Dysthyroid optic neuropathy: emerging treatment strategies.

PURPOSE: Dysthyroid optic neuropathy (DON) is a rare sight-threatening complication of Graves' disease. First-line treatment for DON consists of high-dose intravenous methylprednisolone (ivMP), followed by immediate orbital decompression (OD) if the response is poor or absent as recommended by the 2021 European Group on Graves' orbitopathy guidelines. The safety and efficacy of the proposed therapy have been proven. However, consensus regarding possible therapeutic options for patients with contraindications to ivMP/OD or resistant form of disease is missing. This paper aims to provide and summarize all available data regarding possible alternative treatment strategies for DON. METHODS: A comprehensive literature search within an electronic database was performed including data published until December 2022. RESULTS: Overall, 52 articles describing use of emerging therapeutic strategies for DON were identified. Collected evidence indicates that biologics, including teprotumumab and tocilizumab, may be considered as an important possible treatment option for DON patients. Rituximab should be avoided in DON due to conflicting data and risk of adverse events. Orbital radiotherapy could be beneficial for patients with restricted ocular motility classified as poor surgical candidates. CONCLUSION: Only a limited number of studies have been dedicated to the therapy of DON, mostly retrospective with a small sample size. Clear criteria regarding diagnosis and resolution of DON do not exist, which restricts comparison of therapeutic outcomes. Randomized clinical trials and comparison studies with long-term follow-ups are necessary to verify the safety and efficacy of each therapeutic option for DON.

Nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD): An evidence- and consensus-based approach.

The nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD) is the fourth in a series of web-based guidelines focusing on the diet treatment for inherited metabolic disorders and follows previous publication of guidelines for maple syrup urine disease (2014), phenylketonuria (2016) and propionic acidemia (2019). The purpose of this guideline is to establish harmonization in the treatment and monitoring of individuals with VLCAD of all ages in order to improve clinical outcomes. Six research questions were identified to support guideline development on: nutrition recommendations for the healthy individual, illness management, supplementation, monitoring, physical activity and management during pregnancy. This report describes the methodology used in its development including review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; expert input through two Delphi surveys and a nominal group process; and external review from metabolic physicians and dietitians. It includes the summary statements of the nutrition management recommendations for each research question, followed by a standardized rating based on the strength of the evidence. Online, open access of the full published guideline allows utilization by health care providers, researchers and collaborators who advise, advocate and care for individuals with VLCAD and their families and can be accessed from the Genetic Metabolic Dietitians International (https://GMDI.org) and Southeast Regional Genetics Network (https://southeastgenetics.org/ngp) websites.

Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy.

Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix® Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers.

The current application of ACOSOG Z0011 trial results: Is further implementation of sentinel lymph node intra-operative histopathological examination mandatory in breast cancer patients - a single-centre analysis.

The main objective of the ACOSOG Z0011 trial was to determine the impact of abandoning complete axillary lymph node dissection (ALND) on survival of breast cancer patients with sentinel node lymph (SLN) metastasis in whom breast conserving therapy (BCT) had been performed. The aim of our study was to assess the clinical value of intra-operative histopathological examination of SLN. Our study comprised 1284 invasive breast cancer patients in whom sentinel lymph node biopsy (SLNB) was carried out. SLN intra-operative histopathological assessment was routinely performed in patients treated within the first period (07.2013-06.2014). However, the decision regarding intra-operative assessment was made by the surgeon for the patients who underwent this evaluation in the later period 07.2014-06.2015 and were submitted for BCT. BCT was performed in 72.4% of patients. In total, 316 patients (24.6%) developed SLN-metastasis. Within the period 07.2014-06.2015, SLN intra-operative microscopic evaluation was performed in 20.8% of patients submitted for BCT. ALND was omitted in 27.5% of patients demonstrating SLN metastasis, in comparison with 15.5% of the group from the previous period (p=0.0094). The proportion of patients demonstrating macrometastasis in SLN who received conservative treatment to the axilla increased from 5.4% to 23.1% (p=0.0007). The choice of SLN final histopathological assessment may allow for deferral of decision on more extensive surgery of the axilla in patients submitted for SLNB. The omission of routinely-performed SLN intra-operative histopathological evaluation has led to a statistically significant increase in the proportion of patients in whom complete ALND was avoided.

