Cancer related cognitive impairment: a downside of cancer treatment.

Cancer treatment is associated with long lasting cognitive impairment in cancer survivors. This cognitive impairment is often termed cancer related cognitive impairment (CRCI). Cancer survivors treated for tumors outside the central nervous system are increasingly diagnosed with CRCI. The development of strategies to mitigate the negative effects of cancer treatment on the brain are crucial. Although neuroimaging research has proposed several candidate mechanisms, the pathogenic underpinnings of CRCI remain uncertain. As such, preventative and treatment strategies have not been identified. To fill these gaps, animal models play a vital role in isolating underlying contributing mechanisms that promote CRCI and in testing new therapeutic approaches.

The Distant Molecular Effects on the Brain by Cancer Treatment.

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Cancer treatment induces neuroinflammation and behavioral deficits in mice.

Introduction: Cancer survivors are increasingly diagnosed with a syndrome of neurocognitive dysfunction termed cancer-related cognitive impairment (CRCI). Chemotherapy and radiation therapy have been implicated in CRCI; however, its underlying pathogenesis remains unclear, hindering effective prevention or treatment. Methods: We used the hairless strain SKH1 (11-12-week-old) and treated the mice with radiation to the right hindlimb, doxorubicin (a chemotherapy agent), concurrent radiation, and doxorubicin, or no treatment (control). Neurocognition was evaluated via standardized behavioral testing following treatment. Mice were subsequently humanely euthanized, and plasma and brains were collected to identify inflammatory changes. Results: Mice treated with radiation, doxorubicin, or both radiation and doxorubicin demonstrated equivalent hippocampal dependent memory deficits and significant increases in activated microglia and astrocytes compared to control mice. Doxorubicin-treated mice had significantly increased plasma IL-6 and failed to gain weight compared to control mice over the study period. Discussion: This study demonstrates that non-brain directed radiation induces both gliosis and neurocognitive deficits. Moreover, this work presents the first characterization of SKH1 mice as a relevant and facile animal model of CRCI. This study provides a platform from which to build further studies to identify potential key targets that contribute to CRCI such that strategies can be developed to mitigate unintended neuropathologic consequences associated with anticancer treatment.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.

Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Methods: Retrospective chart review. Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.

Large-scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival.

BACKGROUND: African Americans (AAs) experience a disproportionally high rate of bladder cancer (BLCA) deaths even though their incidence rates are lower than those of other patient groups. Using a metabolomics approach, this study investigated how AA BLCA may differ molecularly from European Americans (EAs) BLCA, and it examined serum samples from patients with BLCA with the aim of identifying druggable metabolic pathways in AA patients. METHODS: Targeted metabolomics was applied to measure more than 300 metabolites in serum samples from 2 independent cohorts of EA and AA patients with BLCA and healthy EA and AA controls via liquid chromatography-mass spectrometry, and this was followed by the identification of altered metabolic pathways with a focus on AA BLCA. A subset of the differential metabolites was validated via absolute quantification with the Biocrates AbsoluteIDQ p180 kit. The clinical significance of the findings was further examined in The Cancer Genomic Atlas BLCA data set. RESULTS: Fifty-three metabolites, mainly related to amino acid, lipid, and nucleotide metabolism, were identified that showed significant differences in abundance between AA and EA BLCA. For example, the levels of taurine, glutamine, glutamate, aspartate, and serine were elevated in serum samples from AA patients versus EA patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as malic enzyme 3, prolyl 3-hydroxylase 2, and lysine demethylase 2A that predicted patient survival exclusively in AA patients with BLCA. CONCLUSIONS: This metabolic profile of serum samples might be used to assess risk progression in AA BLCA. These first-in-field findings describe metabolic alterations in AA BLCA and emphasize a potential biological basis for BLCA health disparities.

A Quality Improvement Initiative to Increase and Sustain Influenza Vaccination Rates in Pediatric Oncology and Stem Cell Transplant Patients.

