Molecular docking targeting autophagy pathway mediate abrogation of NASH by specific functional foods: update review.

Autophagy is a very well-conserved self-digestive mechanism that transports unwanted or disposable cytoplasmic debris to lysosomes for destruction, including misfolded proteins and damaged organelles. Advanced liver illnesses can develop from the prevalent clinical condition known as non-alcoholic steatohepatitis (NASH). There is no effective treatment, is still unclear. Therefore, in order to create novel therapeutics, it is necessary to comprehend the pathogenic pathways causing disease onset and progression. Natural components from medicinal plants are currently the subject of a larger number of studies since they provide fresh promise for NASH. This review provided an overview of the aetiology of NASH, in addition the role of natural products as alternative or complementary therapeutic agent for management of NASH via autophagy induction. It was concluded that, alternative and complementary supplement of natural functional food as Arabica coffee that rich with chlorogenic acid targeting autophagy mechanism mediate amelioration effect of NASH.

Endostatin and Cystatin C as Potential Biomarkers for Early Prediction of Preeclampsia.

Preeclampsia (PE) is characterized by new onset hypertension and proteinuria. Undoubtedly, some individuals do not fit precisely into this description, and it could be challenging to spot newly developed PE in females who already have hypertension or renal illness. Monitoring the disease's progression enables the optimization of delivery time while minimizing premature births. The current study explores the diagnostic benefits of serum endostatin and cystatin C in addition to serum and urinary magnesium (Mg) and fractional excretion magnesium (FEMg) for early prediction of PE. The population sample included 82 pregnant women divided into 3 groups: normal pregnancy group served as a control (n = 26), nonpreeclampsia (NPE, n = 34) group included pregnant women with one or more risk factors but did not progress to PE, and pregnant women who developed preeclampsia (PE, n = 22) group. Blood samples were withdrawn at two sampling times: at 12th to 16th and 24th to 26th weeks of gestation. Compared to normal pregnancy, results (X̅ ± SD) indicated a significant increase in serum endostatin in NPE at the first sample (10.78 ± 3.63 ng/mL) and the second sample (28.03 ± 3.79 ng/mL), while cystatin C was at the first sample (0.68 ± 0.06 mg/dL) and the second sample (0.71 ± 0.07 mg/dL). In the PE group, the serum endostatin was 18.86 ± 4.37 ng/mL at the first sampling time and 53.56 ± 9.76 ng/mL for the second sample. Serum cystatin C was also elevated in PE with X̅ ± SD equivalent to 0.73 ± 0.08 and 0.89 ± 0.08 mg/dL at the first and second samples, respectively. On the other hand, serum and urinary Mg in addition to FEMg levels did not significantly differ across the groups under study. Receiver operating characteristic (ROC) curve analysis proved that both endostatin and cystatin C could be good indicators for PE. The findings imply that measuring endostatin and cystatin C at early pregnancy and before progression to PE may be effective in detecting the likelihood of PE. Endostatin could be more precise and sensitive in assessing the probability of PE than cystatin C; however, coupling of the two parameters may be promising.

Evaluation of miRNA-7, miRNA-10 and miRNA-21 as diagnostic non-invasive biomarkers of hepatocellular carcinoma.

Aim of the study: Liver cancer (hepatocellular carcinoma - HCC) remains a serious health challenge; it is the fourth leading cause of death worldwide. Egypt ranks fifteenth worldwide and the third in Africa in terms of HCC burden. The present study aimed to assess some microRNAs (miRNAs) including miRNA-7, miRNA-10, and miRNA-21, serum markers such as cluster of differentiation-14 (CD-14) and transforming growth factor b1 (TGF-b1), and other biochemical parameters as non-invasive tools for HCC diagnosis. Material and methods: The study included 100 participants divided into five groups: group I (20 normal subjects as a healthy group), group II (20 participants with chronic HCV infection but non-cirrhotic), group III (20 volunteers with chronic HCV infection and compensated cirrhosis), group IV (20 patients with chronic HCV infection and decompensated cirrhosis), and group V (20 participants with HCC). Levels of miR-7, miR-10, and miR-21 were evaluated using qRT-PCR. Serum ALT, AST, total bilirubin, total protein, albumin, PT, INR, and platelet count were determined. FIB-4 and APRI test levels were also calculated. CD-14 and TGF-ß1 serum levels were estimated using enzyme-linked immunosorbent assay (ELISA) kits. Results: The expression levels of miR-21 followed by miR-10 showed high sensitivity and specificity in predicting HCC. Serum CD-14 and TGF-b1 levels were significantly increased in all patient groups. Conclusions: From the study, it is concluded that the expression level of miR-21 has the highest sensitivity and specificity, followed by miR-10, which has high sensitivity and low specificity as non-invasive markers for HCC detection, while miR-7 exhibits high sensitivity and reasonable specificity in fibrosis detection.

