Square-Wave Ocular Oscillation and Ataxia in an Anti-GAD-Positive Individual With Hypothyroidism.

Cerebellar ataxia is an uncommon manifestation of hypothyroidism with unknown pathomechanism. The few descriptions of the clinical phenotype range from limb, gait, and trunk ataxia to various ocular motor abnormalities. We evaluated a 62-year-old woman with previously undetected severe hypothyroidism who presented with prominent saccadic intrusions and gait ataxia. She had high titers of antithyroid autoantibodies and anti-glutamic acid decarboxylase (anti-GAD) antibodies. Horizontal eye movement recordings revealed a series of nearly continuous pseudoharmonic square wave jerks (SWJs) constituting a square wave oscillation. Amplitudes reached maximum values of about 4, and wave frequency approached 100 cycles per minute. Thyroxine substitution and corticosteroid administration had little effect on SWJ parameters. The square wave oscillation nearly completely resolved after a single treatment session with intravenous immunoglobulin suggesting a causal link between an autoimmune process and the cerebellar dysfunction. Current concepts of the genesis of saccadic intrusions favor a role for anti-GAD antibodies in the etiology of SWJs.

Interleukin-15 and interleukin-12 are elevated in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

BACKGROUND: There is evidence that immunological factors may be involved in pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Interleukin (IL)-15 and IL-12 are proinflammatory cytokines produced by activated blood and glial cells. They promote T cell differentiation and proliferation. PATIENTS AND METHODS: We measured by ELISA serum and cerebrospinal fluid (CSF) levels of IL-15 and IL-12 in 21 patients with ALS and 19 patients with other noninflammatory neurological disorders (NIND) studied as a control group. IL-15 and IL-12 serum and CSF levels were also correlated with duration of the disease, the disability level determined using the revised ALS Functional Rating Scale and the clinical subtype of the disease onset in patients with ALS. RESULTS: IL-15 and IL-12 serum levels were higher in patients with ALS as compared with patients with NIND (p = 0.014 and p = 0.011, respectively). IL-15 and IL-12 CSF levels were also increased in patients with ALS (p = 0.011 and p = 0.005, respectively). IL-15 and IL-12 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. CONCLUSIONS: Our findings suggest that these molecules may be involved in the pathogenic mechanisms acting as potential markers of immune activation in ALS.

Circulating interleukin-15 and RANTES chemokine in MS patients: effect of treatment with methylprednisolone in patients with relapse.

INTRODUCTION: Interleukin-15 (IL-15) is a proinflammatory cytokine. RANTES is a member of the beta chemokines subfamily with strong chemoattractant activity for T lymphocytes and monocytes. MATERIALS AND METHODS: We measured by enzyme-like immunosorbent assay (ELISA) serum levels of IL-15 and RANTES in 24 patients with MS in relapse, 27 patients with stable MS and 21 healthy subjects. Serum levels of IL-15 and RANTES were also measured before, 5 days and 1 month after onset of treatment with methylprednisolone i.v. RESULTS: IL-15 serum levels were higher in patients with relapse compared with patients in stable stage of the disease and healthy subjects (p=0.001 and p=0.008 respectively). RANTES serum levels were increased in patients with relapse and stable disease as compared to healthy subjects (p=0.01). IL-15 and RANTES levels were not decreased after treatment with corticosteroids. CONCLUSIONS: Our findings suggest a possible role of IL-15 and RANTES in MS. Treatment with methylprednisolone in relapse had no effect on serum IL-15 and RANTES levels.

Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse.

OBJECTIVES: Interleukin-12 (IL-12), a proinflammatory cytokine produced by Th1 cells, and interleukin-10 (IL-10), a product of Th2 cells, are involved in the pathogenetic mechanisms of multiple sclerosis (MS). CCL2 chemokine expression is induced by Th2 cytokines and is decreased in MS relapse. The mechanisms responsible for the beneficial effects of IVmethylprednisolone in attacks are not clearly established and the duration of the effect of this treatment remains controversial. PATIENTS AND METHODS: We measured by enzyme-like immunosorbent assay (ELISA) serum levels of IL-12, IL-10 and CCL2 before, 5 days and 1 month after the initiation of treatment with IVMP in 20 patients with MS in relapse. RESULTS: A significant increase of IL-10 and decrease of CCL2 serum levels was observed (p=0.0028 and 0.045 respectively) five days after the onset of steroid treatment but not after one month. Steroid treatment had no influence in serum levels of IL-12. CONCLUSIONS: The clinical improvement of our MS patients with relapse following the treatment with methylprednisolone may be associated with an immediate but not a long-term modification of serum levels of IL-10 and CCL2. IL-12 may not be influenced by steroid treatment.

RANTES levels are elevated in serum and cerebrospinal fluid in patients with amyotrophic lateral sclerosis.

Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Chemokines are involved in the recruitment of immune cells. Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a C-C beta-chemokine with strong chemo-attractant activity for T-lymphocytes and monocytes. We examined serum levels of RANTES in 20 patients with amyotrophic lateral sclerosis (ALS), 14 patients with non-inflammatory neurological disorders (NIND) and 13 control subjects (CTRL) and cerebrospinal fluid (CSF) levels of RANTES in ALS and NIND group patients in order to investigate whether RANTES as index of immune activation is present in ALS patients. Patients with ALS had higher RANTES levels compared with the NIND patients and CTRL subjects (p = 0.005 and p = 0.02, respectively). CSF RANTES levels were also higher compared with the NIND patients (p = 0.007). No correlation of serum and CSF RANTES levels with disease duration was found. These results may suggest an activated microglia induced recruitment of peripheral inflammatory cells to sites of inflammation in ALS patients.

A phase II study of the docetaxel-ifosfamide-carboplatin combination in advanced non-small-cell lung cancer.

PURPOSE: In the present phase II study we evaluated the docetaxel-ifosfamide-carboplatin (DICb) combination in the outpatient setting in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC (stages IIIB/IV), WHO performance status (PS) <2, and no prior chemotherapy were eligible. Chemotherapy drug doses were: docetaxel: 80 mg/m2, ifosfamide: 3.5 g/m2, and carboplatin at a target area under the curve of 5 (based on Calvert's formula), all on day 1, followed by prophylactic G-CSF. RESULTS: Fourty patients were entered and all are evaluable for response and toxicity: median age: 64 (48-72); PS: 1 (0-1); gender: 29 males/11 females; stages: IIIB: 13 (33%), IV: 27 (67%). Metastatic sites at diagnosis included: lymph nodes: 25; bone: 7; liver: 4; brain: 5; lung nodules: 13; adrenals: 6. Responses were as follows: 22/40 [55%; 95% confidence interval (CI), 54-81%] evaluable patients responded: 4 complete responses, 18 partial responses, 11 had stable disease, and 7 had progressive disease. The median response duration was 7 months (range 2-14 months), median time to progression 9 months (range 2-18 months) and median overall survival 11 months (range 3-46+ months). 1-year survival was 47.5%. Grade 3/4 toxicities included: neutropenia 28/40, with 12 developing grade 4 and 12% febrile neutropenia, thrombocytopenia grade 3: 3/40 and grade 4: 1/40, no grade 3 neuropathy, grade 1 CNS toxicity in 3, no renal toxicity, 8 grade 2 diarrhea and 4 grade 3 vomiting. CONCLUSION: In the present phase II study the DICb combination yielded important activity and good tolerability in advanced NSCLC.

G-CSF in solid tumor chemotherapy: a tailored regimen reduces febrile neutropenia, treatment delays and direct costs.

BACKGROUND: Current guidelines do not recommend G-CSF for patients with risk factors for neutropenia. MATERIAL/METHODS: One-hundred patients undergoing chemotherapy were randomized to treatment with G-CSF at 5 Kg/kg for established febrile neutropenia (ANC <1000/microl) (Group A) or G-CSF at 263 Kg/day if ANC was 1500/microl or less on the day of the expected nadir, with the duration of treatment determined by the severity of neutropenia (Group B). RESULTS: The number of doses of G-CSF was similar in the two groups. There were 34 cases of febrile neutropenia in Group A, but none in Group B (p=0.0001). Hospital admission for febrile neutropenia, antibiotic use and delays in chemotherapy were all significantly more common in Group A. Total direct costs were estimated to be 66, 646 for Group A and 47, 119 for Group B. CONCLUSIONS: Tailoring treatment does not increase G-CSF use, but significantly reduces febrile neutropenia and treatment delays and lowers direct costs.

Etoposide added to weekly leucovorin (LV)/5-fluorouracil (5-FU) in LV/5-FU pre-treated patients with advanced colorectal cancer.

BACKGROUND: We evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV + 5-FU. MATERIAL/METHODS: Etoposide was administered at 3 different dose levels (DL), in 3 groups of patients (total=60): DL-I - etoposide 80 mg/m2, 45 min i.v. infusion, DL-II - etoposide 120 mg/m2, and DL-III - etoposide 180 mg/m2. In all three levels etoposide was followed by LV 100 mg/m2 i.v., 1-hour infusion, and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered until disease progression or unacceptable toxicity. RESULTS: No patients responded at DL-I, while 2 patients at DL-II and 3 at DL-III had a partial response (PR) (P<0.1). Two patients had stable disease (SD) at DL-I, 8 at DL-II, and 9 at DL-III (P<0.01). More patients progressed at DL-I (n=19) compared to DL-II (n=10) and DL-III (n=8) (p<0.0007). The time to progression was 17, 15, and 14 weeks, respectively, for DL-I, -II, and -III (P=0.9). Median survival was 30, 30, and 32.5 weeks, respectively, for DL-I, -II, and -III (P= 0.27). Toxicity was mainly neutropenia, diarrhea and mucositis at all DLs, significantly more intense in DL-III. No difference was noticed in responses between DL-II and DL-III, but toxicity in DL-III was more severe. CONCLUSIONS: The combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC.