Clinical management of Australian adolescents and young adults with acute lymphoblastic and myeloid leukemias: A national population-based study.

BACKGROUND: While several studies have examined the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), studies of acute myeloid leukemia (AML) are rare. Using national data for Australia, we describe (i) the number and type of treatment centers caring for AYAs, (ii) induction/first-line treatments, and (iii) survival outcomes. PROCEDURE: National population-based study assessing treatment of 15- to 24-year-olds diagnosed with ALL or AML between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult (adult AYA-focused or other adult; and by AYA volume [high/low]). Cox proportional hazard regression analyses examined associations between treatment and overall, event-free, and relapse-free survival outcomes. RESULTS: Forty-seven hospitals delivered induction therapy to 351 patients (181 ALL and 170 AML), with 74 (21%) treated at pediatric centers; 70% of hospitals treated less than two AYA leukemia patients per year. Regardless of treatment center, 82% of ALL patients were on pediatric protocols. For AML, pediatric protocols were not used in adult centers, with adult centers using a non-COG 7+3-type induction protocol (51%, where COG is Cooperative Oncology Group) or an ICE-type protocol (39%, where ICE is idarubicin, cytarabine, etoposide). Exploratory analyses suggested that for both ALL and AML, AYAs selected for adult protocols have worse overall, event-free, and relapse-free survival outcomes. CONCLUSIONS: Pediatric protocols were commonly used for ALL patients regardless of where they are treated, indicating rapid assimilation of recent evidence by Australian hematologists. For AML, pediatric protocols were only used at pediatric centers. Further investigation is warranted to determine the optimal treatment approach for AYA AML patients.

Factors influencing the documentation of fertility-related discussions for adolescents and young adults with cancer.

PURPOSE: A cancer diagnosis and treatment may have significant implications for a young patient's future fertility. Documentation of fertility-related discussions and actions is crucial to providing the best follow-up care, which may occur for many years post-treatment. This study examined the rate of medical record documentation of fertility-related discussions and fertility preservation (FP) procedures for adolescents and young adults (AYAs) with cancer in Australia. METHODS: A retrospective review of medical records for 941 patients in all six Australian states. Patients were identified through population-based cancer registries (four states) and hospital admission lists (two states). Trained data collectors extracted information from medical records using a comprehensive data collection survey. Records were reviewed for AYA patients (aged 15-24 years at diagnosis), diagnosed with acute myeloid leukaemia, acute lymphoblastic leukaemia, central nervous system (CNS) tumours, soft tissue sarcomas (STS), primary bone cancer or Ewing's family tumours between 2007 and 2012. RESULTS: 47.2% of patients had a documented fertility discussion and 35.9% had a documented FP procedure. Fertility-related documentation was less likely for female patients, those with a CNS or STS diagnosis and those receiving high-risk treatments. In multivariable models, adult hospitals with an AYA focus were more likely to document fertility discussions (odds ratio[OR] = 1.60; 95%CI = 1.08-2.37) and FP procedures (OR = 1.74; 95%CI = 1.17-2.57) than adult hospitals with no AYA services. CONCLUSIONS: These data provide the first national, population-based estimates of fertility documentation for AYA cancer patients in Australia. Documentation of fertility-related discussions was poor, with higher rates observed in hospitals with greater experience of treating AYA patients.

Comparisons between myeloperoxidase, lactoferrin, calprotectin and lipocalin-2, as fecal biomarkers of intestinal inflammation in malnourished children.

Fecal biomarkers have emerged as important tools to assess intestinal inflammation and enteropathy. The aim of this study was to investigate the correlations between the fecal markers, myeloperoxidase (MPO), lactoferrin (FL), calprotectin (FC) and lipocalin-2 (Lcn-2), and to compare differences by breastfeeding status as well as normalization by fecal protein or by fecal weight. Simultaneous, quantitative MPO, FL, FC and Lcn-2, levels were determined in frozen fecal specimens collected from 78 children (mean age 15.2 ± 5.3 months) in a case-control study of childhood malnutrition in Brazil. The biomarker concentrations were measured by enzymelinked immunosorbent assay. The correlations among all biomarkers were significant (P<0.01). There were stronger correlations of fecal MPO with fecal lactoferrin and calprotectin, with lower, but still highly significant correlations of all 3 inflammatory biomarkers with Lcn-2 likely because the latter may also reflect enterocyte damage as well as neutrophil presence. Furthermore, the biomarker results with protein normalized compared to simple fecal weight normalized values showed only a slightly better correlation suggesting that the added cost and time for protein normalization added little to carefully measured fecal weights as denominators. In conclusion, fecal MPO correlates tightly with fecal lactoferrin and calprotectin irrespective of breastfeeding status and provides a common, available biomarker for comparison of human and animal model studies.

