Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer.

Background: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Methods: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. Results: In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. Conclusion: MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. METHODS: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. RESULTS: We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL. CONCLUSIONS: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.

Large Scale Ex Vivo Expansion of γδ T cells Using Artificial Antigen-presenting Cells.

Higher γδ T cell counts in patients with malignancies are associated with better survival. However, γδ T cells are rare in the blood and functionally impaired in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and interleukin-2 (IL-2). Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a Good Manufacturing Practice (GMP) compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of coculture with aAPC, which exhibited central (47%) and effector (43%) memory phenotypes. In addition, >90% of the expanded γδ T cells expressed NKG2D, although they have low cell surface expression of PD1 and LAG3 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded γδ T cells were effective in killing target cells. Our results demonstrate that large-scale ex vivo expansion of donor-derived γδ T cells in a GMP-like setting can be achieved with the use of quadruplet aAPC and zol/IL-2 for clinical application.

Combination Nivolumab, CD137 Agonism, and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

PURPOSE: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs. PATIENTS AND METHODS: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production. RESULTS: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. CONCLUSIONS: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs.

Assessment of the LOVO device for final harvest of novel cell therapies: a Production Assistance for Cellular Therapies multi-center study.

BACKGROUND AIMS: The final harvest or wash of a cell therapy product is an important step in manufacturing, as viable cell recovery is critical to the overall success of a cell therapy. Most harvest/wash approaches in the clinical lab involve centrifugation, which can lead to loss of cells and decreased viability of the final product. Here the authors report on a multi-center assessment of the LOVO Cell Processing System (Fresenius Kabi, Bad Homburg, Germany), a cell processing device that uses a spinning filtration membrane instead of centrifugation. METHODS: Four National Institutes of Health Production Assistance for Cellular Therapies cell processing facilities (CPFs) assessed the LOVO Cell Processing System for final harvest and/or wash of the following three different cell products: activated T cells (ATCs), tumor-infiltrating lymphocytes (TILs) and bone marrow-derived mesenchymal stromal cells (MSCs). Each site compared their current in-house, routinely used method of final cell harvest and/or wash with that of the LOVO device. RESULTS: Final harvest and/or wash of ATCs, TILs and MSCs using the LOVO system resulted in satisfactory cell viability and recovery with some substantial improvement over the in-house methods of CPFs. Processing time was variable among cell types/facilities. CONCLUSIONS: The LOVO Cell Processing System provides an alternative to centrifuge-based technologies. The system employs a spinning membrane filter, exposing cells to minimal g-forces compared with centrifugation, and is automated and closed. This small multi-center study demonstrated the ability of the LOVO device to yield satisfactory cell viability and recovery of T cells and MSCs.

Expansion and Enrichment of Gamma-Delta (γδ) T Cells from Apheresed Human Product.

Although Vγ9Vδ2 T cells are a minor subset of T lymphocytes, this population is sought after for its ability to recognize antigens in a major histocompatibility complex (MHC)-independent manner and develop strong cytolytic effector function that makes it an ideal candidate for cancer immunotherapy. Due to the low frequency of Gamma-Delta (γδ) T cells in the peripheral blood, we developed an effective protocol to greatly expand a highly pure γδ T cells drug product for first-in-human use of allogeneic γδ T cells in patients with acute myeloid leukemia (AML). Using healthy donor apheresis as an allogenic cell source, the lymphocytes are isolated using a validated device for a counterflow centrifugation method of separating cells by size and density. The lymphocyte-rich fraction is utilized, and the γδ T cells are preferentially activated with zoledronic acid (FDA-approved) and interleukin (IL)-2 for 7 days. Following the preferential expansion of γδ T cells, a clinical-grade magnetic cell-separation device and TCRαß beads are used to deplete contaminating T-cell receptor (TCR)αß T cells. The highly enriched γδ T cells then undergo a second expansion using engineered artificial antigen-presenting cells (aAPCs) derived from K562 cells-genetically engineered to express single-chain variable fragment (scFv) for CD3 and CD28, 41BBL (CD137L) and IL15-RA-together with zoledronic acid and IL-2. Seeding all day-7 enriched γδ T cells in co-culture with the aAPCs facilitates the manufacture of highly pure γδ T cells with an average fold expansion of >229,000-fold from healthy donor blood.

Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function.

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3+ population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.

Breastfeeding practices among childhood cancer survivors.

PURPOSE: This cross-sectional study compared breastfeeding outcomes among childhood cancer survivors to those of women in the general population and evaluated whether breastfeeding is adversely affected by cancer treatment or endocrine-related late effects. METHODS: A self-reported survey ascertained breastfeeding practices and incorporated items from the questionnaires used in the Infant Feeding Practices Study II (IFPS II) to allow comparison with the general population. Among 710 eligible survivors, 472 (66%) responded. The participants were predominantly non-Hispanic White (84%), married (73%), and had some college or less (60%). The mean maternal age at the time of birth of the first child after cancer treatment was 24 years (SD 24.3 ± 4.8). RESULTS: Fewer survivors planned to breastfeed than did IFPS II controls (67% vs. 82%, P < .0001), and fewer survivors initiated breastfeeding (66% vs. 85%, P < .0001). The median breastfeeding duration was shorter among survivors, with early undesired weaning occurring sooner in the survivor group (1.4 months, interquartile range (IQR) 0.5-3.5 months) than in the IFPS II group (2.7 months, IQR 0.9-5.4 months). A higher proportion of survivors reported an unfavorable breastfeeding experience (19% vs. 7.5%, P < .0001) and early, undesired weaning (57.5%, 95% CI 51-64) than did IFPS II participants (45.2%, 95% CI 44-47, P = .0164). Among survivors who expressed intention and chose to breastfeed, 46% endorsed disrupted lactation related to physiologic problems with high risk in those overweight/obese. CONCLUSIONS: Survivors are at risk of negative breastfeeding experiences; however, lactation outcomes were not significantly associated with cancer diagnosis, treatments, or endocrine complications. IMPLICATIONS FOR CANCER SURVIVORS: Prior research has not examined the association of cancer treatments and clinically validated late effects with lactation outcomes in a clinically diverse childhood cancer survivor cohort. Findings from this study suggest that childhood cancer survivors, especially those who are overweight/obese, are at risk of having negative breastfeeding experiences. Early undesired weaning, physiologic problems related to lactation and misconceptions about breastfeeding, especially fears of passing on cancer through breastmilk, highlight the need for counseling and specialized support to optimize lactation outcomes in this vulnerable population.

Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process.

Adoptive cell therapy of tumor-infiltrating lymphocytes has shown promise for treatment of refractory melanoma and other solid malignancies; however, challenges to manufacturing have limited its widespread use. Traditional manufacturing efforts were lengthy, cumbersome and used open culture systems. We describe changes in testing and manufacturing that decreased the process cycle time, enhanced the robustness of critical quality attribute testing and facilitated a functionally closed system. These changes have enabled export of the manufacturing process to support multi-center clinical trials.

Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

PURPOSE: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL. EXPERIMENTAL DESIGN: Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS). RESULTS: All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 1010 (2.3 × 1010 to 1.0 × 1011) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1). CONCLUSION: Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.

Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia.

BACKGROUND: The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm2 ), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors. PROCEDURE: A 2.5-year randomized controlled trial of 73 patients aged 4-18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T0 ) and end of therapy (T3 ), strength, range of motion, endurance, motor skills, and HRQL at baseline (T0 ), 8 (T1 ), 15 (T2 ), and 135 (T3 ) weeks. RESULTS: There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T3 or physical function and HRQL at T0 -T3 . While BMD declined in both the intervention (T0  = -0.21, T3  = -0.55) and usual care (T0  = -0.62, T3  = -0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T3 bone density with body mass index T1 (P = 0.01), T2 (P = <0.0001), T3 (P = 0.01), T3 ankle flexibility/strength (P = 0.001), and T2 parent (P = 0.02)/T0 child (P = 0.03) perceptions of less bodily pain. CONCLUSIONS: The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship.