Assessment of the hemodynamic profile in periodontal tissues of diabetic subjects with periodontitis by optical spectroscopy.

BACKGROUND AND OBJECTIVE: The influence of diabetes mellitus (DM) on the hemodynamics of periodontal tissues has not been assessed previously. The primary objective of this study was to validate optical spectroscopy as a periodontal diagnostic tool for subjects with type 2 DM and chronic periodontitis. MATERIAL AND METHODS: Using a portable optical near-infrared spectrometer, optical spectra were obtained from healthy (n = 127), gingivitis (n = 115), and periodontitis (n = 109) sites of 65 subjects with type 2 DM and chronic periodontitis. Healthy (n = 65) sites of 15 nondiabetic subjects without periodontitis were used as controls. A modified Beer-Lambert unmixing model that incorporates a nonparametric scattering-loss function was used to determine the relative contribution of deoxygenated hemoglobin and oxygenated hemoglobin (HbO2 ) to the overall spectrum. The balance between tissue oxygen delivery and oxygen utilization in periodontal tissues was assessed. RESULTS: In diabetic subjects, tissue oxygen saturation and HbO2 concentration were significantly decreased in the periodontitis sites (p < 0.01) compared with the healthy and gingivitis sites. Furthermore, tissue oxygenation in healthy sites of control subjects was significantly higher than that in sites of diabetic subjects (p < 0.01). CONCLUSION: In summary, the results of this study suggest that optical spectroscopy can monitor the hemodynamic profile in diabetic subjects with chronic periodontitis. Furthermore, healthy sites of diabetic subjects presented lower tissue oxygenation than did those of nondiabetic subjects.

Calcium-phosphate metabolism in patients with multiple sclerosis.

INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate the concentration of 25-hydroxycholecalciferol and parameters of calcium-phosphate metabolism at different periods of relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: Forty-five patients, residents of Poland (49°-50°, N), were enrolled in the study, i.e. 15 immediately after the diagnosis of RRMS, 15 at the early stage and 15 at the advanced stage of RRMS. The results were compared to values obtained in 20 age- and sex-matched controls. RESULTS: Lower serum concentrations of 25-hydroxycholecalciferol and ionised calcium were found in patients compared to the control group. In patients with the disease duration of 5-6 years, concentrations of 25-hydroxycholecalciferol and ionised calcium were lower than in patients in the earlier period of RRMS. The inverse and clearer direction of changes was found in parathormone serum concentration in patients compared to the controls. In patients with a longer disease duration, a significantly lower 25-hydroxycholecalciferol concentration was found in female patients compared to male patients. In patients, more frequent 25-hydroxycholecalciferol and unsaturated fatty acids' supplementation was observed compared to the controls. CONCLUSIONS: In RRMS patients, calcium-phosphate metabolism is disturbed which increases during disease progression.

[Effectively Preventing Eating Disorders with the School-Based Programs "PriMa" and "Torera" for Adolescents in the 6th and 7th Grades]. / Essstörungen wirksam vorbeugen mit den Schulprogrammen "PriMa" und "Torera" für Jugendliche in Klasse 6 und 7.

The aim of this study was to assess the effects of 2 German school-based primary prevention programmes for (pre)adolescents, aged 11-13 years, with 9 manual-guided lessons. 92 (PriMa, n=1,553 girls) and 22 (Torera, n=256 boys, 277 girls) Thuringian secondary schools participated in controlled trials with pre-post assessment. Girls and students at risk showed significant improvements of conspicuous eating behaviour and body self-esteem with small to medium effect sizes. Implementation costs were € 2.50 per student.

Effectiveness of reducing the risk of eating-related problems using the German school-based intervention program, "Torera", for preadolescent boys and girls.

