Publications by authors named "Ryan Shanley"

82 Publications

Effect of Keratinocyte Growth Factor on Hospital Readmission and Regimen-Related Toxicities after Autologous Hematopoietic Cell Transplantation for Lymphoma.

Transplant Cell Ther 2021 Feb 13;27(2):179.e1-179.e4. Epub 2020 Dec 13.

Blood and Marrow Transplant Program, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization.
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http://dx.doi.org/10.1016/j.jtct.2020.11.005DOI Listing
February 2021

Impact of pediatric hypophosphatasia on behavioral health and quality of life.

Orphanet J Rare Dis 2021 Feb 12;16(1):80. Epub 2021 Feb 12.

Department of Pediatrics, University of Minnesota Medical School, 2450 Riverside Avenue South, RPB 550, Minneapolis, MN, 55454, USA.

Background: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase. It is characterized by defective bone mineralization associated with low alkaline phosphatase activity. Clinical features of pediatric HPP are highly variable, and can include premature loss of teeth, musculoskeletal problems, and impaired mobility. The effects of pediatric HPP on sleep, mood, regulation of attention and behavior, and other aspects of behavioral health have not been comprehensively studied.

Methods: Parents of 30 children with HPP (14 females, 16 males) between the ages of 3 and 16 years (mean age = 8.0 years) enrolled in this cross-sectional survey-based study. Molecular genetic and biochemical testing as well as clinical records were reviewed to verify diagnosis of HPP. The cohort included 15 patients with a more clinically severe presentation of HPP who had received treatment with enzyme replacement therapy (asfotase alfa) and 15 children with less severe HPP who were treatment-naïve. Parents provided information regarding psychopathological comorbidity, emotional and behavioral well-being, and quality of life.

Results: Clinically significant behavioral health challenges were evident in 67% of children with HPP. The most common behavioral findings included sleep disturbance and symptoms of attention deficit hyperactivity disorder (ADHD), each of which were observed ≥ 50% of individuals. Sleep disturbance, pain interference, poor behavioral regulation, and mood/anxiety symptoms were associated with reduced physical and psychosocial quality of life. Behavioral concerns were evident among children with HPP receiving asfotase alfa treatment as well as among children with clinically less severe disease who had not initiated therapy. Although most children in the cohort (77%) had age-typical development of adaptive skills, emotional and behavioral challenges were associated with weaker adaptive function.

Conclusions: Children with HPP are at increased risk for ADHD symptoms and other behavioral health challenges. There is likely an under-recognition of these findings in clinical practice.
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http://dx.doi.org/10.1186/s13023-021-01722-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881480PMC
February 2021

Anxiety and depressive symptoms in adolescents and young adults with epilepsy: The role of illness beliefs and social factors.

Epilepsy Behav 2021 Mar 23;116:107737. Epub 2021 Jan 23.

Department of Pediatrics, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55455, USA.

Purpose: This study examined (1) the prevalence of anxiety and depressive symptoms among adolescents and young adults (AYA) with epilepsy and (2) demographic and medical characteristics, illness beliefs, and social factors associated with anxiety and depressive symptoms to guide intervention development.

Methods: A community-based sample of AYA with epilepsy (n = 179, ages 13-24 years, 39% male) completed online questionnaires measuring anxiety symptoms (GAD-7), depressive symptoms (PHQ-9), illness beliefs (helplessness; acceptance; perceived benefits), and social factors (family functioning; social stigma; connectedness). Participants also reported medical information (epilepsy type; years since diagnosis; time since last seizure; current medications).

Results: Prevalence of clinically significant symptoms of anxiety and depression, 36% and 35%, respectively, was high compared to population prevalence. In multivariable regression models, demographic and medical factors explained only 2% of the variance in depressive symptoms and 6% in anxiety symptoms. Illness beliefs and social factors accounted for a majority of the explanatory power of both models (partial R = 0.37 for anxiety; 0.44 for depression). Specifically, acceptance, family functioning, and social stigma accounted for the greatest variance (p's < 0.01).