Inconsistencies and time delays in site-specific research approvals hinder collaborative clinical research in Australia.

BACKGROUND/AIM: The aim of this study was to describe the time and documentation needed to gain ethics and governance approvals in Australian states with and without a centralised ethical review system. METHODS: This is a prospective descriptive study undertaken between February 2012 and March 2015. Paediatric and adult hospitals (n = 67) in Australian states were approached to allow the review of their medical records. Participants included 15- to 24-year-olds diagnosed with cancer between 2008 and 2012. The main outcomes measures were time (weeks) to approval for ethics and governance and the number and type of documents submitted. RESULTS: Centralised ethics approval processes were used in five states, with approval taking between 2 and 18 weeks. One state did not use a centralised process, with ethics approval taking a median of 4.5 weeks (range: 0-15) per site. In four states using a centralised ethics process, 33 governance applications were submitted, with 20 requiring a site clinician listed as an investigator. Governance applications required the submission of 11 documents on average, including a Site-Specific Assessment form. Thirty-two governance applications required original signatures from a median of 3.5 (range: 1-10) non-research persons, which took a median of 5 weeks (range: 0-15) to obtain. Governance approval took a median of 6 weeks (range: 1-45). Twelve research study agreements were needed, each taking a median of 7.5 weeks (range: 1-20) to finalise. CONCLUSION: The benefits of centralised ethics review systems have not been realised due to duplicative, inflexible governance processes. A system that allowed the recognition of prior ethical approval and low-risk applications was more efficient than a central ethics and site-specific governance process.

A stable-isotope HPLC-MS/MS method to simplify storage of human whole blood samples for glutathione assay.

BACKGROUND: Glutathione is the principal non-protein tripeptide thiol present in most mammalian cells and plays an important role in the redox status of biological systems. The accurate assessment of reduced glutathione (GSH) status as a reliable index of oxidative stress is of research and clinical significance. GSH undergoes rapid oxidation after sample collection and this presents a challenge. METHODS: Validation of an HPLC-MS/MS assay is reported. Storage stability using four variants of a methanolic precipitation with addition of stable isotope internal standard at collection is compared to L-serine borate/EDTA with perchloric acid precipitation (SBPE). RESULTS: Precipitation with methanol and addition of stable isotope on sample collection, combined with storage in solution at -70 °C showed superior storage stability to SBPE and other variants of the methanolic precipitation method up to 99 days. CONCLUSIONS: The combination of stable isotope with methanolic precipitation at collection, with assay by HPLC-MS/MS provides superior results after storage of whole blood samples for at least 99 days.

ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children.

A series of studies have shown that the heavy burdens of diarrheal diseases in the first 2 formative years of life in children living in urban shanty towns have negative effects on physical and cognitive development lasting into later childhood. We have shown that APOE4 is relatively common in shanty town children living in Brazil (13.4%) and suggest that APOE4 has a protective role in cognitive development as well as weight-for-height in children with heavy burdens of diarrhea in early childhood (64/123; 52%), despite being a marker for cognitive decline with Alzheimer's and cardiovascular diseases later in life. APOE2 frequency was higher among children with heaviest diarrhea burdens during the first 2 years of life, as detected by PCR using the restriction fragment length polymorphism method, raising the possibility that ApoE-cholesterol balance might be critical for growth and cognitive development under the stress of heavy diarrhea burdens and when an enriched fat diet is insufficient. These findings provide a potential explanation for the survival advantage in evolution of genes, which might raise cholesterol levels during heavy stress of diarrhea burdens and malnutrition early in life.

ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children

A series of studies have shown that the heavy burdens of diarrheal diseases in the first 2 formative years of life in children living in urban shanty towns have negative effects on physical and cognitive development lasting into later childhood. We have shown that APOE4 is relatively common in shanty town children living in Brazil (13.4 percent) and suggest that APOE4 has a protective role in cognitive development as well as weight-for-height in children with heavy burdens of diarrhea in early childhood (64/123; 52 percent), despite being a marker for cognitive decline with Alzheimer’s and cardiovascular diseases later in life. APOE2 frequency was higher among children with heaviest diarrhea burdens during the first 2 years of life, as detected by PCR using the restriction fragment length polymorphism method, raising the possibility that ApoE-cholesterol balance might be critical for growth and cognitive development under the stress of heavy diarrhea burdens and when an enriched fat diet is insufficient. These findings provide a potential explanation for the survival advantage in evolution of genes, which might raise cholesterol levels during heavy stress of diarrhea burdens and malnutrition early in life.

Using videotelephony to support paediatric oncology-related palliative care in the home: from abandoned RCT to acceptability study.

