Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Neuromyelitis Optica in a Patient from Family with both Myotonic Dystrophy Type 1 and 2.

INTRODUCTION: The aim of this study was to present a family co-segregating myotonic dystrophy type 1 (DM1) and 2 (DM2), and one member affected with neuromyelitis optica (NMO). CASE REPORT: Index case underwent cataract surgery at age 39. Although she had no muscle symptoms, genetic testing revealed a DM2 mutation and a DM1 protomutation. The patient noticed difficulties in climbing stairs at age 47. Clinical examination showed mild muscle weakness, calf hypertrophy, mild myotonia and several multisystem signs. Patient's mother had DM1 protomutation and clinically exhibited only cataract. Two proband's sisters, one with DM2 mutation and another with DM2 mutation and DM1 protomutation, had a clinical presentation similar to the index case. In addition, the latter also developed NMO. CONCLUSION: Our findings suggest that screening for both DM1 and DM2 should be done and a positive result in either gene should not be an indication to stop screening, but to move to the other gene.

Uric acid levels in sera from patients with multiple sclerosis.

The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P = 0.068). However, the mean serum UA level from patients with active MS (202.6 + 67.1 mumol/l) was significantly lower than that in inactive MS patients (226.5 + 78.6 mumol/l; P = 0.046) and OND controls (P = 0.007). We found a significant inverse correlation of serum UA concentration with female gender (P = 0.0001), disease activity (P = 0.012) and duration (P = 0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P = 0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P = 0.0001), disease activity (P = 0.014) and duration of the disease (P = 0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS.

The value of two combined chemoradiotherapy approaches in the treatment of inoperable esophageal cancer.

The antitumor activity of 5-fluorouracil (5-FU), combined either with bleomycin or adriamycin plus radiation, was studied in a controlled randomized clinical trial. Sixty-one previously untreated inoperable esophageal cancer patients entered the study and 56 have been evaluated: 58 male and 3 female patients with a mean age of 57 years (range 37-74). Concerning localization of the tumors in the esophagus, 2 were in the upper third, 36 in the middle third and 18 in the lower third. The length of the filling defects in the esophagogram (X-ray) was in 9 patients less than 5 cm, in 31 5-8 cm, and in 16 patients greater than 8 cm. Squamous cell carcinoma was found in 51 patients, adenocarcinoma in 3, and anaplastic (squamous cell) carcinoma in 2 patients. Modality A consisted of a combination of 5-FU (10 mg/kg i.v. 2 X weekly, 4 weeks) and bleomycin (10 mg/m2 i.v., 2 X 4 weeks) which was given concurrently with radiation (3600-4000 rad - 1000 rad weekly). In modality B the combination of 5-FU (same dose) and adriamycin (30 mg/m2 i.v. day 1, 2, 23 and 24) was applied with the same schedule and dosage of radiation. Seventy-five percent of the patients (21/28) have responded to treatment (CR + PR) in modality A, with 11 complete and 10 partial responses. In arm B, response was recorded in 64% of patients (18/28), with 2 complete and 16 partial responses. The difference in complete responses (39% vs 8%) was statistically significant (P less than 0.05). The median remission duration in complete responders was 12 months in modality A (range 6-18 months), and 6.8 months in modality B (range 3-10 months). All the responses occurred in patients with squamous cell carcinoma, except one partial response in a case of adenocarcinoma. As far as the age is concerned (less than 55 vs greater than 55 years), no significant difference in response rate was found (67% vs 71%). More favorable results were observed in the group of patients with less than 10% weight loss (79% vs 63%). Toxicity was moderate (myelosuppression, cardiotoxicity), but one treatment-related death (pulmonary fibrosis, cardiac failure) was recorded in arm A, as well as one death (rupture of aorta) in group B. Approximately 60% of patients in both modalities suffered from severe mucositis and retrosternal pain. The results of the study showed that the combination of 5-FU with adriamycin and particularly with bleomycin, given concurrently with lower radiation dosage, is an effective palliative treatment for inoperable esophageal cancer.

Bleomycin infusions combined with radiotherapy in the treatment of inoperable esophageal cancer.