Conclusions: This study found a high prevalence of anxiety and depressive symptoms among AYA with epilepsy. Epilepsy variables (seizure type, medications, and years since diagnosis) were not associated with these psychological symptoms. Rather, the majority of variance in symptoms was accounted for by potentially modifiable beliefs and social factors. Interventions that promote illness acceptance, enhance family functioning, and reduce social stigma may ameliorate psychological distress among AYA with epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2020.107737DOI Listing
March 2021

Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells.

Transl Oncol 2021 Feb 15;14(2):100997. Epub 2020 Dec 15.

Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address:

The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.
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http://dx.doi.org/10.1016/j.tranon.2020.100997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749408PMC
February 2021

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

J Clin Oncol 2020 11 15;38(32):3773-3784. Epub 2020 Sep 15.

Miami Cancer Institute, Miami, FL.

Purpose: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility.

Methods: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively.

Results: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively.

Conclusion: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
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http://dx.doi.org/10.1200/JCO.20.01255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655019PMC
November 2020

Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types.

ESMO Open 2020 09;5(5):e000803

Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:

Background: In solid tumours, antibiotic use during immune checkpoint inhibitor (ICI) treatment is associated with shorter survival. Following allogeneic haematopoietic cell transplantation (allo-HCT), antibiotic-induced gut microbiome alterations are associated with risk of relapse and mortality. These findings suggest that the gut microbiota can modulate antitumour immune response across tumour types, though it is not clear if the impact on outcomes is specific to immune therapy. An important limitation of previous studies is that the analysis combined all antibiotic exposures irrespective of the antibiotic spectrum of activity. Whether antibiotic exposure during induction chemotherapy in acute myeloid leukaemia (AML) affects risk of relapse is also unknown.

Patients And Methods: We performed a single-centred retrospective analysis of antibiotic exposures in metastatic/advanced non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) receiving ICI and newly diagnosed AML patients receiving induction chemotherapy achieving a complete remission 1. Antibiotic use within 4 weeks before and 6 weeks after the ICI initiation were included. In AML patients, antibiotic exposures between days 1 and 28 of induction were collected. Antibiotics were a priori stratified based on spectrum of activity. Primary outcomes of interest were progression-free survival (PFS), overall survival (OS) in NSCLC and RCC and relapse-free survival (RFS) in AML.

Results: 140 patients with NSCLC, 55 with RCC and 143 with AML were included. In multivariable analysis, PFS and OS were shorter in NSCLC patients who received broad-spectrum anti-anaerobes (PFS, HR=3.2, 95% CI 1.6 to 6.2, p<0.01; OS, HR=1.7, 95% CI 0.8 to 3.6, p=0.19) or 'other' antibiotics (vancomycin-predominant) (PFS, HR=2.4, 95% CI 1.3 to 4.6, p<0.01; OS, HR=2.4, 95% CI 1.2 to 4.7, p=0.01). In RCC, patients who received penicillins/penicillin-class/early-generation cephalosporins had shorter PFS (HR=3.6, 95% CI 1.7 to 7.6, p<0.01) but similar OS (p=0.37). In the AML cohort, none of the exposures were associated with RFS.

Conclusion: In contrast to AML, antibiotic exposures in solid tumours affected clinical outcomes. The presence of an allogeneic effect (allo-HCT) or an augmented immune system (checkpoint blockade) may be necessary for microbiota mediation of relapse risk.
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http://dx.doi.org/10.1136/esmoopen-2020-000803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477978PMC
September 2020

Effects on time to lapse of switching menthol smokers to non-menthol cigarettes prior to a cessation attempt: a pilot study.

Tob Control 2020 Jul 27. Epub 2020 Jul 27.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

Introduction: Menthol smokers (particularly African-Americans) have lower cessation success rates than non-menthol smokers. With bans being considered on characterising menthol flavour in cigarettes, data are needed regarding how switching to non-menthol cigarettes impacts cessation measures.