Factors supporting cardiomyopathy screening among at-risk adult survivors of pediatric malignancies.

PURPOSE: Anthracyclines and chest irradiation place adult survivors of childhood cancer at risk of cardiomyopathy; many survivors do not obtain the recommended screening. Based on our recent clinical trial, the addition of telephone counseling to a printed survivorship care plan more than doubled survivors' risk-based screening. Here, we sought to measure the impact of specific factors targeted in the intervention for their impact on survivors' screening participation. METHODS: Study population-survivors participating in a randomized longitudinal intervention trial. Survivor questionnaires and medical records at baseline and 1-year follow-up provided the data. Within- and between-group differences in factors were assessed at baseline and follow-up; structural equation modeling (SEM) identified direct and indirect effects on screening participation. RESULTS: Of the 411 survivors, 55.3% were female, 89.3% white, 38.9% college graduates, and age 26-59 years (mean = 41 years, SD = 7.68 years). At follow-up, the counseling group demonstrated higher scores for intent to undergo screening (p < 0.001), adherence determination (p < 0.001), autonomous regulation (p < 0.001), competency (p = 0.03), perceived effort warranted for screening (p < 0.001), and perceived value of screening (p = 0.02). SEM identified four factors that directly influenced screening participation (n = 411, RMSEA = 0.02 [90% CI = 0.000-0.05]; CFI = 0.99; TLI = 0.99; WRMR = 0.63): the counseling intervention (p < 0.0001), intrinsic motivation (p < 0.0001), competency (p < 0.0001), and decisional control (p = 0.001); intrinsic motivation was also a mediator (p = 0.002) of screening participation. CONCLUSIONS: Direct interpersonal interaction that focused on multiple modifiable, autonomy-supportive factors powerfully enhances the efficacy of a print survivorship care plan in increasing survivors' screening participation. This finding challenges providers to reach beyond the disease treatment focus and embrace these strategies in their behavior change efforts.

Increasing Cardiomyopathy Screening in Childhood Cancer Survivors: A Cost Analysis of Advanced Practice Nurse Phone Counseling.

PURPOSE/OBJECTIVES: To document the per survivor and per additional survivor screening costs of a mailed survivorship care plan (SCP) with advanced practice nurse (APN) telephone counseling (SCP+C) or without APN telephone counseling (SCP).
. DESIGN: Randomized, longitudinal clinical trial.
. SETTING: St. Jude Children's Research Hospital in Memphis, Tennessee.
. SAMPLE: 411 at-risk pediatric cancer survivors (aged 26-59 years), stratified by age (younger than 30 years versus 30 years or older), recommended screening frequency (every one, two, or five years), gender, and cancer diagnosis (hematologic versus solid tumor).
. METHODS: Clinical and resource data costs were derived from trial data and external estimates.
. MAIN RESEARCH VARIABLES: The cost-effectiveness of left ventricular systolic function screening per survivor and per each additional survivor screened.
. FINDINGS: The per-survivor costs of SCP (n = 206) and SCP+C (n = 205) were $74.91 and $224.69, respectively. The estimated costs of SCP and SCP+C per additional survivor screened for two years disseminated in a medium-sized clinic (n = 101 survivors annually) were $345.41 and $293.85, respectively.
. CONCLUSIONS: Adding APN counseling to a printed SCP may help preserve cardiac health at little or no cost per additional survivor screened.
. IMPLICATIONS FOR NURSING: APN counseling is cost-effective and superior to the standard of care in supporting at-risk survivors' cardiac screening participation.

The unmet emotional, care/support, and informational needs of adult survivors of pediatric malignancies.