A combination of bleomycin, in a 12 h infusion, and radiotherapy was applied in 25 patients with untreated inoperable esophageal cancer. Bleomycin was administered 15 mg/m2 twice weekly, concurrently with irradiation (total dose 3600-4000 rad). Such combined treatment produced 3 complete remissions of the esophageal tumor, 10 partial remissions (response rate 52%--13/25), 3 stable disease cases, while in 9 cases the disease progressed in spite of therapy. The median duration of remissions was 8.7 months in complete responders, 6.0 months in partial responders, and 3.0 months in stable disease cases. Similarly, median survival was the longest in complete remission cases (10.3 months). Patients who did not respond to therapy had a median survival of only 2.8 months. Adverse treatment reactions were of a milder character, except retrosternal pain and burning caused by irradiation mucositis, which occurred in 80% of patients. The trial showed that the combination of bleomycin applied in the form of 12 h infusion and irradiation can produce remissions in 50% of inoperable esophageal cancer cases, i.e., a rate of remission which is similar to that achieved by irradiation and bleomycin applied in the form of rapid (push) i.v. injections.

Therapy of advanced esophageal cancer with bleomycin, irradiation and combination of bleomycin with irradiation.

Results from treating 51 patients with advanced esophageal cancer are presented. Fifteen patients were treated with Bleomycin, 12 with radiotherapy, and 24 with a combination of bleomycin and radiotherapy. The best results were achieved in the group of patients treated with combined therapy showing 62% objective remissions (15/24) which was statistically significant (P less than 0.001) in comparison to the other groups. In the Bleomycin therapy group, there were 26% objective remissions (4/15), and in the group treated only with radiotherapy 33% (4/12)- The median duration of remission was 9 months in the combined therapy group, 6.3 months in the group treated with radiotherapy, and 2.6 months in the Bleomycin treated group. The authors concluded that the combination of Bleomycin and radiotherapy seems to be a further step in palliative treatment of advanced esophageal cancer.

Combination of 4-epi-doxorubicin and irradiation--a new approach in the treatment of locoregionally advanced inoperable esophageal cancer.

The synergistic activity observed in vitro in V-79 hamster lung cells after treatment with 4-epi-doxorubicin (4-epi-DX) combined with irradiation stimulated a pilot study of 38 patients with inoperable locoregionally advanced squamous cell esophageal cancer. The patients (30 males, 8 females; mean age 60 years) had undergone no prior radiation or cytostatic drug therapy. Twenty tumors were localized in the middle third of the esophagus, and the remainder in the upper or lower third. Histological evidence of the tumor was obtained in all patients before treatment by endoscopy. The 33 evaluable cases included 30 squamous cell carcinomas, 2 anaplastic (squamous cell) carcinomas and 1 adenocarcinoma. The patients were irradiated in two opposite thoracic fields (Betatron-Siemens) with a total dosage of 3600-4000 cGy (200 cGy daily, 1000 weekly). The patients were concurrently administered 4-epi-DX at the dose of 50 mg/m2 i.v. daily on days 1, 2, 22 and 23; the total 4-epi-DX dosage was 200 mg/m2. The results showed that 4-epi-DX combined with irradiation had a pronounced antitumorigenic activity, since the 33 evaluable patients included 11 complete and 12 partial remissions, with a response rate of 70% (23/33). A minor regression (less than 50%) was observed in 6 cases, and progression of the disease in 4. The median duration of the remissions was 9 + months (14 + months in complete responders). In 8 patients with a complete clinical response even the endoscopic biopsy samples were negative. Toxicity was moderate and reversible, and mainly accounted for by radiation mucositis and retrosternal pain, alopecia and mild bone marrow suppression. Transient ECG changes were observed in 3 cases. The results of the pilot study show that the combination of 4-epi-DX and irradiation might constitute successful palliative treatment for squamous cell esophageal cancer.

[Vertebral prostheses in surgical treatment of metastatic disease]. / Proteza kraljeska u operacijskom lijecenju metastatske bolesti.

Metastasis disease is often located at the spine, especially with solid tumors where frequency can reach 80%. Indications for metastasis operational approach are threatening or existing neurologic deficit, static dislocations or even unbearable pain. Operation treatment may be extensive, with radical metastasis removal or even partial one with decompressive laminectomy and tumor reduction and spine stabilization. Using various kinds of alenthesis, the authors have used their own vertebra artificial limb in 10 cases, which enables spine stabilization after radical vertebra removal. They report their experience in the essay.

The involvement of proliferation and apoptosis in the early human gonad development.