Methods: In this randomised pilot study, African-American menthol cigarette smokers interested in quitting smoking either continued smoking menthol cigarettes (n=60) or switched to non-menthol cigarettes (n=62) for a 1-month period prior to a cessation attempt. The primary endpoint was time to smoking lapse (ie, time from quitting until any smoking). Additional endpoints included time to smoking relapse (ie, number of days from quitting until the first of seven consecutive smoking days) and difference between groups in subjective measures.

Results: After attempting to quit, the non-menthol cigarette group had indications of delayed time to lapse (HR 0.82; 95% CI 0.55 to 1.22; p=0.33) and time to relapse (HR 0.67; 95% CI 0.42 to 1.06; p=0.09), although these were not statistically significant. Post hoc analyses suggest that observed differences were largely due to a smaller proportion of participants in the non-menthol group relapsing within the first day of quitting (21% vs 40%; p=0.05). Values of other measures assessed postcessation were largely similar between groups.

Conclusions: These data suggest that among African-American smokers, a menthol cigarette ban would not undermine short-term cessation measures and may result in some benefits. Future research is needed to assess longer term cessation rates and to identify interventions to maximise cessation success in the event of a menthol ban.

Trial Registration Number: NCT02342327.
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http://dx.doi.org/10.1136/tobaccocontrol-2020-055689DOI Listing
July 2020

Correlation of MET and PD-L1 Expression in Malignant Melanoma.

Cancers (Basel) 2020 Jul 9;12(7). Epub 2020 Jul 9.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.

The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, programmed death-ligand 1 (PD-L1), with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions, and in a human melanoma tissue microarray containing one hundreds melanocytic lesions, including primary cutaneous melanomas, primary mucosal melanomas, metastatic melanomas and benign melanocytic nevi as controls. After color deconvolution, each core was segmented to isolate staining and calculate the percentage of positive cells. Overall, MET expression was higher in tumors with increased PD-L1 expression. Moreover, a robust correlation between MET and PD-L1 expression was found in samples from metastatic melanoma and not in primary cutaneous or mucosal melanoma. These data suggest that relative expression levels of these proteins in combination is a marker of advanced disease and testing for expression of these markers should be considered in patients with melanoma.
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http://dx.doi.org/10.3390/cancers12071847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408820PMC
July 2020

Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy.

Neurology 2020 08 2;95(5):e591-e600. Epub 2020 Jul 2.

From the Departments of Pediatrics (E.I.P., R.S.Z., W.P.M., A.O.G., T.C.L., P.J.O., J.B.E.), Radiology (D.R.N.), Bioinformatics and Biostatistics Core (R.S.), and Neurology (D.L.K.-J.), University of Minnesota, Minneapolis; and Sangamo Therapeutics (W.P.M.), Richmond, CA.

Objective: To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.

Methods: Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0-16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.

Results: Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.

Conclusion: To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.
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http://dx.doi.org/10.1212/WNL.0000000000009929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455349PMC
August 2020

Reduction of paediatric head CT utilisation at a rural general hospital emergency department.

BMJ Qual Saf 2020 11 28;29(11):912-920. Epub 2020 Feb 28.

Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

Background: Blunt head injury is a common pediatric injury and often evaluated in general emergency departments. It estimated that 50% of children will undergo a head computed tomography (CT), often unnecessarily exposing the child to ionizing radiation. Pediatric academic centers have shown quality improvement (QI) measures can reduce head CT rates within their emergency departments. We aimed to reduce head CT utilization at a rural community emergency department.

Methods: Children presenting with a complaint of blunt head injury and were evaluated with or without a head CT. Head CT rate was the primary outcome. We developed a series of interventions and presented these to the general emergency department over the duration of the study. The pre and intervention data was analysed with control charts.

