Small-Molecule Integrated Stress Response Inhibitor Reduces Susceptibility to Postinfarct Atrial Fibrillation in Rats via the Inhibition of Integrated Stress Responses.

Phosphorylation of the eukaryotic translation initiation factor 2 α-subunit, which subsequently upregulates activating transcription factor 4 (ATF4), is the core event in the integrated stress response (ISR) pathway. Previous studies indicate phosphorylation of eukaryotic translation initiation factor 2 ɑ-subunit in atrial tissue in response to atrial fibrillation (AF). This study investigated the role of ISR pathway in experimental AF by using a small-molecule ISR inhibitor (ISRIB). Accordingly, rats were subjected to coronary artery occlusion to induce myocardial infarction (MI), or sham operation, and received either trans-ISRIB (2 mg/kg/d, i.p.) or vehicle for seven days. Thereafter, animals were subjected to the AF inducibility test by transesophageal rapid burst pacing followed by procurement of left atrium (LA) for assessment of atrial fibrosis, inflammatory indices, autophagy-related proteins, ISR activation, ion channel, and connexin 43 expression. Results showed a significant increase in the AF vulnerability and the activation of ISR in LA as evidenced by enhanced eukaryotic translation initiation factor 2 ɑ-subunit phosphorylation. ISRIB treatment suppressed upregulation of ATF4, fibrosis as indexed by determination of α-smooth muscle actin and collagen levels, inflammatory macrophage infiltration (i.e., CD68 and inducible nitric oxide synthase/CD68-positive macrophage), and autophagy as determined by expression of light chain 3. Further, ISRIB treatment reversed the expression of relevant ion channel (i.e., the voltage-gated sodium channel 1.5 , L-type voltage-dependent calcium channel 1.2, and voltage-activated A-type potassium ion channel 4.3) and connexin 43 remodeling. Collectively, the results suggest that the ISR is a key pathway in pathogenesis of AF, post-MI, and represents a novel target for treatment of AF. SIGNIFICANCE STATEMENT: The activation of integrated stress response (ISR) pathway as evidenced by enhanced eukaryotic translation initiation factor 2 ɑ-subunit phosphorylation in left atrium plays a key role in atrial fibrillation (AF). ISR inhibitor (ISRIB) reduces AF occurrence and atrial proarrhythmogenic substrate. The beneficial action of ISRIB may be mediated by suppressing ISR pathway-related cardiac fibrosis, inflammatory macrophage infiltration, autophagy, and restoring the expression of ion channel and connexin 43. This study suggests a key dysfunctional role for ISR in pathogenesis of AF with implications for novel treatment.

Angiogenin regulates epithelial-mesenchymal transition of hepatocellular carcinoma through upregulation of HMGA2.

Angiogenin (ANG) is known to alter multiple cell behaviors by directly targeting downstream targets, but its role in hepatocellular carcinoma (HCC) remains to be elucidated. The expression of ANG in HCC cell lines was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The effects of ANG expression on cell proliferation, cell migration, and hallmarks of epithelial-mesenchymal transition (EMT) process were also investigated. The relationship between ANG and high mobility group AT-hook 2 (HMGA2) was evaluated. ANG expression was increased in HCC cell lines. Downregulating of ANG inhibits proliferation, migration, and EMT of HCC cells. The direct regulation of ANG on HMGA2 was verified by luciferase activity reporter assay and western blot assay. Furthermore, overexpression of HMGA2 reversed the inhibitory effects of ANG downregulation on HCC cell behaviors. Our results illustrated the mechanism that ANG promote the EMT of HCC through targeting HMGA2.

Lipid disorder and intrahepatic renin-angiotensin system activation synergistically contribute to non-alcoholic fatty liver disease.

