Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics.
Clinically relevant, ...patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice.
Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient.
Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment.
Background
The Lansky Play‐Performance Scale (LPPS) is often used to determine a child's performance status for cancer clinical trial eligibility. Differences between clinician and caregiver LPPS ...ratings and their associations with child‐reported functioning have not been evaluated.
Methods
Children aged 7 to 18 years who were receiving cancer treatment and their caregivers were recruited from 9 pediatric cancer centers. Caregivers and clinicians reported LPPS scores, and children completed Patient‐Reported Outcomes Measurement Information System (PROMIS) pediatric functioning and symptom measures before treatment (time 1 T1) and after treatment (time 2 T2). t tests and mixed‐linear models were used to assess differences in caregiver and clinician LPPS scores; polyserial correlations quantified associations between PROMIS and LPPS scores.
Results
Of 482 children, 281 had matched caregiver‐ and clinician‐reported LPPS T1/T2 scores. Caregivers rated children significantly worse on the LPPS than clinicians at both T1 (mean, 73.3 vs 87.4; P < .01) and T2 (mean, 67.9 vs 83.1; P < .01). These differences were not related to a child's age (P = .89), diagnosis (P = .17), or sex (P = .64) or to the time point (P = .45). Small to moderate associations existed between caregiver‐ and clinician‐reported LPPS ratings and child‐reported PROMIS scores for mobility (caregiver T1/T2 r = 0.51/0.45; P < .01; clinician T1/T2 r = 0.40/0.35; P < .01), fatigue (caregiver T1/T2 r = –0.46/–0.37; P < .01; clinician T1/T2 r = –0.26/–0.27; P < .01), and pain interference (caregiver T1/T2 r = –0.32/–0.30; P < .01; clinician T1/T2 r = –0.17/–0.31; P < .01). Caregivers and clinicians assigned significantly lower LPPS scores at T2 (caregiver Δ = –5.37; P < .01; clinician Δ = –4.20; P < .01), whereas child‐reported PROMIS scores were clinically stable.
Conclusions
Significant differences between clinician and caregiver LPPS ratings of child performance were sustained over time; their associations with child reports were predominantly small to moderate. These data suggest that clinician‐reported LPPS ratings by themselves are inadequate for determining clinical trial eligibility and should be supplemented by appropriate measures of a child's functional status reflecting the child and caregiver perspectives.
The Lansky Play‐Performance Scale (LPPS) is commonly used by clinicians for determining eligibility for pediatric cancer clinical trials. In this prospective cohort study of children receiving cancer treatment, LPPS ratings differ between clinicians and caregivers and are poorly correlated with child reports. This challenges the use of the LPPS for that purpose.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Parents of children with incurable cancer make complex and difficult decisions about remaining treatment options. We compared the self-reported rationale, good parent definition, and desired clinical ...staff behaviors of parents who recently decided for phase I (P1) chemotherapy with parents who chose a do not resuscitate (DNR) or terminal care (TC) option.
Sixty-two parents of 58 children were asked for the basis of their decision, their definition of a good parent, and what staff behaviors supported their good parent role. After semantic content analysis, results were compared in the P1 versus DNR/TC groups. These categories were mutually exclusive but did not necessarily represent an either/or decision.
Thirty-one decisions were for P1 chemotherapy and 27 for DNR/TC. Median survival time after study enrollment was greater in the P1 group (0.4 v 0.1 years). Most P1 group parents reported having felt compelled to continue cancer-directed therapy (71% v 7%), whereas those who opted for DNR/TC cited quality of life (QOL; 74% v 3%) and patient wishes (67% v 13%). Decision factors common to both groups were medical facts, doing right, and others' opinions. Both groups believed that a good parent did right, provided support and presence, and sacrificed for the child. The groups desired similar support from clinicians and expressed gratitude.
Despite similar definitions of a good parent and desired staff behaviors, parents in the P1 group reported having felt compelled to continue cancer-directed therapy, whereas QOL and patient wishes were emphasized in decisions for DNR/TC.
Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For ...reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting.
Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA.
53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r = 0.050; p = 0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r = −0.69, p = 0.004).
Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.
•Not all cancers with defects in homologous recombination (HR) demonstrate clinical responses to PARP inhibitors.•In a BRCA1-mutant ovarian cancer cell line, 53BP1 loss restores HR and decreases PARP inhibitor sensitivity.•Samples from a phase I trial of the PARP inhibitor ABT-767 were stained with validated IHC assays for DNA repair proteins.•In HR-deficient ovarian cancer, 53BP1 expression negatively correlated with percent change in tumor size from baseline.•Assessment of proteins that modulate DNA repair pathway choice might inform PARP inhibitor response in ovarian cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects ...regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently ...undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001). The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.
•BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein.•Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Children and adolescents with cancer experience treatment-related, subjective adverse events (AEs). Identifying distinct groups of patients who predictably experience higher prevalence of AEs could ...guide patient care.