Pomegranate Peel Extract Sensitizes Hepatocellular Carcinoma Cells to Ionizing Radiation, Induces Apoptosis and Inhibits MAPK, JAK/STAT3, ß-Catenin/NOTCH, and SOCS3 Signaling.

Tumor resistance is typically blamed for the failure of radiotherapy and chemotherapy to treat cancer in clinic patients. To improve the cytotoxicity of tumor cells using radiation in conjunction with specific tumor-selective cytotoxic drugs is crucial. Pomegranate has received overwhelmingly positive feedback as a highly nutritious food for enhancing health and treating a variety of ailments. In the present study, we aimed to examine the effects as well as mechanism of action of pomegranate peel extract (PPE) and/or γ-radiation (6-Gy) on hepatocellular carcinoma (HCC) cell lines HepG2. The findings of this study showed that PPE treatment of HepG2 cells considerably slowed the proliferation of cancer cells, and its combination with γ-irradiation potentiated this action. As a key player in tumor proliferation, and inflammatory cascade induction, the down-regulation of STAT3 following treatment of irradiated and non-irradiated HepG2 cells with PPE as recorded in the present work resulted in reduction of tumor growth, via modulating inflammatory response manifested by (down-regulation of TLR4 expression and NFKB level), suppressing survival markers expressed by reduction of JAK, NOTCH1, ß-catenin, SOCS3, and enhancing apoptosis (induction of tumor PPAR-γ and caspase-3) followed by changes in redox tone (expressed by increase in Nrf-2, SOD and catalase activities, and decrease in MDA concentration). In conclusion, PPE might possess a considerable therapeutic potential against HCC in addition to its capability to enhance response of HepG2 cells to gamma radiation.

Nattokinase attenuates bisphenol A or gamma irradiation-mediated hepatic and neural toxicity by activation of Nrf2 and suppression of inflammatory mediators in rats.

Nattokinase (NK), a protease enzyme produced by Bacillus subtilis, has various biological effects such as lipid-lowering activity, antihypertensive, antiplatelet/anticoagulant, and neuroprotective effects. Exposure to environmental toxicants such as bisphenol A (BPA) or γ-radiation (IR) causes multi-organ toxicity through several mechanisms such as impairment of oxidative status, signaling pathways, and hepatic and neuronal functions as well as disruption of the inflammatory responses. Therefore, this study is designed to evaluate the ameliorative effect of NK against BPA- or IR-induced liver and brain damage in rats. Serum ammonia level and liver function tests were measured in addition to brain oxidative stress markers, amyloid-beta, tau protein, and neuroinflammatory mediators. Moreover, relative quantification of brain nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) genes, as well as apoptotic markers in brain tissue, was carried out in addition to histopathological examination. The results showed that NK improved liver functions, impaired oxidative status, the cholinergic deficits, and minified the misfolded proteins aggregates. Furthermore, NK alleviated the neuroinflammation via modulating NF-κB/Nrf2/HO-1 pathway and glial cell activation in addition to their antiapoptotic effect. Collectively, the current results revealed the protective effect of NK against hepatic and neurotoxicity derived from BPA or IR.

Pre-micro RNA polymorphism detection in small versus large vessel disease in stroke Egyptian patients.

Stroke is the main cause of adult disability and is responsible for around 11% of deaths all over the world. Ischemic stroke encompasses about 80-85% of total stroke cases. Several studies have shown the relation between microRNAs polymorphism and ischemic stroke. The aim of the study was to evaluate the influence of three common single nucleotide polymorphisms in pre-miRNAs (hsa-miR-146a/rs2910164, hsa-miR-196a2/rs11614913 and hsa-miR-499/rs3746444) on individual susceptibility to the risk of ischemic stroke subtypes in Egyptian population with 117 ischemic stroke patients. Results showed that hsa-miR-146a/rs2910164 was significantly associated with the risk of small vessel disease stroke in Egyptian population with no significant association between hsa-miR-196a2/rs11614913 and hsa-miR-499/rs3746444 with the risk of ischemic stroke. Therefore, it can be concluded that miR-146a/rs2910164 polymorphism is involved in the vulnerability to small vessel disease ischemic stroke risk in Egyptian population.

