Childhood Cancer Survivors' Reported Late Effects, Motivations for Seeking Survivorship Care, and Patterns of Attendance.

BACKGROUND: Childhood cancer survivors are vulnerable to long-term treatment-related health conditions, which can lead to poor quality of life. Little data exist on the overall health of long-term Australian and New Zealand childhood cancer survivors or on survivors' motivations for attending survivorship clinics. METHODS: This study administers a cross-sectional questionnaire to long-term survivors ≥5 years from their primary diagnosis. We compared participant-reported number of late effects by a cancer diagnosis, and identified clinical (eg, treatment) and demographic (eg, age) factors that were associated with late effects burden and engagement in cancer survivorship care. RESULTS: A total of 634 participants completed questionnaires (48% male, mean age = 21.7 years). Most participants (79%) reported at least one cancer-related late effect, most commonly fatigue (40%) and memory/learning difficulties (34%). Brain tumor survivors reported a higher total number of late effects than survivors with other diagnoses (mean = 5.7 vs. 3.2, P < .001). Participants' most commonly reported motivators for engaging in care were to understand problems that may occur later in life because of their cancer and/or treatment (98.5%) and to get reassurance about one's health (97.4%). The proportion of survivors endorsing each motivating factor was similar across cancer diagnoses, with the exception of learning more about insurance and pensions (highest in brain tumor survivors = 80%). In multivariable analyses, survivors were more likely to report being engaged in survivorship care if they were younger (P < .001), less time had elapsed since their diagnosis (P < .001), or they reported a higher number of motivating factors (P = .016). CONCLUSION: Survivors report a range of health problems decades after treatment completion. Understanding the burden of late effects, and motivators for seeking survivorship care to manage these health problems, is important for ensuring that tailored interventions or services are available to meet the needs of this growing population and to design effective models of survivorship care.

eHealth tools for childhood cancer survivorship care: A qualitative analysis of survivors', parents', and general practitioners' views.

Objective: We assessed the acceptability of, and perceived benefits/barriers to, using Electronic health (eHealth) technology for childhood cancer survivorship care. Methods: We interviewed survivors, their parents, and their nominated GP. We described a hypothetical eHealth tool to manage survivorship care and asked their likely use of, and perceived benefits/concerns for, the use of the tool. Results: 31 survivors (mean age = 27.0), 29 parents (survivors' mean age = 12.6), and 51 GPs (mean years practising = 28.2) participated. Most survivors/parents (85%) and GPs (75%) indicated that they would be willing to use an eHealth tool. Survivors/parents reported that an eHealth tool would increase their confidence in their ability, and their GP's ability, to manage their survivorship care. GPs agreed that an eHealth tool would provide easier access to survivors' medical information and increase their capacity to provide support during survivorship. Some GPs (7%) and survivors (43%) reported being hesitant to use eHealth tools due to privacy/security concerns. Conclusion: Overall, eHealth tools appear acceptable and may help to improve the management of late effects for childhood cancer survivors and assist their GPs to coordinate their care. Innovation: Concerns raised by key stakeholders should be addressed in the design of eHealth technologies to optimise their uptake and effectiveness.

Re-Engage: A Novel Nurse-Led Program for Survivors of Childhood Cancer Who Are Disengaged From Cancer-Related Care.

BACKGROUND: Survivors of childhood cancer often experience treatment-related chronic health conditions. Survivorship care improves survivors' physical and mental health, yet many are disengaged from care. Innovative models of care are necessary to overcome patient-reported barriers to accessing survivorship care and to maximize survivors' health. METHODS: We piloted a novel survivorship program, called "Re-engage," a distance-delivered, nurse-led intervention aiming to engage, educate, and empower survivors not receiving any cancer-related care. Re-engage involves a nurse-led consultation delivered via telephone/online to establish survivors' medical history and needs. Participants completed questionnaires at baseline, 1 month postintervention, and 6-month follow-up. RESULTS: A total of 27 survivors who had not accessed survivorship care in the last 2 years participated (median age, 31 years; interquartile range [IQR], 27-39 years); of which, 82% were at high-risk for treatment-related complications. Participation in Re-engage was high (75%) and there was no attrition once survivors enrolled. At 1 month postintervention, 92% of survivors reported that Re-engage was "beneficial," which all survivors reported at 6-month follow-up. Survivors' overall satisfaction with their care increased from 52% before Re-engage to 84% at 1 month postintervention. Survivors' mean self-efficacy scores remained similar from baseline to 1 month postintervention (b = -0.33, 95% CI, -1.31 to 0.65), but increased significantly from baseline to 6-month follow-up (b = 1.64, 95% CI, 0.28-3.00). At 6-month follow-up, 73% of survivors showed an increase in health-related self-efficacy compared with baseline. CONCLUSIONS: Re-engage is a highly acceptable and feasible intervention and promotes health-related self-efficacy, which is integral to survivors being advocates for their own health. Further empirical work is needed to evaluate the long-term efficacy of Re-engage. TRIAL REGISTRATION: ACTRN12618000194268.

The Role of Primary Care Physicians in Childhood Cancer Survivorship Care: Multiperspective Interviews.

BACKGROUND: Primary care physicians (PCPs) are well placed to provide holistic care to survivors of childhood cancer and may relieve growing pressures on specialist-led follow-up. We evaluated PCPs' role and confidence in providing follow-up care to survivors of childhood cancer. SUBJECTS, MATERIALS, AND METHODS: In Stage 1, survivors and parents (of young survivors) from 11 Australian and New Zealand hospitals completed interviews about their PCPs' role in their follow-up. Participants nominated their PCP for an interview for Stage 2. In Stage 2, PCPs completed interviews about their confidence and preparedness in delivering childhood cancer survivorship care. RESULTS: Stage 1: One hundred twenty survivors (36% male, mean age: 25.6 years) and parents of young survivors (58% male survivors, survivors' mean age: 12.7 years) completed interviews. Few survivors (23%) and parents (10%) visited their PCP for cancer-related care and reported similar reasons for not seeking PCP-led follow-up including low confidence in PCPs (48%), low perceived PCP cancer knowledge (38%), and difficulty finding good/regular PCPs (31%). Participants indicated feeling "disconnected" from their PCP during their cancer treatment phase. Stage 2: Fifty-one PCPs (57% male, mean years practicing: 28.3) completed interviews. Fifty percent of PCPs reported feeling confident providing care to childhood cancer survivors. PCPs had high unmet information needs relating to survivors' late effects risks (94%) and preferred a highly prescriptive approach to improve their confidence delivering survivorship care. CONCLUSION: Improved communication and greater PCP involvement during treatment/early survivorship may help overcome survivors' and parents' low confidence in PCPs. PCPs are willing but require clear guidance from tertiary providers. IMPLICATIONS FOR PRACTICE: Childhood cancer survivors and their parents have low confidence in primary care physicians' ability to manage their survivorship care. Encouraging engagement in primary care is important to promote holistic follow-up care, continuity of care, and long-term surveillance. Survivors'/parents' confidence in physicians may be improved by better involving primary care physicians throughout treatment and early survivorship, and by introducing the concept of eventual transition to adult and primary services. Although physicians are willing to deliver childhood cancer survivorship care, their confidence in doing so may be improved through better communication with tertiary services and more appropriate training.

'Re-engage' pilot study protocol: a nurse-led eHealth intervention to re-engage, educate and empower childhood cancer survivors.

INTRODUCTION: Many childhood cancer survivors are disengaged from cancer-related follow-up care despite being at high risk of treatment-related late effects. Innovative models of long-term follow-up (LTFU) care to manage ongoing treatment-related complications are needed. 'Re-engage' is a nurse-led eHealth intervention designed to improve survivors' health-related self-efficacy, targeted at survivors disengaged from follow-up. Re-engage aims to overcome survivor- and parent-reported barriers to care and ensure survivors receive the care most appropriate to their risk level. METHODS AND ANALYSIS: This study will recruit 30 Australian childhood cancer survivors who are not receiving any cancer-related care. Participation involves two online/telephone consultations with a survivorship nurse for medical assessment, a case review, risk stratification and creation of a care plan by a multidisciplinary team of specialists. We will assess the feasibility of implementing 'Re-engage' and its acceptability to participants and health professionals involved. The primary outcome will be survivors' health-related self-efficacy, measured at baseline and 1 and 6 months postintervention. Secondary outcomes will include the effect of 'Re-engage' on survivors' health behaviours and beliefs, engagement in healthcare, information needs and emotional well-being. We will also document the cost per patient to deliver 'Re-engage'. If Re-engage is acceptable, feasible and demonstrates early efficacy, it may have the potential to empower survivors in coordinating their complex care, improving survivors' long-term engagement and satisfaction with care. Ideally, it will be implemented into clinical practice to recall survivors lost to follow-up and reduce the ongoing burden of treatment for childhood cancer. ETHICS AND DISSEMINATION: The study protocol has been approved by the South Eastern Sydney Local Health District Human Research Ethics Committee (reference number: 16/366). The results will be disseminated in peer-reviewed journals and at scientific conferences. A lay summary will be published on the Behavioural Sciences Unit website. TRIAL REGISTRATION NUMBER: ACTRN12618000194268.

