Isolated central nervous system relapse in two adolescents with primary mediastinal large B-cell lymphoma after treatment with R-DA-EPOCH.

The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal management of isolated central nervous system (CNS) relapse and role of CNS prophylaxis remains undefined. We present cases of two adolescents with PMBCL who developed isolated CNS relapses. While isolated CNS relapse may be managed with high-dose chemotherapy and autologous stem cell transplant with or without CNS radiotherapy, review of these cases and the literature highlight the need for further work to define risk factors for CNS relapse, and identify patients who may benefit from CNS prophylaxis.

A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

Acute total body ionizing gamma radiation induces long-term adverse effects and immediate changes in cardiac protein oxidative carbonylation in the rat.

Radiation-induced heart disease presents a significant challenge in the event of an accidental radiation exposure as well as to cancer patients who receive acute doses of irradiation as part of radiation therapy. We utilized the spontaneously hypertensive Wistar-Kyoto rat model, previously shown to demonstrate drug-induced cardiomyopathy, to evaluate the acute and long-term effects of sub-lethal total body gamma irradiation at two, four, and fifty-two weeks. We further examined irreversible oxidative protein carbonylation in the heart immediately following irradiation in the normotensive Wistar-Kyoto rat. Both males and females sustained weight loss and anemic conditions compared to untreated controls over a one-year period as reflected by reduced body weight and low red blood cell count. Increased inflammation was detected by elevated IL-6 serum levels selectively in males at four weeks. Serum cardiac troponin T and I analyses revealed signs of cardiomyopathy at earlier timepoints, but high variability was observed, especially at one year. Echocardiography at two weeks following 5.0Gy treatment revealed a significant decrease in cardiac output in females and a significant decrease in both diastolic and systolic volumes in males. Following 10.0Gy irradiation in the normotensive Wistar-Kyoto rat, the heart tissue showed an increase in total protein oxidative carbonylation accompanied by DNA damage indicated by an increase in γ-H2AX. Using proteomic analyses, we identified several novel proteins which showed a marked difference in carbonylation including those of mitochondrial origin and most notably, cardiac troponin T, one of the key proteins involved in cardiomyocyte contractility. Overall, we present findings of acute oxidative protein damage, DNA damage, cardiac troponin T carbonylation, and long-term cardiomyopathy in the irradiated animals.

Obesity and Risk for Second Malignant Neoplasms in Childhood Cancer Survivors: A Case-Control Study Utilizing the California Cancer Registry.

BACKGROUND: Obesity is a known modifiable risk factor associated with adverse outcomes in children with cancer. We sought to determine whether obesity during childhood cancer treatment increases risk for second malignant neoplasms (SMN). METHODS: In this case-control study, cases (with SMN) and controls (with a single-primary cancer) were selected from the California Cancer Registry who had primary cancer diagnosed <21 years treated at Children's Hospital Los Angeles between 1988 and 2014. Controls were matched 3:1 to cases at the registry level by clinical factors. Medical records were abstracted for cancer treatment exposures, cancer predisposition syndrome, body mass index (BMI), BMI Z-score, and BMI category at diagnosis and end of therapy (EOT). RESULTS: A total of 59 cases and 130 controls were included. Median age at primary cancer diagnosis was 6 years, 64.5% were male, median time from primary cancer to SMN was 7.5 years, and 31.7% were obese or overweight. In matched multivariable analyses, there were elevated but nonsignificant associations between SMN and higher BMI Z-score at diagnosis [OR 1.27 (0.99-1.63)] and higher BMI categories at diagnosis [adjusted OR (aOR) overweight, 1.25 (0.55-2.52); aOR obese, 2.51 (1.00-6.29)]. There was a significantly increased risk for SMN among patients who were obese at both diagnosis and EOT [aOR, 4.44 (1.37-14.34)]. CONCLUSIONS: This study suggests that obesity during childhood cancer treatment may be associated with increased risk for SMNs, particularly among those obese throughout therapy. IMPACT: Additional studies to confirm these findings and to develop interventions have the potential to impact SMN development in children with cancer.

Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats.

PURPOSE: Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs. METHODS: SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses. RESULTS: Dox significantly reduced tumor volume (±Drz) and increased heart weight in all genders (13-30% vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts. CONCLUSIONS: Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs.

Atg7- and Keap1-dependent autophagy protects breast cancer cell lines against mitoquinone-induced oxidative stress.

The interplay between oxidative stress and autophagy is critical for determining the fate of cancer cells exposed to redox-active and cytotoxic chemotherapeutic agents. Mitoquinone (MitoQ), a mitochondrially-targeted redox-active ubiquinone conjugate, selectively kills breast cancer cells over healthy mammary epithelial cells. We reported previously that MitoQ, although a derivative of the antioxidant ubiquinone, can generate excess ROS and trigger the Keap1-Nrf2 antioxidant response in the MDA-MB-231 cell line. Following MitoQ treatment, a greater number of cells underwent autophagy than apoptosis. However, the relationship between MitoQ-induced oxidative stress and autophagy as a primary cellular response was unclear. In this report, we demonstrate that MitoQ induces autophagy related gene 7 (Atg7)-dependent, yet Beclin-1-independent, autophagy marked by an increase in LC3-II. Both the ATG7-deficient human MDA-MB-231 cells and Atg7-knockout mouse embryonic fibroblasts exhibited lower levels of autophagy following MitoQ treatment than their respective wild-type counterparts. Increased apoptosis was confirmed in these autophagy-deficient isogenic cell line pairs, indicating that autophagy was attempted for survival in wild type cell lines. Furthermore, we observed higher levels of ROS in Atg7-deficient cells, as measured by hydroethidine oxidation. In Atg7-deficient cells, redox-sensitive Keap1 degradation was decreased, suggesting autophagy- and Atg7-dependent degradation of Keap1. Conversely, downregulation of Keap1 decreased autophagy levels, increased Nrf2 activation, upregulated cytoprotective antioxidant gene expression, and caused accumulation of p62, suggesting a feedback loop between ROS-regulated Keap1-Nrf2 and Atg7-regulated autophagy. Our data indicate that excessive ROS causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response triggered by cytotoxic levels of MitoQ.