Nanomolar quantification and identification of various nitrosothiols by high performance liquid chromatography coupled with flow reactors of metals and Griess reagent

To evaluate the histological findings in patients with chronic hepatitis C and autoimmune features, liver tissue specimens from 60 patients were graded under code for individual features and composite patterns that denoted autoimmune, viral, combined autoimmune and viral, and nondiscriminative changes. Portal, interface, and acinar hepatitis in any combination with plasma cell infiltration connoted an autoimmune pattern that was associated with higher serum levels of gamma-globulin (2.4 +/- 0.2 g/dL vs. 1.7 +/- 0.1 g/dL; P = .0003) and immunoglobulin G (2,211 +/- 227 mg/dL vs. 1,508 +/- 83 mg/dL; P = .001) than patients with other patterns. Patients with the autoimmune pattern also had a greater frequency of cirrhosis (43% vs. 8%; P = .003), higher mean Knodell score (13.2 +/- 0.9 vs. 6.8 +/- 0.9; P < .0001), and a greater occurrence of high-titer smooth muscle antibodies (SMA) (13% vs. 0%; P = .05) than patients with other histological findings. HLA DR3 also occurred more frequently in these individuals than in other patients (48% vs. 15%; P = .01) and normal subjects (43% vs. 16%; P = .01). Patients with nondiscriminative patterns and interface hepatitis had clinical findings similar to those with autoimmune patterns, except for a lower mean serum level of gamma-globulin. We conclude that the composite histological pattern that resembles autoimmune hepatitis is associated with greater immunoreactivity, inflammatory activity, and disease severity than other patterns. Interface hepatitis may be the most important histological finding associated with these clinical manifestations.     

Drug therapy in the management of type 1 autoimmune hepatitis

Prednisone alone or in combination with azathioprine is the treatment of choice for severe type 1 autoimmune hepatitis. The combination regimen is preferred, especially in the elderly, because of a lower incidence of corticosteroid-related complications. Only patients with sustained severe laboratory abnormalities, bridging necrosis or multilobular necrosis on histological assessment, and/or incapacitating symptoms, have absolute indications for treatment based on controlled clinical trials. The institution of therapy must be individualised in other patients, based mainly on symptoms and disease behaviour. Serum aspartate aminotransferase and gamma-globulin levels are the most useful indices to monitor during therapy. Liver tissue examination is the best method of evaluating completeness of response. Most patients enter remission, but relapse occurs in 50 to 86% after drug withdrawal. Maintenance therapy with low dosages of prednisone or azathioprine can be used long term in patients who have relapsed repeatedly. Inability to achieve remission after 3 years (incomplete response), deterioration during therapy (treatment failure) and drug toxicity are unsatisfactory responses that warrant alternative strategies. Liver transplantation is effective in managing decompensated disease, but recurrence of autoimmune hepatitis after transplantation is possible. Tacrolimus and budesonide are promising new drugs.     

Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis

Celiac disease has been associated with autoimmune disorders, but its frequency in autoimmune hepatitis is unknown. Sera from 157 patients with type 1 autoimmune hepatitis, 24 patients with type 2 autoimmune hepatitis, 62 patients with primary biliary cirrhosis, 30 patients with chronic hepatitis B, and 80 patients with chronic hepatitis C were tested for immunoglobulin A anti-endomysial antibodies by indirect immunofluorescence and immunoglobulin A and G antibodies to gliadin by enzyme immunoassay. Duodenal biopsy evaluation was recommended in patients seropositive for immunoglobulin A anti-endomysial antibodies. Immunoglobulin A anti-endomysial antibodies were present in eight of the 181 patients with autoimmune hepatitis (4%), including six with type 1 disease (4%) and two with type 2 disease (8%). Immunoglobulin A antibodies to gliadin were found in six of these eight patients, but they were also present in two others, including one patient with chronic hepatitis C. Five of the eight patients with immunoglobulin A antiendomysial antibodies, including three patients with no gastrointestinal symptoms, had duodenal biopsies and subtotal villous atrophy was present in all of them. No patient with primary biliary cirrhosis or chronic viral hepatitis had antiendomysial antibodies. The presence of celiac disease in autoimmune hepatitis is high (at least one in 36 patients) and it is predominantly asymptomatic. Screening with anti-endomysial and anti-gliadin antibodies should be performed and results confirmed with intestinal biopsy.     