Synthesis and Activity of 6″-Deoxy-6″-thio-α-GalCer and Peptide Conjugates.

A major challenge in the development of highly defined synthetic vaccines is the codelivery of vaccine components (i.e., antigen and adjuvant) to secondary lymphoid tissue to induce optimal immune responses. This problem can be addressed by synthesizing vaccines that comprise peptide antigens covalently attached to glycolipid adjuvants through biologically cleavable linkers. Toward this, a strategy utilizing previously unreported 6″-deoxy-6″-thio analogues of α-GalCer that can undergo chemoselective conjugation with peptide antigens is described. Administration of these conjugate vaccines leads to enhanced priming of antigen specific T cells. This simple vaccine design is broadly applicable to multiple disease indications such as cancer and infectious disease.

A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy.

Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers.

Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in ß-defensin, IL-10, interferon-ß, transforming growth factor-ß, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

Synthesis and mass spectral characterization of mycobacterial phosphatidylinositol and its dimannosides.

A family of naturally occurring mycobacterial phosphatidylinositol (PI) and its dimannosides (PIM(2), AcPIM(2), and Ac(2)PIM(2)) that all possess the predominant natural 19:0/16:0 phosphatidyl acylation pattern were prepared to study their mass spectral fragmentations. Among these, the first synthesis of a fully lipidated PIM (i.e., (16:0,18:0)(19:0/16:0)-PIM(2)) was achieved from (±)-1,2:4,5-diisopropylidene-D-myo-inositol in 16 steps in 3% overall yield. A key feature of the strategy was extending the utility of the p-(3,4-dimethoxyphenyl)benzyl protecting group for its use at the O-3 position of inositol to allow installation of the stearoyl residue at a late stage in the synthesis. Mass spectral studies were performed on the synthetic PIMs and compared to those reported for natural PIMs identified from a lipid extract of M. bovis BCG. These analyses confirm that fragmentation patterns can be used to identify the structures of specific PIMs from the cell wall lipid extract.

Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.

Bis[(1S)-1,4-azanediyl-1-(9-deazaadenin-9-yl)-1,4-dideoxy-5-methylsulfanyl-D-ribitol] tetrakis(hydrochloride) monohydrate: structure, DFT energy and ligand docking results of a potent methylthioadenosine phosphorylase inhibitor found in different molecular conformations.

The title compound, abbreviated as 5'ThiomethylImmA, is a potent inhibitor of methylthioadenosine phosphorylase [Singh et al. (2004). Biochemistry, 43, 9-18]. The synchrotron study reported here shows that the hydrochloride salt crystallizes with two independent, nearly superimposable, dications as a monohydrate with formula 2C(12)H(19)N(5)O(2)S(2+)·4Cl(-)·H(2)O. Hydrogen bonding utilizing the H atoms of the dication is found to favour certain molecular conformations in the salt, which are significantly different from those found as bound in the enzyme. Ligand docking studies starting from either of these dications or related neutral structures successfully place the conformationally revised structures in the enzyme active site but only under particular hydrogen-bonding and molecular flexibility criteria. Density functional theory calculations verify the energy similarity of the independent cations and confirm the significant energy cost of the required conformational change to the enzyme bound form. The results suggest that using crystallographically determined free ligand coordinates as starting parameters for modelling may have serious limitations.

Late mortality and second cancers in an Australian cohort of childhood cancer survivors.