BACKGROUND: This study aimed to investigate the possible synergistic effects of lipid disorder with renin-angiotensin system (RAS) activation in non-alcoholic fatty liver disease (NAFLD). METHODS: Apolipoprotein E gene-knockout mice, angiotensin II (Ang II) type 1 receptor (AT1) gene-knockout mice and human hepatoblastoma cell line (HepG2) were used for experiments. Lipid accumulation was examined by Filipin staining and intracellular cholesterol quantitative assay. The gene and protein expression of molecules involved in RAS and low-density lipoprotein receptor (LDLr) pathway was examined by real-time PCR, immunofluorescent staining and Western blot. RESULTS: There was significantly increased expression of RAS components and extracellular matrix (ECM) in livers of high-fat-diet-fed apolipoprotein E gene-knockout mice compared with controls. Upregulation of RAS components was positively associated with increased plasma levels of lipid profile. The in vitro study further confirmed that cholesterol loading increased supernatant renin activity and Ang II level of HepG2 cells, accompanied by increased ECM production that was positively associated with increased expression of intracellular RAS components. Interestingly, Ang II treatment increased lipid accumulation in livers of C57BL/6 mice and HepG2 cells. Furthermore, Ang II treatment increased gene and protein expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), SREBP-2 and LDLr, which were mediated by enhanced SCAP/SREBP-2 complex translocation from endoplasmic reticulum to Golgi. However, LDLr pathway was accordingly downregulated in livers of AT1 gene-knockout C57BL/6 mice or in HepG2 cells treated by telmisartan. CONCLUSION: These findings demonstrate that lipid disorder and intrahepatic RAS activation synergistically accelerate NAFLD progression.

Mushrooms Adapted to Seawater: Two New Species of Candolleomyces (Basidiomycota, Agaricales) from China.

Marine fungi have been studied for a long history in many realms, but there are few reports on marine mushrooms. In this study, marine fungi with conspicuous subglobose sequestrate basidioma were discovered from mangrove forests in South China. They grow on the deadwood of mangroves in the intertidal zone, periodically submerging into seawater due to the tide. Some marine animals were observed to nest in their basidiomata or consume them as food. The pileus-gleba-inner veil complex (PGI) of the basidioma was observed to be detached from the stipe and transferred into seawater by external forces, and drifting on sea to spread spores after maturity. The detachment mechanism of their PGIs was revealed through detailed microscopic observations. The contrast culturing experiment using freshwater and seawater potato dextrose agar media showed they have probably obligately adapted to the marine environment. Based on morphological and molecular phylogenetic evidence, two new species of Candolleomyces (Basidiomycota, Agaricales), namely C. brunneovagabundus and C. albovagabundus, were described. They are similar and close to each other, but can be distinguished by the size and color of the basidioma, and the size of the basidiospores.

Risk assessment and analysis of Traditional Chinese Medicine intervention in coronavirus disease.

OBJECTIVE: To explore the advantages of Traditional Chinese Medicine (TCM) in "prevention" and "control" of coronavirus disease 2019 (COVID-19) pandemic. METHODS: In this paper, we wish to estimate the effect on the virus transmission of scenarios assuming TCM were used to build the first defense line at the very early stage of the spread in Wuhan. We therefore first developed a classic susceptible infected removed (susceptible infected removed, SIR) transmission model based on the national data in China and then updated it to a TCM-SIR model to assess the potential impact of such assumptions, i.e. the underlying risk of lives lost and social economy loss. RESULTS: (a) With the nationwide community lockdown, the risk value was from 90 000 to 250 000 without TCM intervention and the risk value was from 70 000 to 220 000 with TCM intervention; (b) Based the risk assessment method, we forecasted that the infections peak would be 58016 without TCM intervention, which happened on February 17 2020. However, the infections peak would be 45713 with TCM intervention, which happened on 16 February 2020. CONCLUSIONS: The adoption of nationwide community lockdown is conducive to timely control the epidemic and protect people's lives and safety. At the same time, we can get lower infections if TCM intervention can be considered. We can also get the benefits from TCM prevention of COVID-19 pandemic by the basic number of infections.

Emerging Issues Questioning the Current Treatment Strategies for Lumbar Disc Herniation.