Emotional intelligence and perceived stress among female dental students at King Khalid University, Saudi Arabia.

OBJECTIVE: To assess the emotional intelligence and identify the perceived sources of stress among female dental students and interns at King Khalid University College of Dentistry (KKUCOD), to investigate whether specific stressors were related to the year of study and gender, and to evaluate the relationship between emotional intelligence (EI) and perceived stress (PS). MATERIALS AND METHODS: Total of 150 female undergraduates from 5th and 6th years and dental interns were invited to complete a questionnaire using face-to-face interview. Data on EI was collected using a scale developed by Schutte et al. while a modified version of the Dental Environment Stress (DES) was applied to assess the stress perceived by dental students. RESULTS: 120 students agreed to join the study with a response rate of 84%. Mean EI score for the sample was 120 (SD = 11.56), and the mean PS score was 70.37 (SD = 16.19). One-way ANOVA revealed a significant difference between different age groups and the educational, environmental score (P < 0.05). Correlational analysis showed that the PS scale and its factors correlated positively with each other (P < 0.01) and directly with the total EI score (P > 0.01); except for the living accommodation factor, negative correlations with overall EI score were significant. CONCLUSION: The present study showed that female interns and undergraduate students in clinical years of study at College of Dentistry reported higher EI and PS. The educational environmental score was found to be significantly different among different age groups. In contrary to most published literature, a direct association between EI and PS scores was found, except for the living accommodation factor. This might be attributed to the fact that the study was conducted 1 month prior to final exams. Living accommodation, personal factors, educational environment, academic work and clinical factors were identified as significant predictors of PS.

Amphora algae with low-level ionizing radiation exposure ameliorate D-galactosamine-induced inflammatory impairment in rat kidney.

d-Galactosamine (d-GalN) is a well-known toxin that causes many metabolic and morphological abnormalities resulting in advanced renal failure and liver damage. Occupational exposure to low-level ionizing radiation (<1 Gy) was shown to enhance cell protection via attenuating an established inflammatory process. The present study was therefore aimed to investigate the protective impact of Amphora coffaeiformis extract and low dose gamma radiation against d-GalN induced renal damage in rats. Forty-eight adult male Swiss albino rats were distributed equally into eight groups. The measurements included antioxidants activities (superoxide dismutase, catalase and glutathione peroxidase) as well as lipid peroxidation level in kidney tissue. Also, kidney function tests and inflammatory markers (tumor necrosis factor alpha and nuclear factor kappa-light-chain-enhancer of activated B cells) were measured. Additionally, relative quantification of kidney nuclear factor erythroid 2-related factor 2 (Nrf-2) gene was estimated. Histopathological examination was also performed in kidney tissue. The results revealed decreases in antioxidant activities and downregulation of Nrf-2 expression accompanied by increases in lipid peroxidation level, kidney function tests and inflammatory markers in d-GaIN group. The treatment with Amphora algal extract and low dose gamma radiation ameliorated the previous measurements which were harmony with histopathological findings. In conclusion, A coffaeiformis extract and low dose gamma radiation provided marked functional and histological effects in the treating acute renal damage induced by d-GalN in rats.

Correction to 'On the computation of hybrid modes in planar layered waveguides with multiple anisotropic conductive sheets'.

[This corrects the article DOI: 10.1098/rspa.2018.0288.].

Transfusion-dependent congenital dyserythropoietic anemia type I successfully treated with allogeneic stem cell transplantation.

Until recently, therapy for patients with severe congenital dyserythropoietic anemia (CDA) has been limited to blood transfusions and chelation therapy. Three children with transfusion-dependent CDA type I underwent allogeneic stem cell transplantation (SCT) from matched sibling donors. Conditioning was with cyclophosphamide 50 mg/kg/day for 4 days, busulphan 4 mg/kg/day for 4 days, and antithymocyte globulin (ATG) 30 mg/kg for four doses pre-SCT. All patients engrafted and are alive, and transfusion independent. To our knowledge, this is the first report of successful SCT in the management of CDA type I.

Congenital sideroblastic anaemia successfully treated using allogeneic stem cell transplantation.