OBJECTIVE: The aim of this study was to characterise rates of late mortality and second cancers in an Australian cohort of childhood cancer survivors and compare these to rates observed in the New South Wales population. DESIGN, SETTING AND PARTICIPANTS: Records for 896 childhood cancer survivors treated at the Sydney Children's Hospital between 1972 and 1999 were linked to the National Death Index and NSW Central Cancer Registry to identify deaths and notifications of second cancers. Survivors were defined as those alive for at least 5 years after diagnosis and were followed until death or 31 December 2004, whichever occurred first. MAIN OUTCOME MEASURES: Standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs) were used as measures of relative risk. A Cox proportional hazard model was used to quantify the influence of demographic and disease-related characteristics on the risk of death and second cancers. RESULTS: The SMR and SIR were 7.46 and 4.98 times higher, respectively, among cancer survivors relative to the NSW population. Relative mortality was highest in survivors of soft-tissue sarcoma (SMR, 18.95 [95% CI, 6.88-40.81]) and central nervous system (CNS) malignancies (SMR, 16.78 [95% CI, 7.62-31.64]). The leading causes of death included recurrence of the primary childhood cancer (55%) and second cancers (12%), as well as treatment-related complications (17%) The most frequently observed second cancers were bone and thyroid cancers, melanoma, and CNS malignancies, and second cancers were most common among survivors of leukaemia, soft-tissue sarcoma and Hodgkin's lymphoma. CONCLUSIONS: Compared with the general population, survivors of childhood cancer in Australia are at increased risk of late mortality and second cancers. These findings highlight a continuing need to assess health issues faced by childhood cancer survivors and develop strategies to minimise the adverse outcomes associated with treatment for childhood cancer.

The role of stress and social support in predicting depression among a hypertensive African American sample.

OBJECTIVE: We examined social support, stress, and selected demographic variables as predictors of depression among African Americans with hypertension. METHODS: Archival data collected on 194 hypertensive African Americans ranging in age from 30 to 88 years (mean age = 58.3 years, standard deviation = 12.2; 63% were female) were analyzed in the present study. Hierarchic regression analyses were conducted using two models of depression. The first model included basic demographic characteristics of the sample, including age, sex, educational attainment, income, and employment status. In the second model, the psychosocial variables of stress and social support were added to determine their predictive value. RESULTS: The first model accounted for 14% of the variance in depression and identified sex and age as significant predictors. The second model, in which two psychosocial variables were added, accounted for 45.2% of the total variance, with age, stress, and social support as significant predictors. CONCLUSIONS: Stress and social support are significant predictors of depression in a hypertensive African American population, beyond the influence of various demographic variables. These results have implications for prevention and intervention strategies with the target population.

Concise routes to pyrazolo[1,5-a]pyridin-3-yl pyridazin-3-ones.

Cycloaddition of pyridine N-imine with 6-alkyl-4-oxohex-5-ynoates followed by condensation with hydrazine provides concise access to pharmacologically active 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazinones. For the first time alkynyl heterocycles are also shown to be effective dipolarophiles for pyridine N-imine, and analogous compounds can be accessed directly in modest yields through the reaction of 6-(alkyn-1-yl)pyridazin-3-one derivatives.

Psychometric properties of the State and Trait Food Cravings Questionnaires among overweight and obese persons.

A crucial problem in studies involving food cravings is the lack of a psychometrically sound measure for use among overweight and obese populations. The degree to which the Food Cravings Questionnaires-Trait (FCQ-T) and State (FCQ-S) evidenced acceptable psychometric properties among overweight and obese participants was assessed. In study 1, 109 participants completed the FCQ-T and FCQ-S. Item-total correlations, test-retest reliability, internal consistency, and factor structures were examined. Results indicate good internal consistency and partially support the factor structures. In study 2, the construct and predictive validity of the FCQ-S were examined. Twenty-eight women completed the FCQ-S 15 min after finishing a standardized breakfast and then twice more, 90 min apart. Subsequent ad libitum food intake was recorded. Results suggest that the FCQ-S is sensitive to state changes in food cravings, but that the magnitude of the changes was moderate. The FCQ-S was not a good predictor of subsequent food intake. The FCQ-T and FCQ-S may be useful in studies that examine triggers of and interventions for excessive food intake.