Representative surveys indicate that eating disorders are an increasing problem, especially among (pre)adolescents. We assessed the effects of a German school-based primary prevention program ("Torera") for seventh graders. Torera especially relates to pathological eating behavior in the realm of bulimia nervosa or binge eating disorder. The program is built upon two previously evaluated modules for sixth graders with a gender-specific adaption. The coeducational intervention involves nine manual-guided lessons touching a wide range of eating-related problems. Twenty-two Thuringian secondary schools (n = 256 boys and 277 girls, aged 11-13 years at baseline) participated in a trial with 2 control groups (untreated and pretreated) with pre-post assessment. Primary outcomes were conspicuous eating behavior and body self-esteem, measured by standardized questionnaires (SCOFF, EAT-26D, and FBeK). Girls and students at risk showed significant improvement with small (d = 0.35) to medium (d = 0.66) effect sizes on eating behavior, significantly mediated by body self-esteem. Boys only improved with respect to eating attitudes, revealing a small effect size (d = 0.35). With relatively low implementation costs (about 2.50 per student), Torera provides an efficient model for reducing risky eating behavior and strengthening body self-esteem without negative side effects. To improve the effectiveness of the intervention, further research efforts focusing on at-risk groups (secondary prevention) and structural actions for prevention (e.g., offering healthy school catering) are needed.

On site noninvasive assessment of peri-implant inflammation by optical spectroscopy.

BACKGROUND AND OBJECTIVE: Optical spectroscopy has been proposed to measure regional tissue hemodynamics in periodontal tissue. The objective of this study was to further evaluate the diagnostic potential of optical spectroscopy in peri-implant inflammation in vivo by assessing multiple inflammatory parameters (tissue oxygenation, total tissue hemoglobin, deoxyhemoglobin, oxygenated hemoglobin and tissue edema) simultaneously. MATERIAL AND METHODS: A cross-sectional study was performed in a total of 64 individuals who presented with dental implants in different stages of inflammation. In brief, visible-near-infrared spectra were obtained, processed and evaluated from healthy (n = 151), mucositis (n = 70) and peri-implantitis sites (n = 75) using a portable spectrometer. A modified Beer-Lambert unmixing model that incorporates a nonparametric scattering loss function was employed to determine the relative contribution of each inflammatory component to the overall spectrum. RESULTS: Tissue oxygenation at peri-implantitis sites was significantly decreased (p < 0.05) when compared with that at healthy sites, which was largely due to an increase in deoxyhemoglobin and a decrease in oxyhemoglobin at the peri-implantitis sites compared with the mucositis and healthy sites. In addition, the tissue hydration index derived from the optical spectra in mucositis was significantly higher than that in other groups (p < 0.05). CONCLUSION: In summary, the results of this study revealed that hemodynamic alterations can be detected around diseased peri-implant sites by optical spectroscopy, and this method may be considered an alternative and feasible approach for the monitoring and diagnosis of peri-implant diseases.

[Effectiveness of the school-based prevention program TOPP on factors influencing adiposity in Thuringian schools]. / Evaluation der Wirkung des schulbasierten Präventionsprogramms TOPP "Teenager ohne pfundige Probleme" auf adipositasrelevante Faktoren an Thüringer Schulen.

The onset of puberty is considered a critical period for the development of overweight and obesity. For prevention purposes, we developed the school-based intervention program TOPP (Teenage Obesity Prevention Program), especially for boys. In order to test the effectiveness, we conducted a controlled study using a pre-post design. A total of 84 schools in Thuringian, Germany, with 1,199 boys participated in the study. Program effectiveness was analyzed with mostly standardized questionnaires referring to body-related self esteem, eating behavior, physical activity, teasing, and knowledge. The program was performed during the course of a school project within at least 3 weeks or during the regular school lessons for more than 6 weeks. After 9×90-minute, manual-based lessons, including interactive exercises and poster-based group discussions, significant improvement was only reached for nutritional knowledge. As a main outcome, it could be demonstrated how an area-wide prevention program with low costs could be successfully implemented. The school environment enables us to create a universal, socially equitable, and low-threshold access.

[Self-assessment of BMI data : verification of the practicability of a correction formula on a sample of 11- to 13-year-old girls]. / BMI-Selbstauskünfte : Überprüfung der Praktikabilität einer Korrekturformel an einer Stichprobe elf- bis 13-jähriger Mädchen.