Lumbar disc herniation is among the common phenotypes of degenerative lumbar spine diseases, significantly affecting patients' quality of life. The practice pattern is diverse. Choosing conservative measures or surgical treatments is still controversial in some areas. For those who have failed conservative treatment, surgery with or without instrumentation is recommended, causing significant expenditures and frustrating complications, that should not be ignored. In the article, we performed a literature review and summarized the evidence by subheadings to unravel the cons of surgical intervention for lumbar disc herniation. There are tetrad critical issues about surgical treatment of lumbar disc herniation, i.e., favorable natural history, insufficient evidence in a recommendation of fusion surgery for patients, metallosis, and implant removal. Firstly, accumulating evidence reveals immune privilege and auto-immunity hallmarks of human lumbar discs within the closed niche. Progenitor cells within human discs further expand the capacity with the endogenous repair. Clinical watchful follow-up studies with repeated diagnostic imaging reveal spontaneous resolution for lumbar disc herniation, even calcified tissues. Secondly, emerging evidence indicates long-term complications of lumbar fusion, such as adjacent segment disease, pseudarthrosis, implant failure, and sagittal spinal imbalance, which get increasing attention. Thirdly, systemic and local reactions (metallosis) for metal instrumentation have been noted with long-term health concerns and toxicity. Fourthly, the indications and timing for spinal implant removal have not reached a consensus. Other challenging issues include postoperative lumbar stiffness. The review provided evidence from a negative perspective for surgeons and patients who attempt to choose surgical treatment. Collectively, the emerging underlying evidence questions the benefits of traditional surgery for patients with lumbar disc herniation. Therefore, the long-term effects of surgery should be closely observed. Surgical decisions should be made prudently for each patient.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.

BACKGROUND: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. PATIENTS AND METHODS: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. RESULTS: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. CONCLUSIONS: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Sirolimus inhibits endogenous cholesterol synthesis induced by inflammatory stress in human vascular smooth muscle cells.

Inflammatory stress accelerates the progression of atherosclerosis. Sirolimus, a new immunosuppressive agent, has been shown to have pleiotropic antiatherosclerotic effects. In this study we hypothesized that sirolimus inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR)-mediated cholesterol synthesis in human vascular smooth muscle cells (VSMCs) under inflammatory stress. Using radioactive assay, we demonstrated that sirolimus inhibited the increase of interleukin-1beta (IL-1beta)-induced cholesterol synthesis in VSMCs. Further studies showed that sirolimus inhibited both the HMGR gene and protein expression in VSMCs treated with or without IL-1beta. These effects were mediated by inhibiting the gene expression of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP-2 cleavage-activating protein (SCAP) as checked by real-time PCR, Western blot analysis, and confocal microscopy for the observation of decreased protein translocation of the SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Insulin-induced gene-1 (Insig-1) is a key ER protein controlling the feedback regulation of HMGR at transcriptional and posttranscriptional levels. We demonstrated that sirolimus increased Insig-1 expression which may bind to the SCAP, preventing the exit of SCAP-SREBP complexes from the ER. The increased Insig-1 also accelerated HMGR protein degradation in VSMCs as shown by pulse-chase analysis. In conclusion, sirolimus inhibits cholesterol synthesis induced by inflammatory stress through the downregulation of HMGR expression and the acceleration of HMGR protein degradation. These findings may improve our understanding of the molecular mechanisms of the antiatherosclerosis properties of sirolimus.

Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice.

UNLABELLED: The prevailing theory in non-alcoholic fatty liver disease (NAFLD) is the "two-hit" hypothesis. The first hit mainly consists of lipid accumulation, and the second is subsequent systemic inflammation. The current study was undertaken to investigate whether inflammatory stress exacerbates lipid accumulation in liver and its underlying mechanisms. We used interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulation in human hepatoblastoma cell line (HepG2) cells and primary hepatocytes in vitro, and casein injection in apolipoprotein E knockout mice in vivo to induce inflammatory stress. The effects of inflammatory stress on cholesterol accumulation were examined by histochemical staining and a quantitative intracellular cholesterol assay. The gene and protein expressions of molecules involved in cholesterol trafficking were examined by real-time polymerase chain reaction (PCR) and western blot. Cytokine production in the plasma of apolipoprotein E knockout mice was measured by enzyme-linked immunosorbent assay. Our results showed that inflammatory stress increased cholesterol accumulation in hepatic cells and in the livers of apolipoprotein E knockout mice. Further analysis showed that inflammatory stress increased the expression of low-density lipoprotein (LDL) receptor (LDLr), sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), and SREBP-2. Confocal microscopy showed that IL-1beta increased the translocation of SCAP/SREBP-2 complex from endoplasmic reticulum (ER) to Golgi in HepG2 cells, thereby activating LDLr gene transcription. IL-1beta, TNF-alpha, and systemic inflammation induced by casein injection also inhibited expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and liver X receptor-alpha (LXRalpha). This inhibitory effect may cause cholesterol efflux reduction. CONCLUSION: Inflammatory stress up-regulates LDLr-mediated cholesterol influx and down-regulates ABCA1-mediated cholesterol efflux in vivo and in vitro. This may exacerbate the progression of NAFLD by disrupting cholesterol trafficking control, especially during the second hit phase of liver damage.