Therapy for patients with congenital sideroblastic anaemia has been limited to blood transfusions and chelation. Three children with congenital sideroblastic anaemia (SA) who were blood transfusion dependent underwent stem cell transplantation (SCT) from matched sibling donors. Conditioning consisted of cyclophosphamide 50 mg/kg/d for 4 d, busulphan 4 mg/kg/d for 4 d and anti-thymocyte globulin (ATG) 30 mg/kg for four doses pretransplant. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin A and methotrexate. All patients engrafted, and are alive and transfusion independent. SCT can be curative for patients with SA.

Bone marrow transplantation from matched siblings in patients with fanconi anemia utilizing low-dose cyclophosphamide, thoracoabdominal radiation and antithymocyte globulin.

Nineteen patients with Fanconi anemia (FA) and bone marrow failure underwent bone marrow transplantation (BMT) from matched siblings. Median age at BMT was 8.7 years. Conditioning consisted of low-dose cyclophosphamide (CY 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI 400 cGy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) in 13 patients and CsA plus methotrexate in 6 patients. Antithymocyte globulin (ATG) was added in the pretransplant as well as the post-transplant period. All patients received high-dose acyclovir from day 2 pre-BMT to day 28 post BMT, and intravenous immunoglobulins (IVIG), 500 mg/kg weekly from day 7 pre-BMT to day 90 post BMT. No fungal prophylaxis was given. All patients engrafted, (median, 14 days for an absolute neutrophil count > or =0.5 x 10(9)/l; median, 37 days for platelet count > or =20 x 10(9)/l). Fourteen (74%) patients are alive with sustained engraftment and are transfusion independent. Three (16.6%) patients developed acute GVHD; none developed chronic GVHD. Five (26%) patients developed invasive fungal infections, and two (10%) developed fatal CMV disease. We believe the addition of ATG may have contributed to the increased incidence of severe life-threatening fungal and viral infections in our series.

Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia.

BACKGROUND: In view of the recent trend toward monotherapy in the treatment of bacterial infection, we evaluate the clinical efficacy and safety of cefepime vs. ceftazidime for the empiric treatment of febrile episodes in neutropenic pediatric cancer patients. METHODS: In a single site, open label study, 104 neutropenic pediatric cancer patients [96% with absolute neutrophil count (ANC) of <500 neutrophils/mm3] with a median age of 6 years were randomized (1:1) to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose every 8 h; < or = 6 g/day) for empiric treatment of fever (temperature >38.0 degrees C occurring at least twice in 24 h, or single >38.5 degrees C). Febrile episodes were classified as either microbiologically or clinically documented infection or fever of unknown origin. Therapy continued until the ANC was > or = 1,000 neutrophils/mm3 or there was an increasing ANC in low risk patients (maximum duration of treatment, 8 weeks). The primary efficacy endpoints assessed were clinical and microbiologic response to assigned drug therapy. Secondary outcome measures were rate of early discontinuation of study drug and use of concomitant antibiotic therapy to modify initial study drug regimen. RESULTS: Of 68 patients who could be evaluated for efficacy, 74% (26 of 35) of cefepime-treated patients and 70% (23 of 33) of ceftazidime-treated patients responded to treatment. The small number of study patients precluded statistical analysis of results. In a modified intent-to-treat analysis, 59% of the patients treated with cefepime and 47% of ceftazidime-treated patients responded to therapy. Cefepime patients developed fewer new infections than ceftazidime patients (9% vs. 21%, respectively) and early discontinuation of study drug therapy occurred slightly more often in the ceftazidime group. Further, the use of concomitant systemic antimicrobial therapy (mostly vancomycin) occurred less often in the cefepime-treated patients, as compared with the ceftazidime group [35% [17 of 49] vs. 44% (24 of 55), respectively]. No deaths or serious adverse events were considered to be related to study therapy. The most frequent adverse event was rash that was moderate in severity, and it occurred equally in both groups. CONCLUSION: Cefepime appears to be safe and effective compared with ceftazidime for initial empiric therapy of febrile episodes in neutropenic pediatric cancer patients.

Evaluation of the safety and efficacy of repeated sedations for the radiotherapy of young children with cancer: a prospective study of 1033 consecutive sedations.