The decision to measure or to ask about data concerning height and weight in order to calculate body mass index (BMI) has an influence on the economy and validity of the measurements. Although self-reported information is less expensive, this information may possibly have a bias on the determined prevalences of different weight groups. Using representative data from the KiGGS study with a comparison of directly measured and self-reported BMI data, Kurth and Ellert (2010) developed two correction formulas for prevalences resulting from self-reported information. The aim of the study was to examine the practicability of the proposed correction formulas on our own data concerning self-reported BMI data of 11- to 13-year-old girls (n=1,271) and to assess the plausibility of the corrected measurements. As a result, the prevalences of our own data changed in the expected direction both for underweight and for overweight. Both formulas were found to be practicable, the consideration of the subjective weight status (formula 2) resulted in a greater change in prevalences compared to the first correction formula.

Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.

Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has allowed for early detection and initiation of treatment in many patients with maple syrup urine disease (MSUD) (OMIM 248600), however, a recent report suggests that variants forms may be missed. Information on these patients is limited. We present clinical, biochemical and molecular information on patients with variant forms of MSUD not detected by the California Newborn Screening Program. Between July 2005 and July 2009, 2200,000 newborns were screened in California by MS/MS. Seventeen cases of MSUD were detected and three (two siblings) were missed. Additionally, the NBS cards of two siblings with late onset MSUD, who were born pre-expanded NBS, were retrospectively analyzed. None of the five patients met criteria to be considered presumptive positive for MSUD (leucine>200micromol/L and a ratio of leucine/alanine>or=1.5). Alloisoleucine (allo-ile) was subsequently analyzed in the NBS cards of all five patients, two of whom were found to have elevated levels. The proband in each family was diagnosed following symptoms triggered by an intercurrent illness or increased protein intake. At diagnosis, leucine levels ranged between 561 and >4528micromol/L, and allo-ile ranged from 137 to 239micromol/L. Two affected siblings had normal plasma amino acids when asymptomatic; however, their biochemical profiles were diagnostic of MSUD during intercurrent illnesses. The median age at diagnosis of all patients was one year (range 0.8-6.7). Heterozygous BCKDHB (E1beta) mutations (c.832G>A/c.970C>T) were identified in one family and a homozygous DBT (E2) sequence variant (c.1430 T>G) in another. The third family had one identifiable DBT mutation (c.827T>G), however, a second mutation was not detected. This report provides further evidence that NBS by MS/MS is unable to detect all cases of MSUD. Second-tier testing with allo-ile may improve sensitivity; however, some children with variant forms will invariably be missed.

In vivo determination of multiple indices of periodontal inflammation by optical spectroscopy.

BACKGROUND AND OBJECTIVE: Visible, near-infrared (optical) spectroscopy can be used to measure regional tissue hemodynamics and edema and therefore may represent an ideal tool with which to study periodontal inflammation in a noninvasive manner. The study objective was to evaluate the ability of optical spectroscopy to determine simultaneously multiple inflammatory indices (tissue oxygenation, total tissue hemoglobin, deoxyhemoglobin, oxygenated hemoglobin and tissue edema) in periodontal tissues in vivo. MATERIAL AND METHODS: Spectra were obtained, processed and evaluated from healthy, gingivitis and periodontitis sites (n = 133) using a portable optical, near-infrared spectrometer. A modified Beer-Lambert unmixing model that incorporates a nonparametric scattering loss function was used to determine the relative contribution of each inflammatory component to the overall spectrum. RESULTS: Optical spectroscopy was harnessed to generate complex inflammatory profiles of periodontal tissues. Tissue oxygenation at periodontitis sites was significantly decreased (p < 0.05) compared to sites with gingivitis and healthy controls. This was largely the result of an increase in deoxyhemoglobin in the periodontitis sites compared with healthy (p < 0.01) and gingivitis (p = 0.05) sites. Tissue water content per se showed no significant difference between the sites, but a water index associated with tissue electrolyte levels and temperature differed significantly between periodontitis sites and both healthy and gingivitis sites (p < 0.03). CONCLUSION: This study established that optical spectroscopy can simultaneously determine multiple inflammatory indices directly in the periodontal tissues in vivo. Visible, near-infrared spectroscopy has the potential to be developed into a simple, reagent-free, user-friendly, chairside, site-specific, diagnostic and prognostic test for periodontitis.

An automatable platform for genotoxicity testing of nanomaterials based on the fluorometric γ-H2AX assay reveals no genotoxicity of properly surface-shielded cadmium-based quantum dots.