Sirolimus modifies cholesterol homeostasis in hepatic cells: a potential molecular mechanism for sirolimus-associated dyslipidemia.

BACKGROUND: Sirolimus is a potent immunosuppressive agent, which is associated with dyslipidemia in clinical transplantation. The present study was undertaken to investigate the potential hepatocyte mechanisms by which sirolimus causes dyslipidemia. METHODS: Using both a quantitative assay of intracellular cholesterol and an [3H]-labeled cholesterol efflux assay, we studied the effect of sirolimus on cholesterol accumulation and cholesterol efflux in HepG2 cells in the absence or presence of inflammatory stress induced by interleukin-1beta. The gene and protein expression of molecules involved in cholesterol homeostasis were examined by real-time reverse-transcription polymerase chain reaction and Western blotting. RESULTS: Sirolimus inhibited low-density lipoprotein (LDL) receptor (LDLr)-mediated cholesterol ester accumulation induced by interleukin-1beta in HepG2 cells. This inhibitory effect was mediated by down-regulation of sterol regulatory element-binding proteins (SREBP) cleavage activating protein (SCAP) and SREBP-2 mRNA expression. Using confocal microscopy, we demonstrated that sirolimus reduced translocation of SCAP-SREBP2 complex from endoplasmic reticulum to Golgi for activation, thereby inhibiting LDLr gene transcription. Reduction of LDLr in the liver may result in a delay of LDL-cholesterol clearance from circulation causing an increase of plasma cholesterol concentration. Furthermore, sirolimus increased cholesterol efflux mediated by adenosine triphosphate-binding cassette transporter A1 gene expression by increasing peroxisome proliferator-activated receptor-alpha and liver X receptor-alpha gene and protein expression. Increased cholesterol efflux from HepG2 cells may increase high-density lipoprotein cholesterol level and also contribute to apolipoprotein B lipoprotein formation by enhancing transfer of high-density lipoprotein cholesterol to apolipoprotein B lipoproteins. CONCLUSIONS: This study demonstrates that the increase of LDL cholesterol by sirolimus is partly due to the reduction of LDLr on hepatocytes.

The Neuroimaging Center of the Pediatric Brain Tumor Consortium-collaborative neuroimaging in pediatric brain tumor research: a work in progress.

As an essential part of the National Cancer Institute (NCI)-funded Pediatric Brain Tumor Consortium (PBTC), the Neuroimaging Center (NIC) is dedicated to infusing the study of pediatric brain tumors with imaging "best practice" by producing a correlative research plan that 1) resonates with novel therapeutic interventions being developed by the wider PBTC, 2) ensures that every PBTC protocol incorporates an imaging "end point" among its objectives, 3) promotes the widespread implementation of standardized technical protocols for neuroimaging, and 4) facilitates a quality assurance program that complies with the highest standards for image data transfer, diagnostic image quality, and data integrity. To accomplish these specific objectives, the NIC works with the various PBTC sites (10 in all, plus NCI/ National Institute of Neurological Diseases and Stroke representation) to ensure that the overarching mission of the consortium--to better understand tumor biology and develop new therapies for central nervous system tumors in children--is furthered by creating a uniform body of imaging techniques, technical protocols, and standards. Since the inception of the NIC in 2003, this broader mandate has been largely accomplished through a series of site visits and meetings aimed at assessing prevailing neuroimaging practices against NIC-recommended protocols, techniques, and strategies for achieving superior image quality and executing the secure transfer of data to the central PBTC. These ongoing evaluations periodically examine investigations into targeted drug therapies. In the future, the NIC will concentrate its efforts on improving image analysis for MR imaging and positron-emission tomography (PET) and on developing new ligands for PET; imaging markers for radiation therapy; and novel systemic, intrathecal, and intralesional therapeutic interventions.

Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines.