Results: The preintervention and intervention groups consisted of 576 children: 237 patients with a median age of 8.0 years and 339 patients with a median age of 9.00 years (p=0.54), respectively. The preintervention HCT rate was 41.8% (95% CI 35.6% to 48.1%) and the postintervention rate was 27.7% (95% CI 23.3% to 32.7%), a decrease of 14.1% (95% CI 6.2% to 21.9%, p=0.0004). During the intervention period, there was a decrease in HCT rate of one per month (OR 0.96, 95% CI 0.92 to 1.00, p=0.07). The initial series of interventions demonstrated an incremental decrease in HCT rates corresponding with a special cause variation.

Conclusion: The series of interventions dispersed over the intervention period was an effective methodology and successfully reduced HCT utilisation among children with blunt head injury at a rural community emergency department.
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http://dx.doi.org/10.1136/bmjqs-2019-010322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684645PMC
November 2020

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

Int J Radiat Oncol Biol Phys 2020 06 19;107(2):334-343. Epub 2020 Feb 19.

Miami Cancer Institute, Miami, Florida.

Purpose: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.

Methods And Materials: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.

Results: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).

Conclusions: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276246PMC
June 2020

Development of a disease-specific graded prognostic assessment index for the management of sarcoma patients with brain metastases (Sarcoma-GPA).

BMC Cancer 2020 Feb 12;20(1):117. Epub 2020 Feb 12.

Gustave Roussy Cancer Campus, Villejuif, France.

Background: Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases.

Methods: We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index.

Results: The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status.

Conclusions: The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.
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http://dx.doi.org/10.1186/s12885-020-6548-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014599PMC
February 2020

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

Neuro Oncol 2020 09;22(9):1359-1367

Miami Cancer Institute, Miami, Florida, USA.

Background: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).

Methods: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.

Results: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).

Conclusions: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.

Key Points: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.
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http://dx.doi.org/10.1093/neuonc/noaa025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523450PMC
September 2020

Reduced-Toxicity (BuFlu) Conditioning Is Better Tolerated but Has a Higher Second Transplantation Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders.

Biol Blood Marrow Transplant 2020 03 18;26(3):486-492. Epub 2019 Nov 18.

Pediatric Blood and Marrow Transplant Program, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota.

Hematopoietic stem cell transplantation (HCT) is a primary treatment for various inherited metabolic disorders (IMDs). Achieving stable and sustained engraftment while minimizing transplantation-related morbidity and mortality is critical to optimizing outcomes for IMDs. Traditional regimens have used myeloablative approaches, primarily busulfan and cyclophosphamide (BuCy), which is associated with significant regimen-related toxicity. Alternatively, reduced-toxicity regimens, such as busulfan and fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplantation-related outcomes with BuCy-based and BuFlu-based conditioning in patients with IMDs. We retrospectively analyzed the University of Minnesota's transplantation database for patients with IMDs who underwent HCT using a BuCy (with alemtuzumab) or BuFlu (with antithymocyte globulin) preparative regimen between March 2008 and September 2017. Overall survival (OS), event-free survival (EFS), and incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis, and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure with and without autologous recovery. The incidence of viral infections post-transplantation in the 2 regimens was also determined. A total of 99 patients underwent HCT for IMDs during the study period. Sixty-four patients received BuCy conditioning, and the other 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were the most common IMDs, and umbilical cord blood was the most common graft source (74%). One-year OS was similar in the 2 groups (81.2% in BuCy versus 85.5% in BuFlu; P = .8), with an EFS of 75% versus 63%, respectively. The 2 groups also had similar incidences of grade III-IV acute GVHD (9% versus 6%; P = .5) and chronic GVHD (9% versus 7%; P = .67). Neutrophil and platelet recovery were similar in the 2 groups, with a significantly shorter duration of hospital stay noted in the BuFlu cohort (median, 21 days versus 34 days; P = .002). The cumulative incidence of graft failure was significantly higher in the BuFlu group (29% versus 14%; P = .08), as was the rate of second HCT (27% versus 3%; P = .001). The incidences of adenoviral infection (14% versus 0%; P = .02) and hemorrhagic cystitis (23% versus 3%; P = .01) were higher in the BuCy group. T cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post-transplantation, but donor myeloid engraftment was similar in the 2 groups. Our data indicate that reduced-toxicity conditioning is associated with lower rates of infection and other transplantation-related complications but is concerning for a higher rate of graft failure in patients with IMDs. Alternate immunosuppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.014DOI Listing
March 2020

Surveillance Imaging after Autologous Hematopoietic Cell Transplantation Predicts Survival in Patients with Diffuse Large B Cell Lymphoma.