Distributions of the Ki-67, TP53, caspase-3 and AIFM1 markers were histologically investigated in the 5th to 9th week developing gonads of 12 human conceptuses using immunohistochemical and immunofluorescence methods. Between the 5th and 8th developmental week, proliferation gradually increased in the surface gonad epithelium (26-52 %) and stroma (19-42 %), but then slightly decreased in the surface epithelium (35 %) during the early foetal period. In medulla, low proliferation activity decreased from 15 to 12 % between the 7th and 9th week. At earliest stages of gonadal development, primordial germ cells (PGC) were only rarely TP53 positive. In the 7th and 8th week, almost all PGC-s displayed TP53 positivity, while their number decreased in early fetal period. During the investigated period, caspase-3 reactivity gradually decreased in surface epithelium, while it increased in PGC and medulla of developing gonad AIFM1-positivity first appeared in surface gonad epithelium and then predominantly in PCG-s while caspase-3 characterized different cell populations within the developing gonad. AIFM1 and caspase-3 co-localized only during the migration of PCG-s. The number and distribution of Ki-67, TP53, caspase-3 and AIFM1 reacting cells changed coincidently with development end regression of the sex cords in indifferent and early fetal gonad. Our results indicate that the number of PGC might be controlled by balance of TP53 and AIFM1, leading to caspase-3 independent cell death. Other cell populations are probably eliminated by caspase-3-dependent cell death. Both pathways of cell death seem to operate during early human gonad development, while their intensity varies depending on the cell type and developmental period analysed.

Quality of life in patients with multiple sclerosis in Serbia.

OBJECTIVES: The aim of this investigation was to evaluate factors that might influence the health-related quality of life (HRQoL) in multiple sclerosis (MS) patients in Serbia. MATERIALS AND METHODS: This cross-sectional study was performed on a group of 156 patients with MS. HRQoL was assessed by using the SF-36 questionnaire. Expanded Disability Status Scale (EDSS) and Beck Depression Inventory (BDI) scale were assessed as variables affecting the HRQoL of MS patients. RESULTS: EDSS score correlated negatively with all SF-36 health dimensions, and the highest statistically significant coefficients were for physical functioning (r = -0.682), and social and role functioning (r = -0.407 and -0.405 respectively). BDI correlated statistically significantly negatively (P < 0.01) with all SF-36 health dimensions. CONCLUSIONS: Our findings suggest that both disability and depression significantly influence the HRQoL in Serbian MS patients, with depressive symptoms having the major influence.

Localization of radioactive sources by radiotherapy simulator and application to gynaecology.

During a short-lasting high radioactivity gynaecological treatment the position of the sources does not change significantly. A fast and accurate technique was developed allowing for the determination of source positions. It is based on the use of a radiotherapy simulator. The simulator was declined by 20 degrees to the right, and the X-ray projection of the sources was copied with blue colour on a PVC foil firmly attached to the intensifier display. This was repeated with the simulator declined by 20 degrees to the left and with red. From the paralax shift the three dimensional position of sources was evaluated, and dose distribution was then calculated using a computer program.

Combination of bleomycin and adriamycin with and without radiation on the treatment of inoperable esophageal cancer. A randomized study.

In a prospective randomized study, 31 patients with inoperable esophageal cancer were treated with a combination of bleomycin and adriamycin, and with a combination of these cytostatics and radiation. Evaluation of treatment results showed 3 partial remissions and 2 stable-disease cases in the group of 16 patients treated by cytostatic drugs alone; in all other cases, the disease progressed. The response rate achieved in this group was 19%. In the group including 15 patients who were irradiated with a dose of 3600--4000 rad and received simultaneously the same cytostatics with a somewhat lower dose of adriamycin, there were 3 complete remissions, 6 partial remissions, and 4 stable-disease cases, while in 2 cases the disease progressed. The response rate was 60%, which was statistically significant (P less than 0.025) when compared with the results achieved by the group receiving the bleomycin adriamycin combination. The average duration of remissions in the complete-response cases was 11 months, and in the partial-response cases, 5.2 months with combined treatment, and 4.2 months with combination chemotherapy. The toxic side-effects were tolerable for the patients, albeit more intensive with the combined-treatment modality. Four esophagobronchial fistulas (four disease progressions) and one rupture of the aorta were noted during treatment. This study has shown the advantages of chemoradiotherapeutic treatment of inoperable esophageal cancer.