The large number of nanomaterial-based applications emerging in the materials and life sciences and the foreseeable increasing use of these materials require methods that evaluate and characterize the toxic potential of these nanomaterials to keep safety risks to people and environment as low as possible. As nanomaterial toxicity is influenced by a variety of parameters like size, shape, chemical composition, and surface chemistry, high throughput screening (HTS) platforms are recommended for assessing cytotoxicity. Such platforms are not yet available for genotoxicity testing. Here, we present first results obtained for application-relevant nanomaterials using an automatable genotoxicity platform that relies on the quantification of the phosphorylated histone H2AX (γ-H2AX) for detecting DNA double strand breaks (DSBs) and the automated microscope system AKLIDES® for measuring integral fluorescence intensities at different excitation wavelengths. This platform is used to test the genotoxic potential of 30 nm-sized citrate-stabilized gold nanoparticles (Au-NPs) as well as micellar encapsulated iron oxide nanoparticles (FeOx-NPs) and different cadmium (Cd)-based semiconductor quantum dots (QDs), thereby also searching for positive and negative controls as reference materials. In addition, the influence of the QD shell composition on the genotoxic potential of these Cd-based QDs was studied, using CdSe cores as well as CdSe/CdS core/shell and CdSe/CdS/ZnS core/shell/shell QDs. Our results clearly revealed the genotoxicity of the Au-NPs and its absence in the FeOx-NPs. The genotoxicity of the Cd-QDs correlates with the shielding of their Cd-containing core, with the core/shell/shell architecture preventing genotoxicity risks. The fact that none of these nanomaterials showed cytotoxicity at the chosen particle concentrations in a conventional cell viability assay underlines the importance of genotoxicity studies to assess the hazardous potential of nanomaterials.

Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38alpha pathway.

Besides its matrix metalloproteinases inhibitory activity, TIMP-1 exhibits other biological activities such as cell survival and proliferation. The intracellular signalling pathway elicited by TIMP-1 begins to be elucidated. We have shown previously that the caspase-3 and the p38alpha MAP kinase were activated during TIMP-1-induced UT-7 cells erythroid differentiation. In this study, we demonstrated that TIMP-1 differentiating effect can be extended to the IL-3-dependent myeloid murine 32D cell line and human erythroid progenitors derived from cord blood CD34(+) cells. By performing small interfering RNA transfection and using chemical inhibitors, we evidenced that caspase-3 was involved in TIMP-1 differentiating effect. We then identified the MEKK1 kinase as a caspase-3 substrate and demonstrated that the MEKK1/MEK6/p38alpha pathway was activated downstream the caspase-3 in TIMP-1-induced hematopoietic differentiation.

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent.

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.

DNA fragmentation in developing lung fibroblasts exposed to Stachybotrys chartarum (atra) toxins.

Stachybotrys chartarum (atra) is a toxic mold that grows on water-damaged cellulose-based materials. Research has revealed also that inhalation of S. chartarum spores caused marked changes in respiratory epithelium, especially to developing lungs. We analyzed the epigenetic potential of S. chartarum spore toxins on developing rat lung fibroblasts using single cell gel electrophoresis (comet assay). Isolated fetal lung fibroblasts were exposed to S. chartarum spore toxins for 15 min, 3, 14, or 24 hr and control cells were exposed to saline under the same conditions. Cells were embedded in agarose, electrophoresed under alkaline conditions and silver stained. DNA damage was assessed in terms of fragmentation as measured by comet tail length (DNA migration) and intensity (% DNA contained within head and tail). Upon visual inspection, control fibroblasts showed no DNA fragmentation whereas S. chartarum-treated cells had definable comets of various degrees depending upon the time-course. Analyses of the comets revealed that exposure to S. chartarum spore toxins for at least 15 min to 14 hr, induced increased DNA fragmentation in a time-dependent manner. The fact that exposure to toxins for 24 hr showed less damage suggested that developing lung fibroblasts may have the capability of repairing DNA fragmentation.

Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

Alterations in gastric mucin with malignant transformation: novel pathway for mucin synthesis.