Biol Blood Marrow Transplant 2020 02 24;26(2):272-277. Epub 2019 Oct 24.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, Minnesota, USA. Electronic address:

The utility of surveillance imaging after autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory diffuse large B cell lymphoma (DLBCL) remains unclear. The purpose of this study was to determine whether surveillance imaging predicts survival after AHCT. At the University of Minnesota, serial imaging for early relapse detection has been used prospectively for all consecutive AHCT recipients treated since 2010. The present analysis included 91 AHCT recipients with DLBCL who underwent F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) scan at day +100 post-AHCT. F-FDG-PET parameters included the Deauville (D) 5-point scale, peak standardized uptake values (SUV), total legion glycolysis (TLG), and total metabolic tumor volume (TMTV). Survival of patients with clinically symptomatic versus asymptomatic radiographically detected relapsed DLBCL after AHCT was compared. Sixty patients experienced relapse; 35% was detected on day +100 surveillance PET scan. 5-year overall survival (OS) by F-FDG-PET scan at day +100 post-AHCT was significantly lower in D4 and D5 patients (37%; 95% confidence interval [CI], 14% to 100% versus 25%; 95% CI, 43% to 89%) compared with patients with D1 and D2 (62%; 95% CI, 43% to 89% versus 62%; 95% CI, 46% to 84%). TLG and TMTV were not prognostic. SUV at day +100 varied from 1.5 (D1) to 17.9 (D5). In multivariate analysis, only SUV was predictive of relapse and OS; mortality increased 1.8-fold with each SUV doubling (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.3; P < .01). At a median follow-up of 3.3 years (range, 1 to 12 years), lymphoma-related mortality was 1.8-fold higher among patients whose relapse was detected clinically (symptomatic) versus radiographically on surveillance scan (HR, 1.8; 95% CI, .9 to 3.4; P = .08). In patients with relapsed/refractory DLBCL, a routine PET imaging at day +100 post-AHCT detects asymptomatic relapse and high SUV identifies patients with poor expected survival of less than 1 year. Identifying this high-risk cohort can potentially highlight patients who might benefit from preemptive interventions to prevent or delay relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.013DOI Listing
February 2020

Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes.

Sci Rep 2019 Oct 1;9(1):14105. Epub 2019 Oct 1.

University of Minnesota, Division of Pediatric Blood and Marrow Transplant, Minneapolis, 55455, USA.

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
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http://dx.doi.org/10.1038/s41598-019-50595-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773848PMC
October 2019

Emotional functioning among children with neurofibromatosis type 1 or Noonan syndrome.

Am J Med Genet A 2019 12 30;179(12):2433-2446. Epub 2019 Sep 30.

Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.

While neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are clinically distinct genetic syndromes, they have overlapping features because they are caused by pathogenic variants in genes encoding molecules within the Ras-mitogen-activated protein kinase signaling pathway. Increased risk for emotional and behavioral challenges has been reported in both children and adults with these syndromes. The current study examined parent-report and self-report measures of emotional functioning among children with NF1 and NS as compared to their unaffected siblings. Parents and children with NS (n = 39), NF1 (n = 39), and their siblings without a genetic condition (n = 32) completed well-validated clinical symptom rating scales. Results from parent questionnaires indicated greater symptomatology on scales measuring internalizing behaviors and symptoms of attention deficit hyperactivity disorder (ADHD) in both syndrome groups as compared with unaffected children. Frequency and severity of emotional and behavioral symptoms were remarkably similar across the two clinical groups. Symptoms of depression and anxiety were higher in children who were also rated as meeting symptom criteria for ADHD. While self-report ratings by children generally correlated with parent ratings, symptom severity was less pronounced. Among unaffected siblings, parent ratings indicated higher than expected levels of anxiety. Study findings may assist with guiding family-based interventions to address emotional challenges.
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http://dx.doi.org/10.1002/ajmg.a.61361DOI Listing
December 2019

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

Clin Transl Radiat Oncol 2019 Sep 27;18:39-45. Epub 2019 Jun 27.