INTRODUCTION: Influenza vaccination of pediatric oncology and stem cell transplant (SCT) patients is crucial due to high risk of complications. Achieving high vaccination rates to prevent illness is often limited by competing demands and intensive treatment. A quality improvement (QI) initiative beginning influenza season 2012-2013 aimed to achieve and sustain high vaccination rates in active patients > 6 months of age, receiving cancer therapy or SCT within 6 months before or at any time during the season, and > 100 days after allogeneic SCT. METHODS: We identified key drivers and barriers to success from an initially developed vaccination process that proved to be burdensome. Change ideas were implemented through multiple tests of change during the QI initiative. Iterations within and across 4 subsequent seasons included patient identification through chemotherapy orders, provider education, incorporating vaccination into routine work-flow, continuous data analysis and feedback, and use of new reporting technology. RESULTS: Initial vaccination rates were < 70%, increasing to 89% after the QI initiative began and subsequently sustained between 85% and 90%. Active patients were significantly more likely to be vaccinated during the initiative (odds ratio, 3.7; 95% CI, 2.9-4.6) as compared with the first 2 seasons. CONCLUSIONS: High influenza vaccination rates can be achieved and maintained in a pediatric oncology/SCT population using strategies that correctly identify patients at highest risk and minimize process burden.

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism.

There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor-mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

Synchronous occurrence of acute lymphoblastic leukemia and wilms tumor in two patients: underlying etiology and combined treatment plan.

Synchronous cancers are extraordinarily rare in pediatric patients and present a therapeutic challenge. Patient A presented with synchronous unilateral Wilms tumor (WT) and standard-risk (SR) B-precursor acute lymphoblastic leukemia (ALL). Genetic testing revealed bialleleic BRCA2/FANCD1 mutations. Patient B, after SR B-precursor ALL induction therapy, was noted on fever workup to have a renal mass; pathology demonstrated lesion indeterminate between WT and nephrogenic rest. Therapy was customized for each patient to treat both cancers. Both patients have ongoing remission from their cancers, without excessive toxicity. We report two regimens for treating synchronous WT and ALL and recommend screening such patients for cancer predisposition.

Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study.

Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted.

Myogenic tumors in nevoid Basal cell carcinoma syndrome.

In mice, activated Hedgehog (Hh) signaling induces tumors with myogenic differentiation. In humans, hyperactive Hh signaling due to germline PATCHED1 (PTCH1) mutations has been linked to nevoid basal cell carcinoma syndrome (NBCCS). We report an embryonal rhabdomyosarcoma in a 16-month-old girl with NBCCS and review the literature on myogenic neoplasms in NBCCS, including 8 fetal rhabdomyomas and 3 rhabdomyosarcomas. Of note, 3 population studies, including 255 individuals with NBCCS aged 4 months to 87 years, did not identify any myogenic tumors. Thus, myogenic tumors in NBCCS are rare and include both rhabdomyosarcomas and fetal rhabdomyomas.

Reversal of severe angioproliferative pulmonary arterial hypertension and right ventricular hypertrophy by combined phosphodiesterase-5 and endothelin receptor inhibition.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are treated with vasodilators, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylyl cyclase activators, and prostacyclin. Despite recent advances in pharmacotherapy for individuals with PAH, morbidity and mortality rates in this patient population remain unacceptably high. Here, we tested the hypothesis that combination therapy with two PAH drugs that target distinct biochemical pathways will provide superior efficacy relative to monotherapy in the rat SU5416 plus hypoxia (SU-Hx) model of severe angioproliferative PAH, which closely mimics the human condition. METHODS: Male Sprague Dawley rats were injected with a single dose of SU5416, which is a VEGF receptor antagonist, and exposed to hypobaric hypoxia for three weeks. Rats were subsequently housed at Denver altitude and treated daily with the PDE-5 inhibitor, tadalafil (TAD), the type A endothelin receptor (ETA) antagonist, ambrisentan (AMB), or a combination of TAD and AMB for four additional weeks. RESULTS: Monotherapy with TAD or AMB led to modest reductions in pulmonary arterial pressure (PAP) and right ventricular (RV) hypertrophy. In contrast, echocardiography and invasive hemodynamic measurements revealed that combined TAD/AMB nearly completely reversed pulmonary hemodynamic impairment, RV hypertrophy, and RV functional deficit in SU-Hx rats. Efficacy of TAD/AMB was associated with dramatic reductions in pulmonary vascular remodeling, including suppression of endothelial cell plexiform lesions, which are common in human PAH. CONCLUSIONS: Combined therapy with two vasodilators that are approved for the treatment of human PAH provides unprecedented efficacy in the rat SU-Hx preclinical model of severe, angioproliferative PAH.

Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic kidney disease-induced vascular calcification.

BACKGROUND: Cardiovascular diseases such as atherosclerosis and vascular calcification are a major cause of death in patients with chronic kidney disease (CKD). Recently, the long-awaited results of the Study of Heart and Renal Protection trial were reported. This large randomized clinical trial found that an extensive cholesterol-lowering therapy through the combination of simvastatin and ezetimibe significantly reduced cardiovascular diseases in a wide range of patients with CKD. However, the mechanism by which this cholesterol-lowering therapy reduces CKD-dependent vascular diseases remains elusive. The objective of the present study was to determine the contribution of the oxysterol-induced pro-apoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP) on the pathogenesis of CKD-dependent cardiovascular diseases through endoplasmic reticulum stress signaling. METHODS AND RESULTS: CKD increased levels of serum oxysterols such as 7-ketocholesterol in human patients and ApoE(-/-) mice. Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD-dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction. This therapy also reduced aortic endoplasmic reticulum stress induced by CKD. The short hairpin RNA-mediated knockdown of CHOP and activating transcription factor-4 in vascular smooth muscle cells attenuated oxysterol-induced mineralization, osteogenic differentiation, and endoplasmic reticulum stress. In addition, CHOP deficiency protected ApoE(-/-) mice from CKD-dependent vascular calcification, cardiac dysfunction, and vascular cell death. CONCLUSIONS: These data reveal that the cholesterol-lowering therapy of simvastatin plus ezetimibe attenuates CKD-dependent vascular diseases through a reduction of oxysterol-mediated endoplasmic reticulum stress. CHOP plays a crucial role in the pathogenesis of CKD-dependent vascular calcification.

Effects of neoadjuvant chemotherapy on hepatoblastoma: a morphologic and immunohistochemical study.

Neoadjuvant chemotherapy followed by resection has become the mainstay in the treatment of hepatoblastoma (HB). The changes after chemotherapy typically result in tumor necrosis and a fibrohistiocytic response. We have observed that treated HBs undergo additional morphologic changes that have not been described. Herein, we report a 15-year retrospective study of HBs in 22 children who received neoadjuvant chemotherapy according to the Children's Oncology Group protocols. The medical records, diagnostic imaging, and histopathology were reviewed. Besides treated HBs having characteristic necrosis and fibrohistiocytic response, two-thirds had areas of cytoarchitectural differentiation ("maturation") mimicking non-neoplastic liver, and a quarter had alterations mimicking hepatocellular carcinoma. Nuclear expression of beta-catenin and keratin profiles were useful in distinguishing residual tumor with "maturation" from non-neoplastic liver and therefore in the assessment of surgical margins. Statistical analysis revealed that larger pretreatment and posttreatment imaged tumor size, larger tumor size at pathologic examination, and vascular invasion were significant univariate predictors of metastatic disease, whereas pretreatment imaged tumor size and vascular invasion were also significant independent predictors (multivariate logistic regression analysis). Multifocality, greater posttreatment necrosis and hepatocellular carcinoma-like morphology were more often associated with metastatic disease, but did not reach statistical significance.