PURPOSE: A prospective observational study to examine our current practice of either conscious sedation (C.S.) or general anesthetic (G.A.) for children undergoing radiation therapy (we use the term sedation to include both C.S. and G.A.). Specifically, the study examines the reasons for selection of patients, choice of drugs, safety and effectiveness of the procedure, side effects of repeated daily sedation, and compliance of the family with the regimen. METHODS AND MATERIALS: Recorded data included patient demographics, sedation technique, time for various stages of the procedure, breathing support required, sedation outcome, and complications. RESULTS: One hundred ninety-eight consecutive children underwent 4232 procedures involving either simulation or radiation treatment, an average of 21 procedures each. Seventy-four (37%) required sedation for a total of 1033 procedures, an average of 14 sedations each. For those patients who received sedation, the age ranged from 9 months to 14 years (median, 3.8) and 96% had a mold, (85% of the head and neck). The doctor's assessment of the need for sedation was correct 89% of the time. Thirty-seven percent required sedation at the start of treatment, but, even after 30 fractions, 15% still required sedation. Presedation status correlated with successful sedation and treatment (p = 0.0001). Ninety-six percent had some form of i.v. access, usually a portacath (76%); 883 sedations were performed with G.A. and 148 with C.S.; 93% of sedations were completed satisfactorily, 5% with some difficulty, and the patient was unable to be treated in 2%. With G.A., satisfactory sedation was achieved 97% of the time, whereas, with C.S., satisfactory sedation was achieved only 68% of the time. There were no complications for 97% of observations. Not one serious complication occurred. An endotracheal tube was used only twice during G.A. For C.S., the results for chloral hydrate, meperidine, and midazolam were, respectively, at least one complication, 23%, 0%, 5%; satisfactory sedation for treatment, 60%, 60%, 82%; and unable to treat 20%, 13%, 5%. For G.A., only 1 patient was unable to be treated. The median time from start of medication to the end of radiation treatment was a median of 10 min (75% complete within 15 min) for G.A., vs. 30 min (75% complete in 50 min) for C.S. On multivariate analysis, the only significant factor predicting a successful outcome was a G.A. using propofol (odds ratio, 20.6), vs. C.S. using either chloral hydrate, meperidine, or midazolam. (p = 0.0001). CONCLUSION: In this study, there were no serious complications of sedation in 1033 procedures. As a result of the study, we developed improved methods for better preparation of the patient and family to try to reduce the need for sedation, and reduce the indications for C.S., while confirming the safety and efficacy of a G.A. with propofol for children needing sedation for daily radiation therapy.

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

Searching for socioeconomic risk factors in perinatal mortality in Kuwait: a case control study.

The aim of this paper was to investigate whether socioeconomic factors such as parent's education, occupation, and income constitute risk factors in perinatal mortality after controlling for biological variables such as birth weight and length of gestation, and maternal factors such as age, parity and reproductive history. A case-control study covering all perinatal deaths in Kuwait was conducted for one year from 1 October, 1997 to 30 September, 1998. Each case (perinatal death) was matched with a control (live birth). Matching criteria were: father's nationality, place, and date of birth. Information was successfully collected on 463 matched pairs, 274 Kuwaitis and 189 non-Kuwaitis. Only singleton births were included in the analysis. Bivariate analysis showed that several of the socioeconomic variables (e.g. lower education, lower income) increased the risk of a perinatal death. However, none of these variables remained significant in the multivariate analysis in which birth weight and length of gestation emerged as the two major determinants of perinatal deaths among both nationality groups. Among the Kuwaitis, primiparity and high parity, and previous history of miscarriage were also significant risk factors. Among the non-Kuwaitis, none of the socioeconomic factors, or the maternal factors, were significant predictors of perinatal mortality. For Kuwaitis, it appears that the government's policies and programs aimed at reducing social inequalities in the society have been effective in eliminating perinatal mortality differences between socioeconomic groups. Among non-Kuwaitis, the lack of differences is reflective of the fact that this group is relatively homogenous and selective of the more affluent who can bring the family to Kuwait. Both nationality groups benefit from the government's free health services. However, charges for non-Kuwaitis are due to be levied soon which may increase disparities in access to health care.

Use of amphotericin B colloidal dispersion in children.

PURPOSE: To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. PATIENTS AND METHODS: Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. RESULTS: In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. CONCLUSIONS: ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.

Extramedullary myeloid tumors in children: the limited value of local treatment.