Miami Cancer Institute, USA.

Background: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.

Methods: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.

Results: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).

Conclusions: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.
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http://dx.doi.org/10.1016/j.ctro.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612649PMC
September 2019

Haptoglobin genotype and gut barrier-related complications of allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2020 02 8;55(2):464-466. Epub 2019 May 8.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

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http://dx.doi.org/10.1038/s41409-019-0540-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933095PMC
February 2020

Red blood cell product utilization in patients undergoing allogeneic stem cell transplantation.

Transfusion 2019 07 8;59(7):2301-2307. Epub 2019 Apr 8.

Blood and Marrow Transplant Program, University of Minnesota Medical Center, Minneapolis, Minnesota.

Background: The risk of transfusion reactions (TR) and the cost of blood has led to efforts to reduce blood use. We changed our practice to transfuse just one instead of two units of red blood cells (RBC) when hemoglobin ≤8 g/dL due to patient blood management (PBM) recommendations.

Methods And Materials: We compared RBC utilization in patients receiving allogeneic HCT in the 10 months before (control arm) and 13 months after implementation of this new practice (intervention arm). We used regression models to estimate the independent effect of transfusion practice, length of hospitalization, the conditioning regimen, and donor type for patients who received at least one RBC unit. The outcome variable was total number of inpatient transfusions. In addition, a survey assessed the impact of this.

Results: Cohorts were matched for age, primary diagnosis, graft source, and conditioning regimen. The median number of RBC units transfused/patient was identical in both arms (4; interquartile range 19 units/patient). Using the regression model, only length of stay (relative increase of 1.035 units/day; 95%CI, 1.0271.043) was an independent predictor of the number of RBC units a patient received. When data were normalized/1000 patient days, the control arm received 240 units vs the intervention arm, which received 193 units, resulting in a reduction of 47 units transfused/1000-patient-days, which was not statistically significant (p-value = 0.32). The survey of RNs showed that it positively affected the workflow.

Conclusions: There was a modest reduction in RBC utilization based on units transfused/1000-patient-days. There was a positive impact on RN workflow.
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http://dx.doi.org/10.1111/trf.15285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713712PMC
July 2019

Survival and prognostic factors in patients with gastrointestinal cancers and brain metastases: have we made progress?

Transl Res 2019 06 27;208:63-72. Epub 2019 Feb 27.

Miami Cancer Institute.

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.
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http://dx.doi.org/10.1016/j.trsl.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527460PMC
June 2019

Mixed vs full donor engraftment early after hematopoietic cell transplant: Impact on incidence and control of cytomegalovirus infection.

Transpl Infect Dis 2019 Jun 29;21(3):e13070. Epub 2019 Mar 29.

Division of Hematology, Oncology and Transplantation, Department of Medicine, Program in Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Recovery of cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is essential in controlling CMV infection. We hypothesize that mixed donor engraftment as measured by chimerism at day 30 in CMV D(+) HCTs and full chimerism in CMV D(-) HCTs will be predictive of CMV reactivation. Prospectively collected data for 407 CMV R+ HCT recipients transplanted from 2006 to 2014 at the University of Minnesota were retrospectively analyzed. Full and mixed donor engraftment were defined as ≥95% or <95% donor cells at day 30, respectively. Source of engraftment determination included preferentially peripheral blood CD3 fraction, then myeloid cell fraction (CD15+), then bone marrow. In 407 CMV R+ subjects, 77% (n = 313) were CMV D(-) cells from umbilical cord blood (n = 209), peripheral blood (n = 58) or marrow (n = 46). Fifty three per cent received reduced intensity conditioning (RIC). At day +30, full donor engraftment was seen in 82% of myeloablative and 55% of RIC transplants. The cumulative incidence of CMV infection 1-year after transplant was not different in patients with full (54%, n = 276) or mixed (53%, n = 131) donor engraftment. Control of CMV did not significantly differ among the two groups. In multiple regression analysis, there was no significant association between donor engraftment (mixed or full) and incidence or control of CMV.
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http://dx.doi.org/10.1111/tid.13070DOI Listing
June 2019