OBJECTIVE: Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation. METHODS AND RESULTS: IL-1beta enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1beta, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1beta enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1beta also caused overexpression of the sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression. CONCLUSIONS: These observations demonstrate that IL-1beta disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein.

Isolation of novel HLA-DR restricted potential tumor-associated antigens from the melanoma cell line FM3.

Endogenous peptides bound to the constitutively expressed MHC class II molecules HLA-DR and HLA-DQ of the melanoma cell line FM3 were examined. By a combination of analytical methods (narrow bore and capillary reversed-phase high-performance liquid chromatography with subsequent spotting on polyvinylidene difluoride membranes, matrix-assisted laser desorption ionization mass spectrometry, and Edman microsequencing), we were able to isolate and identify a panel of HLA-DR4/2 (HLA-DRB1*0401/0201/DRB5*0101)-associated self-peptides from the melanoma cell line FM3. Among ubiquitously HLA-DR-associated peptides such as peptides from the class II-associated invariant chain peptide region of the invariant chain, HLA-class I, the transferrin receptor, and the IFN-gamma receptor, we identified several potential tumor-associated antigens stemming from the MHC class I-restricted tumor antigen gp100, the Ca2(+)-binding protein annexin II, and proteins from the hsp70 family. Chinese hamster ovary cells cotransfected with HLA-DRA, DRB1*0401, and CD80 genes were shown specifically to prime T lymphocytes from HLA-DRB1*0401 donors to the annexin II and gp100 peptides. These results demonstrate that MHC class II molecules expressed by melanoma cells potentially present a variety of novel antigens to the immune system, some of which could be exploited for immunotherapy.

Development and characterization of human ependymoma xenograft HxBr5.

We describe the successful heterotransplantation of a human ependymoma in CBA/CaJ mice immune deprived by infant thymectomy and whole-body irradiation. The xenograft, HxBr5, was established from a fourth ventricular ependymoma, locally recurrent in an 11-yr-old girl who had been treated with radiation therapy to the posterior fossa. HxBr5 retains histological and ultrastructural fidelity to the tumor from which it was derived as does the DNA content, as confirmed by flow cytometric analysis. The karyotype of the xenograft, which is pseudodiploid and exhibits trisomy 1q and deletion of 1p, is the first human ependymoma banded karyotype to be reported. Growth rates of the xenograft tumors are similar to the primary tumor as clinically observed with a doubling time of approximately 42 days. Cell kinetic parameters indicate that this slow-growing tumor has a relatively high growth fraction of 70.8% with a high cell loss of approximately 91%. We anticipate that HxBr5 may be useful as one component of a more complex model for studying the biology and differentiation of human ependymoma.

Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate.

The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same wether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.

Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization.

We analyzed 27 samples of primary medulloblastoma, using comparative genomic hybridization and a novel statistical approach to evaluate chromosomal regions for significant gain or loss of genomic DNA. An array of nonrandom changes was found in most samples. Two discrete regions of high-level DNA amplification of chromosome bands 5p15.3 and 11q22.3 were observed in 3 of 27 tumors. Nonrandom genomic losses were most frequent in regions on chromosomes 10q (41% of samples), 11 (41%), 16q (37%), 17p (37%), and 8p (33%). Regions of DNA gain most often involved chromosomes 17q (48%) and 7 (44%). These findings suggest a greater degree of genomic imbalance in medulloblastoma than has been recognized previously and highlight chromosomal loci likely to contain oncogenes or tumor suppressor genes that may contribute to the molecular pathogenesis of this tumor.

Metastatic Ewing's sarcoma: remission induction and survival.

Eighteen patients with previously untreated metastatic Ewing's sarcoma (ES) entered a protocol designed to evaluate the response rate to cyclophosphamide and doxorubicin induction therapy delivered before delayed surgery and delayed lower dose, limited-field radiation therapy, (RT), and maintenance chemotherapy. With chemotherapy and delayed surgery, 14 of 18 were rendered free of gross tumor. RT was delivered to the primary site of 11 of these responding patients, plus four of those not free of gross disease. Following RT, two more attained complete clinical remission. Site of primary or metastases did not influence outcome; however, the size of the primary at diagnosis did appear to do so. Ten patients remain disease-free 16 to 82 months (median, 47 months) from diagnosis.

Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy.

In an effort to reduce the severity of late neurotoxicities associated with cranial irradiation, 14 infants and young children with malignant brain tumors were given preirradiation chemotherapy for 2 to 22 months (median, 8 months). Prospective neurodevelopmental evaluations were routinely conducted and now extend from 35 to 60 months (median, 41 months) postdiagnosis, and 10 to 52 months (median, 31 months) postirradiation in the 12 surviving children. At the initiation of chemotherapy, less than one fourth of the patients displayed normal performance status or mental functioning on age-corrected tests; the majority remained stable or declined while receiving chemotherapy. Declining mental development and adaptive behavior were noted in six patients following radiation therapy with only two patients now functioning in the normal range for age. The analysis suggests that neurodevelopmental progress is a function of multiple factors, including neurologic and sensorimotor deficits associated with the tumor, surgical intervention, and chemotherapy that antedated radiation therapy. This implies that delaying irradiation will not necessarily improve the patients' functional status. Whether the interval of postponement of irradiation evidenced in this sample will translate into an ultimately better quality of life remains unknown. Given the probable interaction of multiple risk factors, well-controlled prospective clinical trials are needed to definitively analyze this issue.

Long-term survivors of leukemia treated in infancy: factors associated with neuropsychologic status.

PURPOSE: Because of concerns about late toxicities of treatment among infants diagnosed with acute lymphoblastic leukemia (ALL), and especially the effects of cranial radiation therapy (CRT), we compared the functional and neuropsychologic status of 26 long-term survivors of ALL who were diagnosed in the first 24 months of life versus 26 children who were treated previously for Wilms' tumor. PATIENTS AND METHODS: Of the children with ALL, CNS prophylaxis included no CRT in six, 18 Gy CRT in five, 20 Gy CRT in seven, and 24 Gy CRT in five. Three additional children experienced CNS relapse and received total CRT doses of 24, 40, and 44 Gy. All children received neuropsychologic testing; children with ALL also participated in diagnostic imaging studies. RESULTS: As a group, the children who were treated for ALL did not differ significantly from those who were treated for Wilms' tumor on objective measures of global functional status. However, children treated for ALL had a significantly lower mean intelligence quotient (IQ) (87 v 96), poorer performance on four of six measures of visual and auditory memory, lower achievement with regard to arithmetic skills, and a greater frequency of special educational intervention than those who were treated for Wilms' tumor. IQ and auditory memory performance in the ALL group was correlated inversely with time since the completion of therapy and total CRT dose. CONCLUSIONS: These results reinforce the contemporary trend of prophylactic CRT omission in very young children except for those who are at risk for CNS relapse. For infants and very young children who require CRT, evidence is presented that supports the approach for the delay of CRT until the child is older.

Silent lacunar lesions detected by magnetic resonance imaging of children with brain tumors: a late sequela of therapy.

BACKGROUND: Cerebral lacunes, which generally appear on magnetic resonance imaging as foci of white matter loss, usually occur in adults after ischemic infarcts. We report the development of lacunes in children after therapy for brain tumors. PATIENTS AND METHODS: We reviewed the clinical characteristics and radiologic studies of 524 consecutive children with brain tumors treated over a 10-year period. We documented the neuropsychologic findings associated with lacunes and the factors predictive of lacunar development. RESULTS: Lacunes developed in none of the 103 patients observed or treated with surgery alone. Twenty-five of the 421 patients treated with chemotherapy or radiation therapy or both had lacunes. Patients were a median of 4.5 years old at the time of both diagnosis (range, 0.3 to 19.8 years) and radiotherapy (range, 1.5 to 20 years). Fourteen patients were treated with craniospinal irradiation, and 11 were treated with local radiotherapy. The median time from radiotherapy to the appearance of lacunes was 2.01 years (range, 0.26 to 5.7 years). For all patients, lacunes were an incidental finding with no corresponding clinical deficits. The factor most predictive of lacunar development was age less than 5 years at the time of radiotherapy (P =.010). There was no significant difference in estimated decline in intelligence quotient scores between patients with lacunes and age and diagnosis-matched controls. CONCLUSION: Lacunes may be caused by therapy-induced vasculopathy in children with brain tumors, with the most significant predictor being age less than 5 years at the time of radiotherapy.