Systemic chemotherapy alone for patients with non-acquired immunodeficiency syndrome-related central nervous system lymphoma: a pilot study of the BOMES protocol

BACKGROUND: Anecdotal reports have suggested that systemic chemotherapy with agents that better cross the blood-brain barrier may result in long term disease remission in some patients with central nervous system (CNS) lymphoma. This treatment strategy has the advantage of sparing patients the late neurologic complications from brain irradiation. METHODS: Eligible patients were required to 1) have tissue-proven and measurable non-acquired immunodeficiency syndrome (AIDS)- related primary or metastatic CNS lymphoma; 2) have normal hemogram, renal function, and hepatic function; 3) be age < or = 75 years; and 4) have provided informed consent. Patients with lymphoblastic lymphoma or patients who previously had been exposed to nitrosoureas, etoposide, or high dose methotrexate were not eligible. The systemic chemotherapy (BOMES regimen) included carmustine, 65 mg/m2/day, intravenously (i.v.) on Days 1-2; vincristine, 2 mg/day, i.v. on Days 1 and 8; methotrexate, 1.5 g/m2, i.v. on day 15 followed by leucovorin rescue; etoposide, 50 mg/m2/day, i.v. on Days 1-5; and methylprednisolone, 200 mg/day, i.v. on Days 1-7; repeated every 4 weeks (BOMES regimen). Four doses of intrathecal methotrexate were given to patients who had involvement in the cerebrospinal fluid. RESULTS: Between March 1991 and March 1997 a total of 19 patients were enrolled on the study. There were 13 men and 6 women, with a median age of 57 years. Fourteen patients had primary CNS lymphoma and 5 patients had concurrent extra-CNS lymphoma. Nine patients previously had been treated by radiotherapy (four patients), chemotherapy (three patients), or both (two patients). There were 11 complete remissions (CR) (57.9%) and 5 partial remissions (26.3%), with a total remission rate of 84.2%. One patient had had progressive brain lymphoma during systemic chemotherapy with the conventional cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen, but achieved CR soon after the regimen was changed to BOMES. The median time to progression of the responders was 6 months. At last follow-up, 4 patients were alive without lymphoma at 10, 47, 64, and 66 months, respectively. There were two treatment-related deaths due to sepsis. Another two patients died of fulminant hepatitis that most likely was chemotherapy-related reactivation of chronic B viral hepatitis. CONCLUSIONS: The authors believe systemic chemotherapy alone may result in long term disease remission in some select patients with non-AIDS-related CNS lymphoma. Further investigation for better protocols is mandatory.     

Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases

OBJECTIVE: We report five cases (four male; median age 20 yr, range 14-38 yr) of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. The patients presented with jaundice, elevated serum aminotransferase and alkaline phosphatase activities, hyperglobulinemia with high immunoglobulin G (IgG) levels, circulating antinuclear and/or smooth muscle autoantibodies (> or = 1:40), and moderate to severe interface hepatitis on liver biopsy (with biliary features in four). METHODS: All five fulfilled criteria for diagnosis of "definite" autoimmune hepatitis and showed marked responses to prednisolone and azathioprine therapy, with relapses occurring during reduction or withdrawal of treatment. Cholangiographic features of primary sclerosing cholangitis were found in three patients at presentation and after intervals of 7 and 14 yr in the other two. Only two had evidence of inflammatory bowel disease. Diagnostic criteria for identifying those patients who may benefit from immunosuppressive therapy were reviewed. RESULTS: Review of the literature revealed only 11 similar cases that were sufficiently well described for comparison. However, in contrast to these and the present cases, preliminary data from other studies have suggested a marked association with ulcerative colitis and a poor response to immunosuppressive therapy. CONCLUSIONS: It is recommended that the possibility of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome responsive to immunosuppressive therapy should be considered in any patient presenting with a hepatitic illness with hyperglobulinemia, antinuclear or smooth muscle autoantibodies, and biliary changes on liver biopsy. Cholangiography should be considered in such patients.     