[Experience in the treatment of malignant obstructions of the vena cava superior by means of chemotherapeutic decompression and subsequent irradiation]. / Erfahrungen bei der Behandlung maligner Obstruktionen der oberen Hohlvene durch chemotherapeutisches Dekompressionsverfahren und Nachbestrahlung

The clinical picture, pathogenesis and etiology of malignant vena cava obstruction are described. The importance of using modern methods to treat this critical condition is emphasized. Furthermore, the authors examine the principles of chemotherapeutic decompression followed by irradiation. A single dose of nitrogen mustard was applied intravenously, followed by irradiation, on 24 patients with malignant vena caval obstruction. The results of this treatment are presented. The effect of this treatment was controlled by measuring the venous blood pressure and with chest X-rays. The authors conclude, that this method of decompression is successful in the palliative treatment of this syndrom.

[Findings of cerebrospinal fluid in the diagnosis of multiple sclerosis]. / Likvorski nalazu dijagnostici multiple skleroze.

In order to define the cerebrospinal fluid (CSF) profile indicative of multiple sclerosis (MS), it is essential that each laboratory specifies the percentage of clinically definite MS patients with as well as the ranges of obtained values for each CSF parameter in these patients. CSF of 92 patients with clinically defined MS were analysed for cell count, concentrations of total protein, albumin and IgG, blood-CSF barrier function as assessed by CSF/serum albumin quotient, quantitative measurements of intrathecal IgG production (IgG index and IgG daily synthesis rate) and the presence of CSF oligoclonal IgG. For the detection of CSF oligoclonal IgG the isoelectric focusing (IEF) of unconcentrated CSF on agarose with transfer of proteins to cellulose nitrate and immunoperoxidase staining, was performed. CSF oligoclonal IgG bands not matched in parallel sera were detected in 96% of MS patients. Quantitative measurements of intrathecal IgG synthesis were significantly less sensitive than IEF. The concentration of total proteins in CSF was normal in 48% of patients, slightly elevated in 7% of patients and moderately elevated in 4% of patients with clinically definite MS. CSF cell count was normal in 71% of patients and slightly increased in the remaining 29%. The differential cell count was normal in all patients. CSF albumin and CSF/serum albumin quotient were elevated in 58 identical MS patients of 92 tested, indicating slight or, rarely moderate dysfunction of CSF-brain barrier in these patients. In 99% of MS patients, the total protein was <980 mg/L, the albumin <740 mg/L and the total cell count <20 cells per mm3. According to our data, the CSF findings that support the diagnosis of clinically definite MS are: 1) the presence of intrathecally produced CSF oligoclonal IgG by IEF; 2) normal or slightly to moderately elevated level of CSF proteins and albumin; 3) normal CSF-brain barrier function or slight to, rarely, moderate CSF-brain barrier dysfunction as assesed by CSF/serum albumin quotient, and 4) normal cell count or slight pleocytosis. If this profile is not found in a patient suspected of MS, the diagnosis should be questioned or a complication should be expected.

Primary progressive multiple sclerosis: clinical and paraclinical characteristics with application of the new diagnostic criteria.

The aim of our study was to analyse clinical and paraclinical characteristics of patients with multiple sclerosis (MS) with previous diagnosis of primary-progressive (PP) MS according to the Poser's criteria and further investigate if they fulfil the McDonald's diagnostic criteria for this disorder. A total of 561 MS patients were registered in the database at the Institute of Neurology, Belgrade, from 1 January 1997 to 31 December 2000 and 63 of them (11.2%) with previous diagnosis of PPMS were analysed retrospectively. Male/female ratio was 1.3:1 and mean age at onset 33.2 years. Most frequent at onset were pyramidal (in 73% of patients) and sensory symptoms (in 41% of patients); 74.6% of patients had greater than or equal to nine brain magnetic resonance imaging (MRI) lesions. Intrathecal oligoclonal immunoglobulin G (IgG) was detected in 96.7% and prolonged visual evoked potentials (VEP) P100 latency in 82.4% of patients. Of the total study group of 561 patients, 10.2% fulfilled the recently recommended McDonald's diagnostic criteria for the diagnosis of PPMS. Our findings further support the significance of the brain/spinal cord MRI, cerebrospinal fluid and VEP findings for precise diagnostic assessment in patients with suspected PP form of MS.