Study aims were to 1) identify groups of children and adolescents reporting AEs using the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE); 2) determine whether demographic and clinical characteristics predict AE group membership; and 3) examine whether AE group membership was related to the distal outcome of psychological stress.
Four hundred seventy-seven patients self-reported AEs via the Ped-PRO-CTCAE at T1 (beginning of treatment) and the PROMIS Pediatric Psychological Stress measure at T2 (7–28 days later). Latent class analysis was conducted to identify groups of patients and the relationships of the groups with demographic and clinical characteristics, and with stress.
Three distinct a priori unknown AE groups were identified (high AE prevalence, moderate AE prevalence, and low AE prevalence). Females, blacks, patients with high psychological stress, and patients more recently diagnosed were more likely to be in the high AE prevalence group. Gender, age, race, and time since diagnosis were associated with psychological stress.
Children with cancer are heterogeneous in experiencing subjective AEs. Gender, race, and time since diagnosis were significantly associated with higher subjective AE prevalence that may lead to psychological stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Obesity correlates with adverse events (AEs) in children with acute myelogenous leukemia and during maintenance therapy for acute lymphoblastic leukemia (ALL). Less is known about AEs in ...obese ALL patients during pre‐maintenance chemotherapy. We evaluated the relationship between obesity (body mass index (BMI) ≥ 95th percentile) and AEs during pre‐maintenance chemotherapy in pediatric patients with ALL.
Methods
One hundred fifty‐five pediatric ALL patients diagnosed at a single institution between 2006 and 2012 were retrospectively evaluated for infections, treatment‐requiring hypertension, insulin‐requiring hyperglycemia, pancreatitis, pediatric intensive care unit admissions, sepsis, febrile neutropenia (FN) admissions, thrombosis, hepatotoxicity, and nephrotoxicity. Univariate and multivariable analyses compared proportions of obese versus nonobese patients experiencing AEs.
Results
AEs occurring significantly more frequently in obese patients by univariate analysis included treatment‐requiring hypertension (17.5% vs 6.1%; OR, 3.27; 95% CI, 1.1–10.0, P = 0.0497) and insulin‐requiring hyperglycemia (25.0% vs 11.3%; OR, 2.62; 95% CI, 1.04–6.56, P = 0.04). Obese patients had greater incidence rates for recurrent admission‐requiring infections (incidence rate ratio (IRR) 1.64; 95% CI, 1.08–2.48, P = 0.02) and recurrent FN admissions (IRR, 1.53; 95% CI, 1.10–2.12, P = 0.01). Accounting for combined age and NCI risk status, obesity was a risk factor for treatment‐requiring hypertension (OR, 3.90; 95% CI, 1.19–12.76, P = 0.02), insulin‐requiring hyperglycemia (OR, 3.92; 95% CI, 1.39–11.05, P = 0.01), and FN admission (OR, 2.92; 95% CI, 1.27–6.73, P = 0.01).
Conclusions
During pre‐maintenance chemotherapy for ALL, obesity is a risk factor for the development of hypertension, hyperglycemia, and FN admissions. This research provides implications for augmented preventive and supportive care guidelines in obese ALL patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Collecting symptom, function, and adverse event (AE) data directly from children and adolescents undergoing cancer care is more comprehensive and accurate than relying solely on their ...caregivers or clinicians for their interpretations. We developed the pediatric patient‐reported outcomes version of the Common Terminology Criteria for Adverse Events (Ped‐PRO‐CTCAE) measurement system with input from children, parents, and clinicians. Here, we report how we determined the recommended Ped‐PRO‐CTCAE item scoring approach.
Methods
Data from 271 patients were analyzed using three scoring approaches: (a) at the AE attribute (frequency, severity, interference) using ordinal and dichotomous measures; (b) a weighted composite AE item score by AE attribute (0.5 ‐ frequency; 1.0 ‐ severity; 1.5 ‐ interference); and (c) overall number of AEs endorsed. Associations of each AE attribute, AE item score, and overall AE score with the Patient‐Reported Outcome Measurement Information System (PROMIS) Pediatric measures were examined. The ability of the overall Ped‐PRO‐CTCAE AE score to identify patients with PROMIS symptom T‐scores worse than reference population scores was assessed. Clinician preference for score information display was elicited through interviews with five pediatric oncology clinical trialists.
Results
The diverse scoring approaches yielded similar outcomes, including positive correlations of the Ped‐PRO‐CTCAE attributes, AE item score, and the overall AEs score with the PROMIS Pediatric measures. Clinicians preferred the most granular display of scoring information (actual score reported by the child and corresponding descriptive term).
Conclusions
Although three scoring approaches yielded similar results, we recommend the AE attribute level of one score per Ped‐PRO‐CTCAE AE attribute for its simplicity of use in care and research.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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