BACKGROUND: Mucins are high-molecular-weight glycoproteins produced by both normal and cancer cells. However, in cancer cells, abnormal mucins are synthesized and potentially can be used as markers for the development and progression of certain malignancies. In a previous study, we reported the production of a new monoclonal antibody directed against a mucin antigen termed F1 alpha, an O-linked oligosaccharide similar to sialyl Tn and Thomsen-Friedenreich (T) antigens, that has not been previously detected in human cancers. F1 alpha is expressed in a high percentage (80.2%; 89/111) of gastric cancers. PURPOSE: In the present study, we compared the expression of F1 alpha with that of sialyl Tn and T antigens in human gastric cancer tissues to determine how differences in the expression of these cancer-associated antigens correlated with the biological properties of cancer cells. METHODS: A total of 141 cases of gastric cancer were studied. Sections of formalin-fixed, paraffin-embedded tissue were immunostained for F1 alpha, sialyl Tn, and T antigens. The relationship between the expression of these antigens and the patient's clinicopathologic characteristics was studied. The chi-square test (two-sided) was used for statistical analyses. RESULTS: F1 alpha was expressed in a high percentage of the cases of early to advanced cancers, irrespective of the degree of malignant progression. The rate of expression of sialyl Tn antigen in early carcinoma was low, but it increased significantly as depth of invasion increased (P < .05) and was significantly higher in patients with hepatic or lymph node metastasis than in those without such metastasis (P < .01). Expression of T antigen significantly increased with depth of invasion (P < .01) and was significantly higher in patients with hepatic metastasis (P < .05), lymph node metastasis (P < .05), or peritoneal dissemination (P < .01) than in those without such metastasis or dissemination. In consecutive sections of the same specimen, the sites of staining for F1 alpha and sialyl Tn antigens seldom coincided. In many cases, F1 alpha staining was predominant, but the sialyl Tn-dominant region tended to increase as gastric cancer progressed. Regions of T-antigen staining were usually circumscribed by those of F1 alpha staining. CONCLUSION: Our findings indicate that the expression of F1 alpha begins almost at the same time as does carcinogenesis in gastric epithelial cells. Moreover, in association with progression of gastric carcinoma, synthetic pathways for sialyl Tn antigen and T antigen probably are activated independently.

Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone.

UNLABELLED: Multiple sclerosis (MS) prevalence is higher in geographic regions with less sunlight exposure. Melatonin participates in the effects of sunlight in healthy individuals and could play a role in MS pathophysiology. Melatonin crosses the blood-brain barrier and exerts antioxidative, immunomodulatory, and anti-inflammatory effects. Chronic fatigue syndrome concerns 80 - 90% MS patients. The pathophysiology of chronic fatigue syndrome is unknown, however activation of immune, inflammatory, oxidative and nitrosative stress mechanisms and plasma lipid peroxide elevation was reported. Homocysteine increases plasma lipid hydroperoxides levels. The aim was to determine the effect of melatonin supplementation on chronic fatigue syndrome in MS patients and evaluate plasma lipid hydroxyperoxides (LHP) and homocysteine concentrations as a potential biochemical fatigue biomarkers. Into a case-control prospective study 102 MS patients divided according receiving immunomodifying MS treatment into groups: RRMS-pretreated, RRMS-INF-beta, SP/PPMS-mitoxantrone, RRMS-relapse were enrolled. Patients were supplemented with melatonin over 90 days. Plasma LHP, homocysteine concentration, brain MRI and fatigue score were examined. Results show that LHP concentrations were significantly higher in all studied MS groups vs. CONTROLS: In all MS patient groups melatonin application resulted in significant decrease in plasma LHP concentrations. Plasma homocysteine concentration was similar in healthy people, RRMS-pretreated, RRMS-INF-beta and SP/PP-MS-mitoxantrone groups. However, in the RRMS-relapse group plasma levels of homocysteine were significantly higher compared to the RRMS-pretreated group. There were no significant differences in plasma homocysteine concentration in the studied groups before and after melatonin application. The fatigue score was significantly lower in RRMS pretreated group compared to RRMS-INF-beta and SP/PP MS-mitoxantrone treated patients. Plasma lipid hydroxyperoxides could be potential biochemical chronic fatigue syndrome biomarker in MS patients and homocysteine could be a potential marker of acute phase of MS. Melatonin exerts beneficial effects in MS patients based on its' proved antioxidative properties.