This analysis identifies core components for de...

Background Over 12,000 children are diagnosed with cancer every year in the United States. In addition to symptoms associated with their disease, children undergoing chemotherapy frequently experience significant pain, which is unfortunately often undertreated. The field of m-Health offers an innovative avenue for pain assessment and intervention in the home setting. The current study describes the development and initial evaluation of a tablet-based program, Pain Buddy, aimed to enhance pain management and foster improved quality of life in children ages 8–18 years undergoing cancer treatment. Methods An animated avatar-based tablet application was developed using state-of-the-art software. Key aspects of Pain Buddy include daily pain and symptom diaries completed by children, remote monitoring of symptoms by uploading patient’s data through internet to a cloud server, cognitive and behavioral skills training, interactive three-dimensional avatars that guide children through the program, and an incentive system to motivate engagement. Twelve children between the ages of 8 and 18 participated in a pilot study of Pain Buddy. Results Children were highly satisfied with the program. Pain and appetite disturbances were most frequently endorsed. Symptom trigger alerts to outside providers were largely related to clinically significant pain. Children infrequently used analgesics, and reported using some non-pharmacological pain management strategies. Conclusion Pain Buddy appears to be a promising tool to improve pain and symptom management in children undergoing cancer treatment. Results from the current study will inform future improvements to Pain Buddy, in preparation for a randomized controlled trial to assess the efficacy of this innovative treatment.

BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.Methods and FindingsTwenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).ConclusionsDFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.Trial RegistrationClinicaltrials.gov NCT#01059071

BackgroundAn estimated 15,000 children and adolescents under the age of 19 years are diagnosed with leukemia, lymphoma and other tumors in the USA every year. All children and adolescent acute leukemia patients will undergo chemotherapy as part of their treatment regimen. Fortunately, survival rates for most pediatric cancers have improved at a remarkable pace over the past three decades, and the overall survival rate is greater than 90 % today. However, significant differences in survival rate have been found in different age groups (94 % in 1–9.99 years, 82 % in ≥10 years and 76 % in ≥15 years). ALL accounts for about three out of four cases of childhood leukemia. Intensive chemotherapy treatment coupled with prophylactic or therapeutic antibiotic use could potentially have a long-term effect on the resident gastrointestinal (GI) microbiome. The composition of GI microbiome and its changes upon chemotherapy in pediatric and adolescent leukemia patients is poorly understood. In this study, using 16S rRNA marker gene sequences we profile the GI microbial communities of pediatric and adolescent acute leukemia patients before and after chemotherapy treatment and compare with the microbiota of their healthy siblings.ResultsOur study cohort consisted of 51 participants, made up of matched pediatric and adolescent patients with ALL and a healthy sibling. We elucidated and compared the GI microbiota profiles of patients and their healthy sibling controls via analysis of 16S rRNA gene sequencing data. We assessed the GI microbiota composition in pediatric and adolescent patients with ALL during the course of chemotherapy by comparing stool samples taken before chemotherapy with stool samples collected at varying time points during the chemotherapeutic treatment. The microbiota profiles of both patients and control sibling groups are dominated by members of Bacteroides, Prevotella, and Faecalibacterium. At the genus level, both groups share many taxa in common, but the microbiota diversity of the patient group is significantly lower than that of the control group. It was possible to distinguish between the patient and control groups based on their microbiota profiles. The top taxa include Anaerostipes, Coprococcus, Roseburia, and Ruminococcus2 with relatively higher abundance in the control group. The observed microbiota changes are likely the result of several factors including a direct influence of therapeutic compounds on the gut flora and an indirect effect of chemotherapy on the immune system, which, in turn, affects the microbiota.ConclusionsThis study provides significant information on GI microbiota populations in immunocompromised children and opens up the potential for developing novel diagnostics based on stool tests and therapies to improve the dysbiotic condition of the microbiota at the time of diagnosis and in the earliest stages of chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2965-y) contains supplementary material, which is available to authoriz...

STUDY QUESTION Is it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities? SUMMARY ANSWER Centralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice. WHAT IS KNOWN ALREADY Several centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring. STUDY DESIGN, SIZE, DURATION Testicular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS Human testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient’s tissue was donated to research and 75% was stored for patient’s future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1. MAIN RESULTS AND THE ROLE OF CHANCE The average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg—6880.2 mg. Malignancies ( n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders ( n = 45) and other conditions ( n = 26). Thirty nine percent ( n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132. LIMITATIONS, REASONS FOR CAUTION This is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size. WIDER IMPLICATIONS OF THE FINDINGS Patients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated...

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase whose activity contributes to leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit rapamycin-resistant functions and have enhanced anti-cancer activity in mouse models. MLN0128 (formerly known as INK128) is a novel, orally active mTOR kinase inhibitor currently in clinical development. Here we evaluated MLN0128 in preclinical models of B-cell acute lymphoblastic leukemia (B-ALL). MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human leukemia cells from adult and pediatric B-ALL patients. MLN0128 also boosted the efficacy of dasatinib in Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens, MLN0128 significantly enhanced the efficacy of dasatinib. In non-Ph B-ALL xenografts, single agent MLN0128 had a cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models, MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors.

Adolescent and young adult cancer survivors face unique challenges not systematically addressed by cancer clinicians. Four focus groups and two individual interviews were conducted with 19 survivors to profile experiences and identify key concerns for future interventions. The resultant themes reflect cancer care continuum challenges (such as delays in diagnosis, problems with adherence), psychosocial concerns (such as infertility and reproductive concerns, changing social relationships, financial burden), and the paradox of being diagnosed with cancer as a young adult. Future intervention development for adolescent and young adult survivors should involve patient voices at each stage of the research process.