Detection of Salmonella in animal protein by Rappaport-Vassiliadis broth using indirect impediometry

To determine if glipizide could enhance remission induction in new onset type 1 diabetes compared to intensive insulin treatment alone, 27 patients with type 1 diabetes were intensively treated in an open randomized trial with subcutaneous injections for one month. The insulin was randomly either discontinued (Group A) or the insulin discontinued and glipizide begun (Group B) Three patients in Group A (22%) and 7 in Group B (54%, p < .05) underwent insulin-free remissions for 10.3 +/- 4.4 and 8.7 +/- 2.6 months, respectively (p = NS). Mean blood glucose levels during insulin treatment were lower in patients entering remissions (94 +/- 3 mg/dl versus 102 +/- 5 mg/dl, p < 0.05). C-peptide levels were performed 0, 4, 8, and 24 weeks after insulin treatment. When all patients were examined, mean stimulated C-peptide levels at 4 weeks (0.58 +/- 0.09 pm/ml) were increased compared to time 0 (0.32 +/- 0.05 pm/ml, p < 0.02). Patients not entering remission had higher 4-week stimulated values (0.67 +/- 0.12 pm/ml) compared to time 0 values (0.29 +/- 0.06 pm/ml, p < .01), whereas remission patients' mean C-peptide levels remained similar at 0, 4, 8 and 24 weeks. These data indicate that a) insulin treatment plus glipizide induces higher rates of remission compared to intensive insulin treatment alone, b) the intensity of initial metabolic control may be an important determinant for remission induction, and c) endogenous insulin secretion is not associated with remission induction, suggesting that glipizide alters insulin sensitivity or is immunomodulatory in the context of new onset type 1 diabetes.     

Prenatal diagnosis of de novo interstitial 16q deletion in a fetus associated with sonographic findings of prominent coronal sutures, a prominent frontal bone, and shortening of the long bones

Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 +/- 24 IU/L and 170 +/- 17 IU/L before UDCA therapy to 31 +/- 3 IU/L and 25 +/- 5 IU/L (P < 0.001) after 1 year of treatment and 28 +/- 2 IU/L and 23 +/- 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5 patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.     

Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis

To determine the significance of antibodies to single-stranded (anti-ssDNA) and double-stranded DNA (anti-dsDNA) in antinuclear antibody (ANA)-positive type 1 autoimmune hepatitis, sera from 53 patients were tested by enzyme immunosorbent assay (ELISA) and indirect immunofluorescence using the Crithidia luciliae substrate. Anti-dsDNA were detected in 18 patients (34%) by ELISA and 12 patients (23%) by the Crithidia-based assay. Twenty patients with anti-dsDNA by either assay (38%) had higher serum levels of immunoglobulin G (3971 +/- 270 mg/dL vs. 3201 +/- 247 mg/dL, P = .05) than seronegative patients. They also had human leukocyte antigen (HLA) DR4 more commonly than other patients (83% vs. 41%, P = .006) and normal subjects (83% vs. 30%, P = .00007). In contrast to patients seropositive by the Crithidia-based assay, those seropositive by ELISA failed corticosteroid therapy more commonly (24% vs. 3%, P = .04). Anti-ssDNA were found in 45 patients (85%) and they did not distinguish patients with different clinical features or outcomes. We conclude that anti-dsDNA are common in ANA-positive type 1 autoimmune hepatitis. HLA DR4 is associated with their production, and seropositivity by ELISA characterizes patients who have a poorer immediate response to corticosteroid treatment. Anti-ssDNA are common but they do not have important clinical implications.     