PURPOSE: To determine the incidence of extramedullary tumors (EMT) in Saudi Arabian children with acute myeloid leukemia, the factors associated with these tumors and the impact of local treatment on local tumor control, complete remission and survival rates. PATIENTS AND METHODS: One hundred children, median age 6 years, who received their primary treatment for acute myeloid leukemia at King Faisal Specialist Hospital and Research Center, from 1983 to 1997 were studied. EMT at diagnosis occurred in 18 (18%) patients at 25 sites. Meningeal leukemia, hepatosplenomegaly, lymph node enlargement, gingival hypertrophy, and cutaneous infiltration were not included in the definition of EMT. With these exclusions, children with EMT were younger than those without EMT (median age, 3.5 v. 7.5 years) and were more likely to have meningeal leukemia at diagnosis (33% v. 10%). The t(8;21) translocation was associated with a 47% EMT incidence compared with 23% without the translocation. Local radiation treatment was given to 16 of 25 (64%) EMT sites. RESULTS: The overall 5-year survival rate for all patients was 28%, and this was not significantly influenced by the drug regimen used, meningeal leukemia at diagnosis, the presence of the (8;21) translocation, M4 and M5 morphology combined, or EMT at diagnosis. Significant differences were observed in the 5-year survival rates for patients who underwent allogeneic bone marrow transplantation (52%; N = 37) and those who attained complete remission (CR) but did not undergo transplantation (21%; N = 44) and those who did not achieve complete remission with initial therapy (5%; N = 19). Systemic and local EMT CR was achieved in 17 of 18 patients with EMT, including 12 patients who underwent radiation treatment and 5 of 6 of those who did not. Isolated relapse was not seen at an EMT site and was not noted at any later stage of the disease. CONCLUSIONS: Permanent local control at sites of EMT was achieved in all patients who attained a bone marrow CR, whether or not the site was irradiated. Local radiation treatment of an EMT site did not appear to contribute to overall CR and survival rates. The use of radiation treatment should be conservative and limited to patients in whom there is a real and immediate threat to vision or renal function or when the spinal cord is compromised.

Adjuvant chemotherapy with vincristine, doxorubicin, and cyclophosphamide in the treatment of postenucleation high risk retinoblastoma.

PURPOSE: To study risk factors and outcome of children with high risk retinoblastoma who receive postenucleation vincristine, doxorubicin, and cyclophosphamide. PATIENTS AND METHODS: Charts of all patients who received adjuvant chemotherapy for retinoblastoma were reviewed. Thirty-six patients were identified who received chemotherapy for high risk histopathologic features. Histopathology slides of these 36 patients were retrieved and reviewed, and the disease was staged according to the modified St. Jude staging system. The disease was unilateral in 23 patients (64%). There were 9 patients with stage I disease, 18 with stage II, and 9 with stage III. Twenty-four patients (67%) completed 12 of the 12 scheduled chemotherapy cycles, and 11 patients (30%) received 4 to 11 cycles because of relapse, disease progression, or family reasons. A life-threatening complication developed in one patient after the first cycle, and this patient received no further chemotherapy. RESULTS: Five (3 with unilateral and 2 with bilateral disease) of the 36 patients developed distant metastasis and subsequently died. All had massive tumors; three had choroidal and up to surgical margin optic nerve invasion, and two had tumor extending posterior to lamina cribrosa. Six other patients had local relapse or progressive disease. All of these six patients had bilateral disease and failed in the intact eye during (three patients) or after (three patients) chemotherapy. Only two of the six patients were alive with no disease 50 and 102 months from diagnosis. With a median follow-up of 5.6 years, the 5-year and 10-year actuarial overall survival rates were 86% and 74%, respectively. The 5-year survival rates for patients with modified St. Jude stage I, II, and III disease were 100%, 91% (95% confidence interval, 57% to 100%), and 58% (95% confidence interval, 22% to 94%), respectively (P = 0.008). The survival rate was significantly different among patients with optic nerve involvement anterior to lamina cribrosa, posterior to lamina cribrosa, and surgical margin involvement (100%, 55%, and 41%, respectively; P = 0.003). Multivariate analysis showed that only the degree of optic nerve involvement (and therefore, modified St. Jude stage) was predictive of poor outcome. CONCLUSION: Patients with retinoblastoma involving the optic nerve beyond the lamina cribrosa have low survival rate despite local therapy and adjuvant chemotherapy with vincristine, doxorubicin, and cyclophosphamide. Progression of disease in the intact eye of three patients receiving chemotherapy is of concern. Alternative chemotherapeutic agents should be considered for patients with such high risk features.