PURPOSE: This study describes the prevalence and predisposing factors for potentially modifiable unmet emotional, care/support, and information needs among adult survivors of childhood malignancies. METHODS: A randomly selected/stratified sample of participants in the Childhood Cancer Survivor Study (CCSS) responded to the CCSS-Needs Assessment Questionnaire (CCSS-NAQ) (n = 1189; mean [SD] current age, 39.7 [7.7], range = 26-61 years; 60.9 % women; mean [SD] years since diagnosis, 31.6 [4.7]). Survivors self-reported demographic information, health concerns, and needs; diagnosis/treatment data were obtained from medical records. Adjusted proportional risk ratios (prevalence ratios, PRs) were used to evaluate 77 separate needs. RESULTS: Fifty-four percent of survivors reported unmet psycho-emotional, 41 % coping, and 35 % care/support needs; 51, 35, and 33 %, respectively, reported unmet information needs related to cancer/treatment, the health care system, and surveillance. Female sex and annual income <$60K were associated with multiple needs; fewer needs were linked to diagnosis/years since/or age at diagnosis. Having moderate/extreme cancer-related anxiety/fear was associated with all needs, including a >6-fold increased prevalence for help dealing with "worry" (PR = 6.06; 95 % confidence interval [CI], 3.79-9.69) and anxiety (PR = 6.10; 95 % CI, 3.82-9.72) and a >5-fold increased prevalence for "needing to move on with life" (PR = 5.56; 95 % CI, 3.34-9.25) and dealing with "uncertainty about the future" (PR = 5.50; 95 % CI, 3.44-8.77). Radiation exposure and perceived health status were related to 42 and 29 needs, respectively. CONCLUSIONS: Demographic factors, disease/treatment characteristics, and intrapersonal factors can be used to profile survivors' unmet emotional, care/support, and information needs. IMPLICATIONS FOR CANCER SURVIVORS: These data can be used to enhance provider-survivor communication, identify at-risk subsamples, and appraise core intervention content.

Health care utilization, lifestyle, and emotional factors and mammography practices in the Childhood Cancer Survivor Study.

BACKGROUND: Women with a history of chest radiotherapy have an increased risk of breast cancer; however, many do not undergo annual recommended screening mammography. We sought to characterize the relationship between mammography and potentially modifiable factors, with the goal of identifying targets for intervention to improve utilization. METHODS: Of 625 female participants sampled from the Childhood Cancer Survivor Study, who were treated with chest radiotherapy, 551 responded to a survey about breast cancer screening practices. We used multivariate Poisson regression to assess several lifestyle and emotional factors, health care practices, and perceived breast cancer risk, in relation to reporting a screening mammogram within the last two years. RESULTS: Women who had a Papanicolaou test [prevalence ratio (PR): 1.77; 95% confidence interval (CI) 1.26-2.49], and who perceived their breast cancer risk as higher than the average woman were more likely to have had a mammogram (PR, 1.26; 95% CI, 1.09-1.46). We detected an attenuated effect of echocardiogram screening [PR, 0.70; 95% CI (0.52-0.95)] on having a mammogram among older women compared with younger women. Smoking, obesity, physical activity, coping, and symptoms of depression and somatization were not associated with mammographic screening. CONCLUSION: Our findings suggest that compliance with routine and risk-based screening can be an important indicator of mammography in childhood cancer survivors. In addition, there is a need to ensure women understand their increased breast cancer risk, as a means to encouraging them to follow breast surveillance guidelines. IMPACT: Screening encounters could be used to promote mammography compliance in this population.

Skeletal, neuromuscular and fitness impairments among children with newly diagnosed acute lymphoblastic leukemia.