Longitudinal observation and outcome of nonfamilial childhood haemophagocytic syndrome receiving etoposide-containing regimens

The long-term outcome of 22 children treated with etoposide-containing regimens for haemophagocytic syndrome (HS) were longitudinally studied; none of them had a family history of the disease. All patients received etoposide-containing (150 mg/m2/d) regimens, combined, in 16 cases, with intravenous immunoglobulin (IVIG) and prednisolone. Complete remission (CR) was achieved in 12 patients, partial remission in seven, and early mortality occurred in three. Of the 12 CR patients, only four remain alive and disease-free, with a median follow-up of 47.4 months; one CR patient died due to infection and the remaining seven had relapsed diseases. Three patients with a partial response or with relapsed disease progressed to T-cell lymphoma, characterized, in the two cases tested, by clonal chromosomal abnormalities. Epstein-Barr virus (EBV) infection was implicated in disease pathogenesis in 15/22 patients. The overall survival was 45.5%, 40.9% and 40.9% at 1, 3 and 5 years, respectively, and disease-free survival for CR patients at these same times was 45.5%, 36.4% and 36.4%. The etoposide-containing regimen would appear to be an effective initial therapeutic option for childhood HS. However, in view of the frequency of partial remissions and relapsed disease, a more intensive chemotherapy or bone marrow transplantation should be applied. The progression to EBV-containing T-cell lymphoma in three patients is consistent with the previous observation that EBV-associated HS is a potentially malignant disease.     

Chronic non-A, non-B, non-C hepatitis: is hepatitis G/GBV-C involved?

BACKGROUND: Hepatitis G virus/GBV-C is a recently discovered virus, and its relevance in chronic hepatitis is still debated. METHODS: We have previously described 127 long-term-studied and well-characterized patients with chronic non-A, non-B hepatitis (NANBH). Ninety-one (71.7%) were positive for hepatitis C virus antibodies (anti-HCV) in a first-generation anti-HCV enzyme-linked immunosorbent assay (ELISA). We now reanalyzed the same group of patients and added a third-generation anti-HCV ELISA and recombinant immunoblot assay and, in negative patients, also polymerase chain reactions for hepatitis C virus RNA, hepatitis GBV-C RNA, and hepatitis B virus DNA. Additional tests for autoimmune hepatitis types 2 and 3 were also included. RESULTS: Anti-HCV were detected in 114 of the 123 evaluable patients (92.7%). Of the remaining nine anti-HCV-negative patients one had misdiagnosed primary biliary cirrhosis, and two had autoimmune hepatitis type 3. None of the anti-HCV-negative patients were hepatitis GBV-C RNA-, HCV RNA-, or HBV DNA-positive. Thus, 114 of 120 NANBH patients (95.0%) had chronic hepatitis C. None of the remaining six patients had received blood transfusions or was a drug addict, and two of them were successfully treated with steroids. CONCLUSIONS: Hepatitis G/GBV-C as a single cause of chronic non-A, non-B hepatitis is uncommon, and in all patients with parenteral risk factors hepatitis C was detected.     

Blood flow and leukocyte adhesiveness are reduced in the microcirculation of a peritoneal disseminated colon carcinoma

BACKGROUND/AIMS: Transforming growth factor-beta1 (TGF-beta1) is considered the most important mediator of hepatic fibrogenesis. At the same time, TGF-beta1 is an immunosuppressive cytokine. Development of fibrosis, often rapid, is a characteristic of autoimmune hepatitis, as is spontaneous systemic immunosuppression. The aim of our study was therefore to define the role of TGF-beta1 in autoimmune hepatitis. METHODS/RESULTS: Using the MV 1Lu bioassay, we found markedly elevated serum levels of TGF-beta1 (median 109 ng/ml) in active autoimmune hepatitis, which normalised when patients reached biochemical remission following immunosuppressive therapy (median 34 ng/ml; p=0.0001 compared to active disease). With a newly established ELISPOT-assay for TGF-beta1-producing cells, we could exclude an increase in TGF-beta1-producing peripheral blood cells as a source of the elevated TGF-beta1. However, by in situ hybridisation and immunohistochemistry, we found strong TGF-beta1 expression in the inflamed liver. In addition to non-parenchymal and infiltrating cells, many hepatocytes showed strong staining for TGF-beta1. TGF-beta1 expression in the liver normalised in remission, yet was still somewhat increased in patients with biochemical remission but remaining histological disease activity. CONCLUSIONS: These results suggest that TGF-beta1 is an important mediator in active autoimmune hepatitis. They support the theory that immunosuppressive therapy needs to be guided by histology, as prevention of the development of cirrhosis presumably requires near complete suppression of TGF-beta1 in the liver; this is only found when there is no longer any histological evidence of inflammation.     