Pretransplant Serum Citrulline Predicts Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2018 11 7;24(11):2190-2196. Epub 2018 Jul 7.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day -7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P < .05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P = .02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P < .001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251308PMC
November 2018

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Neuro Oncol 2018 11;20(12):1652-1660

Miami Cancer Institute, Department of Radiation Oncology, Miami, Florida.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.

Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.

Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.

Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.
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http://dx.doi.org/10.1093/neuonc/noy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231200PMC
November 2018

Analysis of BMT CTN-0201 and -0901 samples did not reproduce the reported association between recipient REG3A rs7588571 and chronic GVHD.

Bone Marrow Transplant 2019 03 31;54(3):490-493. Epub 2018 Aug 31.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

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http://dx.doi.org/10.1038/s41409-018-0331-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395530PMC
March 2019

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

Cancer Med 2018 09 16;7(9):4447-4455. Epub 2018 Aug 16.

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.

Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).

Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).

Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
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http://dx.doi.org/10.1002/cam4.1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144246PMC
September 2018

Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples.

Br J Haematol 2018 09 13;182(6):887-894. Epub 2018 Jul 13.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN-0201 and a SNP × conditioning intensity term in CTN-0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II-IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37-0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01-2·32, P = 0·05] in CTN-0201, but not CTN-0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function.
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http://dx.doi.org/10.1111/bjh.15492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128755PMC
September 2018

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

Int J Radiat Oncol Biol Phys 2018 07 12;101(4):845-853. Epub 2018 Apr 12.

Miami Cancer Institute, Miami, Florida.

Purpose: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).

Methods And Materials: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed.

Results: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes.

Conclusions: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925530PMC
July 2018

Social skills in children with RASopathies: a comparison of Noonan syndrome and neurofibromatosis type 1.

J Neurodev Disord 2018 06 18;10(1):21. Epub 2018 Jun 18.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota, Mayo Mail Code 484, 420 Delaware Street SE, Mayo Mail Code 486, Minneapolis, MN, 55455, USA.

Background: Gene mutations within the RAS-MAPK signaling cascade result in Noonan syndrome (NS), neurofibromatosis type 1 (NF1), and related disorders. Recent research has documented an increased risk for social difficulties and features of autism spectrum disorder (ASD) among children with these conditions. Despite this emerging evidence, the neuropsychological characteristics associated with social skills deficits are not well understood, particularly for children with NS.

Methods: Parents of children with NS (n = 39), NF1 (n = 39), and unaffected siblings (n = 32) between the ages of 8 and 16 years were administered well-validated caregiver questionnaires assessing their child's social skills, language abilities, attention-deficit hyperactivity disorder (ADHD) symptoms and anxiety.

Results: With respect to overall social skills, average ratings of children in both clinical groups were similar, and indicated weaker social skills compared to unaffected siblings. Although ratings of social skills were outside of normal limits for more than four in ten children within the clinical groups, most of the deficits were mild/moderate. Fifteen percent of the children with NS and 5% of the children with NF1 were rated as having severe social skills impairment (< - 2SD). Independent of diagnosis, having fewer ADHD symptoms or better social-pragmatic language skills was predictive of stronger social skills.

Conclusions: Amidst efforts to support social skill development among children and adolescents with RASopathies, neuropsychological correlates such as social language competence, attention, and behavioral self-regulation could be important targets of intervention.
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http://dx.doi.org/10.1186/s11689-018-9239-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006579PMC
June 2018