This study describes skeletal, neuromuscular and fitness impairments among 109 children (median age 10 [range 4-18] years, 65.1% male, 63.3% white) with acute lymphoblastic leukemia (ALL). Outcomes were measured 7-10 days after diagnosis and compared to age- and sex-specific expected values. Associations between function and health-related quality of life (HRQL) were evaluated with logistic regression. Children with ALL had sub-optimal bone mineral density (BMD) Z-score/height (mean ± standard error: - 0.53 ± 0.16 vs. 0.00 ± 0.14, p < 0.01), body mass index percentile (57.6 ± 3.15 vs. 50.0 ± 3.27%, p = 0.02), quadriceps strength (201.9 ± 8.3 vs. 236.1 ± 5.4 N, p < 0.01), 6 min walk distance (385.0 ± 13.1 vs. 628.2 ± 7.1 m, p < 0.001) and Bruininks-Oseretsky Test of Motor Proficiency scores (23 ± 2.5 vs. 50 ± 3.4%, p < 0.01). Quadriceps weakness was associated with a 20.9-fold (95% confidence interval 2.5-173.3) increase in poor physical HRQL. Children with newly diagnosed ALL have weakness and poor endurance and may benefit from early rehabilitation that includes strengthening and aerobic conditioning.

Increasing cardiomyopathy screening in at-risk adult survivors of pediatric malignancies: a randomized controlled trial.

PURPOSE: To determine whether the addition of advanced-practice nurse (APN) telephone counseling to a printed survivorship care plan (SCP) significantly increases the proportion of at-risk survivors who complete cardiomyopathy screening. PATIENTS AND METHODS: Survivors age ≥ 25 years participating in the Childhood Cancer Survivor Study who received cardiotoxic therapy and reported no history of cardiomyopathy screening in the previous 5 years were eligible for enrollment. The 472 participants (mean age, 40.1 years; range, 25.0 to 59.0; 53.3% women) were randomly assigned to either standard care, consisting of an SCP summarizing cancer treatment and cardiac health screening recommendations (n = 234), or standard care plus two APN telephone counseling sessions (n = 238). The primary outcome-completion of cardiomyopathy screening within 1 year-was validated by medical records and compared between the two arms using adjusted relative risks (RRs) with 95% CIs. RESULTS: Participants in the standard and APN counseling groups were not statistically different by demographic or clinical characteristics. At the time of 1-year follow-up, 107 (52.2%) of 205 survivors in the APN group completed screening compared with 46 (22.3%) of 206 survivors in the non-APN group (P < .001). With adjustment for sex, age (< 30 v ≥ 30 years), and Children's Oncology Group-recommended screening frequency group (annual, 2 years, or 5 years), survivors in the APN group were > 2× more likely than those in the control group to complete the recommended cardiomyopathy screening (RR, 2.31; 95% CI, 1.74 to 3.07). CONCLUSION: The addition of telephone counseling to an SCP with cardiac health screening recommendations increases cardiomyopathy screening in at-risk survivors.

Noncancer-related mortality risks in adult survivors of pediatric malignancies: the childhood cancer survivor study.

PURPOSE: We sought to identify factors, other than cancer-related treatment and presence/severity of chronic health conditions, which may be associated with late mortality risk among adult survivors of pediatric malignancies. METHODS: Using the Childhood Cancer Survivor Study cohort and a case-control design, 445 participants who died from causes other than cancer recurrence/progression or non-health-related events were compared with 7,162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at-risk. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for overall/cause-specific mortality. Independent measures included number/severity of chronic conditions, medical care, health-related behaviors, and health perceptions/concerns. RESULTS: Adjusting for education, income, chemotherapy/radiation exposures, and number/severity of chronic health conditions, an increased risk for all-cause mortality was associated with exercising fewer than 3 days/week (OR = 1.72, CI 1.27-2.34), being underweight (OR = 2.58, CI 1.55-4.28), increased medical care utilization (P < 0.001), and self-reported fair to poor health (P < 0.001). Physical activity was associated with a higher risk of death among males (OR = 3.26, CI 1.90-5.61) reporting no exercise compared to those who exercised ≥3 times per week. Ever consuming alcohol was associated with a reduced risk of all-cause (OR = 0.61, CI 0.41-0.89) and other nonexternal causes of death (OR = 0.40, CI 0.20-0.79). Concerns/worries about future health (OR = 1.54, CI 1.10-2.71) were associated with increased all-cause mortality. CONCLUSIONS: Factors independent of cancer treatment and chronic health conditions modify the risk of death among adult survivors of pediatric cancer. IMPLICATIONS FOR CANCER SURVIVORS: Continued cohort observation may inform interventions to reduce mortality.