Videotelephony (real-time audio-visual communication) has been used successfully in adult palliative home care. This paper describes two attempts to complete an RCT (both of which were abandoned following difficulties with family recruitment), designed to investigate the use of videotelephony with families receiving palliative care from a tertiary paediatric oncology service in Brisbane, Australia. To investigate whether providing videotelephone-based support was acceptable to these families, a 12-month non-randomised acceptability trial was completed. Seventeen palliative care families were offered access to a videotelephone support service in addition to the 24 hours 'on-call' service already offered. A 92% participation rate in this study provided some reassurance that the use of videotelephones themselves was not a factor in poor RCT participation rates. The next phase of research is to investigate the integration of videotelephone-based support from the time of diagnosis, through outpatient care and support, and for palliative care rather than for palliative care in isolation. Trial registration ACTRN 12606000311550.

Dose finding study of oral PSC 833 combined with weekly intravenous etoposide in children with relapsed or refractory solid tumours.

PSC 833 is an effective MDR1 reversal agent in vitro, including studies with paediatric cancer cell lines such as neuroblastoma and rhabdomyosarcoma. This study was performed to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in children with solid tumours and to determine the influence of PSC 833 on the pharmacokinetics of co-administered etoposide. Each patient received one cycle of intravenous etoposide (100 mg/m2 daily for 3 days on three consecutive weeks) to document baseline pharmacokinetics, and subsequently the same schedule using a dose of 50 mg/m2 was given combined with PSC 833 given orally every 6h at a starting dose of 4 mg/kg. Thirty two eligible patients (23 male, median age 8.3 years) were enrolled. Neuroblastoma and rhabdomyosarcoma were the common disease types. Brain tumours were excluded. DLT was defined as any non-haematological grade 3-4 toxicity (common toxicity criteria) and using a specific toxicity scale for cerebellar toxicity. The MDT was defined as the first dose below which 2 or more patients per dose level experienced DLT. Grade 1-2 ataxia occurred in cohorts 2 and 3 (4 and 5 mg/kg, respectively). Three patients developed grade 3 neurotoxicity in the 6 mg/kg cohort and this defined the MTD. Six responses were observed (2 CR, 4 PR). Pharmacokinetic studies indicated that the clearance of etoposide was reduced by approximately 50% when combined with PSC 833. It is concluded that the toxicity profile and MDT is similar in both children and adults, as is the effect on etoposide metabolism. The study demonstrated the feasibility and safety of carrying out a paediatric phase 1 trial across European boundaries and acts as a model for future cooperative studies in rare cancers among children.

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors.

PURPOSE: Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission. PATIENTS AND METHODS: A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response. RESULTS: At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with > or = two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively. CONCLUSION: A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.

Medical students' perceptions of sexual health issues prior to a curriculum enhancement.

The objectives were to compare first, second and third year medical students on self-perceived sexual health knowledge, comfort in addressing sexual health problems, and attitudes towards the importance of addressing sexual health issues with patients as part of a sexual health medical curriculum enhancement project. A paper-and-pencil questionnaire survey was designed and administered to first and second year medical students at the start of the fall semester, resulting in high participation rates for both years (98% and 86%, respectively). Third year students were surveyed through an on-line version of the questionnaire yielding a lower response rate (52%). Multivariate statistical analyses were used to compare knowledge, comfort and attitudes by year in medical school. Results were as follows: As might be expected, sexual health knowledge and comfort in addressing sexual health problems increased linearly from first to third year (P<0.01) for all questions. Unexpectedly, second year students had significantly higher scores on questions assessing attitudes towards the importance of addressing sexual health issues than either first or third year students (P<0.001). Female medical students reported that addressing sexual health issues with patients was significantly more important than did male medical students; however, male students reported higher levels of self-reported knowledge and comforting related to sexual health issues than did female students in a number of areas. In conclusion, knowledge gained from this survey was used to finalize the design of an enhanced, integrated curriculum on sexual health for medical students. Further investigation of gender differences related to training medical students in this area is suggested.

EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation.

Sixteen children and young adults were treated with high-dose cyclosporin combined with a combination of cytotoxics (epirubicin, vincristine and etoposide) (EVE) known to be influenced by P-glycoprotein-mediated multidrug resistance (MDR). Tumour types were neuroblastoma 3, Ewing's sarcoma 2, rhabdomyosarcoma 5, osteosarcoma 3, desmoplastic small round cell tumour 1, nephroblastoma 1, T-acute lymphoblastic leukaemia (ALL) 1. All had progressed or relapsed following at least two of the drug types included in EVE. Acute reactions to cyclosporin and myelosuppression were the major toxicities documented. Renal and hepatic toxicity was rarely severe and always transient. Partial responses (PR) were observed in 2 patients (1 rhabdomyosarcoma, 1 Ewing's sarcoma). We conclude that this combination is tolerable in heavily pretreated patients and may be suitable for further evaluation in untreated poor risk tumours.

Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.

Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction.

BACKGROUND: We examine changes in sexual functioning and depressive symptoms in patients' transition from a selective serotonin reuptake inhibitor (SSRI), which induced both a therapeutic response and sexual dysfunction, to bupropion sustained release (SR) over the course of an 8-week trial. METHOD: The study included 11 adults (8 women and 3 men) who had a DSM-IV diagnosis of major depressive disorder in remission (Hamilton Rating Scale for Depression [HAM-D] score < 11) and were receiving an SSRI. Depression (using the HAM-D) and sexual dysfunction (using the Changes in Sexual Functioning Questionnaire) were assessed at baseline, 2 weeks after bupropion SR was added to the current antidepressant (combined treatment), 2 weeks after taper of the SSRI was initiated and completed, and after 4 weeks of bupropion SR monotherapy. T tests were performed to assess changes in depression and sexual function. RESULTS: Patient participation dropped from the initial group of 11 at week 2 to 9 at week 4 and to 6 by week 8. Sexual functioning improved from week 0 (baseline) to week 2 and from week 2 to week 4. The patients showed no significant change in mean HAM-D scores in weekly comparisons during the study period; 55% of patients completed the substitution without significant adverse events or recurrence of depressive symptoms. CONCLUSION: Bupropion SR as a treatment for depression also alleviates sexual dysfunction due to SSRI treatment. Results show that sexual functioning improves after the addition of bupropion SR to SSRI treatment and continues to improve, after discontinuation of the SSRI, with bupropion SR treatment alone.

Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year.

PURPOSE: In this prospective, multicenter study, the independent prognostic power of neuroblastoma cells detected by reverse transcriptase polymerase chain reaction (RT-PCR) for tyrosine hydroxylase (TH) mRNA was evaluated. PATIENTS AND METHODS: The clinical significance of disease detected by RT-PCR in peripheral blood from children at diagnosis was compared with established prognostic markers [ie, age, lactate dehydrogenase (LDH), neuron-specific enolase, ferritin, and MYCN gene amplification] by multivariate analysis. The value of disease detection by RT-PCR during treatment and follow-up was also examined. RESULTS: TH mRNA was detected in peripheral blood from 33 of 49 (67%) children with stage 4 neuroblastoma > 1 year old at diagnosis and was a significant predictive factor for overall survival [hazard ratio (HR) = 2.40, 95% confidence interval (CI) 1.19 to 4.84, P =.014) and event-free survival (HR = 2.09, 95% CI 1.06 to 4.17, P =.034) in a multivariate analysis. Detection of disease in blood from clinically disease-free children was related to increased risk of death (HR 2.54, 95% CI 1.42 to 4.55, P =.0014). CONCLUSION: TH mRNA in peripheral blood of children with neuroblastoma is a poor prognostic indicator, reflecting the propensity for dissemination via the bloodstream. When combined with a serum LDH > 1500 IU/L, this is the most powerful poor prognostic model at diagnosis for children > 1 year old with stage 4 disease. The detection of TH mRNA in peripheral blood from clinically disease-free children is related to increased risk of relapse and death.

Psychological sequelae and alopecia among women with cancer.

PURPOSE: This article reviews the relevant literature on treatment-induced alopecia in women with cancer and describes the development of a computer-assisted intervention to reduce distress associated with this side effect. DESCRIPTION OF PROGRAM: Alopecia has been cited as the most disturbing anticipated side effect by up to 58% of women preparing for chemotherapy, with 8% being at risk for avoiding treatment. Women with cancer who experience alopecia as a side effect, compared with women with cancer and no alopecia, report lower self-esteem, poorer body image, and lower quality of life. Although physicians' recommendations are the most influential factor on cancer treatment choice, body image and effects on sexuality are the next most influential factors. A study of a computer-imaging intervention, based on concepts related to guided imagery and anticipatory grief, has been launched in an effort to aid women in coping with anticipated treatment-related alopecia. RESULTS: While we are still waiting for final data collection and analysis from the computer intervention study, the feedback thus far has been positive. CLINICAL IMPLICATIONS: The intervention described here may prove to be effective in desensitizing women with cancer to hair loss and facilitating an adjustment to self-acceptance. As such, a higher quality of life during the difficult time of coping may be maintained. The development of a computer-imaging intervention offers an opportunity to integrate a standard psychosocial intervention, personalized for each patient, into the routine patient care in the oncology setting.

Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.

BACKGROUND: Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. PATIENTS AND METHODS: Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. RESULTS: No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. CONCLUSIONS: Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.