Survivor typologies predict medical surveillance participation: the childhood cancer survivor study.

BACKGROUND: Adult survivors of childhood cancer adhere poorly to recommended medical surveillance. We sought to identify modifiable factors that contribute to non-adherence. METHODS: Latent class analysis categorized survivors (ages 18-52 years) at risk of cardiac, breast, or bone late sequelae on the basis of their health-related concerns, fears, and motivation. These classifications were compared at two time points for self-reported adherence to recommended echocardiography, mammography, and bone densitometry screening. RESULTS: Three classes (worried, collaborative, and self-controlling) characterized survivors in each of the three risk groups: cardiac (N=564; Bayesian information criterion [BIC] =10,824.66; Lo-Mendell-Rubin parametric likelihood ratio test [LRMLRT] P= .002), breast (N=584; BIC=11,779.97; LRMLRT P< .001), and bone (N=613; BIC=11,773.56; LMRLRT P= .028). Only 9% of at-risk survivors in the self-controlling class reported undergoing bone density screening in 2005, compared with 17.2% in the collaborative class (P= .034). Thirteen percent of the self-controlling, 24% of collaborative (P= .025), and 34% of worried (P= .010) classes reported undergoing bone densitometry in 2009. Whereas 73% of at-risk survivors in the worried class reported having had an echocardiogram in 2009, only 57% of the collaborative (P= .040) and 43% of self-controlling (P< .001) classes did. In 2005 and 2009, respectively, fewer survivors in the self-controlling class (37% and 53%) than in the collaborative (51%, P= .038 and 70%, P= .01) and worried (58%, P= .002 and 69%, P= .025) classes reported undergoing mammograms. CONCLUSIONS: Modifiable intrapersonal characteristics associated with these three classes predict self-reported participation in medical surveillance. Continued observation and validation of these survivor profiles may inform tailored interventions to enhance survivors' screening participation. Copyright © 2012 John Wiley & Sons, Ltd.

Development of a comprehensive health-related needs assessment for adult survivors of childhood cancer.

PURPOSE: Examine the construct validity, stability, internal consistency, and item-response performance of a self-report health needs assessment for adult survivors of childhood cancer. METHODS: A 190-item mailed survey was completed by 1,178 randomly selected (stratified on age, diagnosis, time since diagnosis) Childhood Cancer Survivor Study participants (mean age, 39.66 [SD 7.71] years; time since diagnosis, 31.60 [SD 4.71] years). Minorities and rural residents were oversampled at a 2:1 ratio. RESULTS: The final instrument included 135 items comprising nine unidimensional subscales (Psycho-emotional, Health System Concerns, Cancer-Related Health Information, General Health, Survivor Care and Support, Surveillance, Coping, Fiscal Concerns, and Relationships). Confirmatory factor analysis (n = 1,178; RMSEA = 0.020; 90 % CI = 0.019-0.020; CFI = 0.956; TLI = 0.955) and person-item fit variable maps established construct validity. Across subscales, Cronbach's alpha was 0.94-0.97, and the 4-week test-retest correlations were 0.52-0.91. In a Rasch analysis, item reliability was 0.97-0.99, person reliability was 0.80-0.90, and separation index scores were 2.00-3.01. Significant subscale covariates of higher need levels included demographics, diagnosis, and treatment exposures. CONCLUSIONS: The Childhood Cancer Survivor Study Needs Assessment Questionnaire (CCSS-NAQ) is reliable and construct-valid, has strong item-response properties, and discriminates need levels. IMPLICATIONS FOR CANCER SURVIVORS: The CCSS-NAQ potentially can be used to: (1) directly assess adult childhood cancer survivors' self-reported health-related needs, (2) identify individuals or subgroups with higher-level needs, (3) inform prevention and direct intervention strategies, and (4) facilitate prioritization of health-care resource allocation.