Frequency and significance of antibodies to P450IID6 protein in Japanese patients with chronic hepatitis C

BACKGROUND/AIMS: The aims of the current study were to assess the frequency and the significance of antibodies to cytochrome P450IID6 protein (anti-P450IID6) in various diseases among Japanese patients. METHODS: Sera from 541 patients were tested by indirect immunofluorescence, and the specificity of anti-P450IID6 was ascertained by either enzyme immunoassay (ELISA) or Western blot using recombinant antigen or rat liver microsomes. RESULTS: Anti-P450IID6 was found in only 6 of 235 patients (2.6%) with chronic active hepatitis (CAH) positive for hepatitis C virus (HCV) antibody and quantitative HCV-RNA with genotypes II and IV. The predominant epitopes on immunoblots were 66 and 50KD, a 10KD band being the newly underfined microsomal antigen. Even in the patients negative for autoantibodies to nuclear antigens (ANA) by routine indirect immunofluorescence test, various ANA were detected by the newly developed recombinant ELISA. These patients were younger, with lower gamma-globulin and IgG levels than patients with autoimmune hepatitis. Three of five patients with anti-P450IID6 responded well to interferon therapy and one received prednisone when interferon was ineffective. Interestingly, only this patient was diagnosed as definite autoimmune hepatitis according to the criteria proposed by the International Autoimmune Hepatitis Group (IAHG). The other five patients who did not satisfy the IAHG criteria might be considered as CAH-C with autoimmune features. No autoimmune hepatitis patients positive for anti-P450IID6 were identified in the current study, indicating that the variant is very rare in Japan. CONCLUSIONS: Anti-P450IID6 in CAH-C patients in Japan is not as rare as expected. Anti-P450IID6 among Japanese patients has uncertain significance and precludes further characterization of CAH-C with autoimmune features, which might require interferon therapy.     

Comparison of two cyclophosphamide treatment regimens in nephrotic patients with chronic glomerulonephritis

AIM: Comparison of two cyclophosphamide (CPA) treatment regimens in chronic glomerulonephritis (CGN) patients: oral daily CPA versus intravenous CPA pulses (IV-CPA) MATERIALS AND METHODS: 31 nephrotic patients entered the trial: 12, 16 and 3 with membraneous, mesangial proliferative and mesangiocapillary CGN, respectively. The patients were randomized into two groups. 13 patients of group 1 received oral CPA (1.5-2.0 mg/kg/day for 6 months, while 18 patients of group 2 received IV-CPA pulses (20 mg/kg/monthly, at least 6 pulses) combined with oral prednisolone (40-6-mg/day during 1.5 mo with subsequent tapering). At entry, no statistical differences (p > 0.05) were found between groups 1 and 2 by age, gender, duration of the renal disease, serum creatinine levels, frequency of arterial hypertension. Mean duration of follow-up was 27.6 and 22.6 mo (p > 0.05) for group 1 and 2, respectively. RESULTS: After 6 months of follow-up there was no difference in the rate of complete and partial remission between the groups (69 and 83% for group 1 and 2, respectively). The rate of renal function deterioration was also similar. Side effects occurred 3 times more frequently in group 1 than group 2. The mean cumulative course dose of CPA per 1 patient in group 1 was 35.6 g, in group 2--5.6 g. CONCLUSION: The effectiveness of methods was similar irrespective of CGN morphological form, but in spite of similar rates of remission of nephrotic syndrome, pulse CPA is preferable being more safe as to possible complications.     

TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates

OBJECTIVE: We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease. DESIGN: Open non-randomized prospective study. SETTING: University Hospital of Montpellier, France. SUBJECTS: Sixty-six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3'-triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow-up. The remaining 48 patients were available for analysis of both remission and relapse. RESULTS: The median duration of therapy was 18 months (range, 4-41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups. CONCLUSION: TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.     

Liver pathology in juvenile chronic polyarthritis

Besides lymphodenopathy and splenomegaly, hepatomegaly may also be detected in 25-50% of children with juvenile rheumatoid arthritis. This is particularly evident in patients with complete Still's syndrome. The hepatomegaly increases during relapse situations and disappears during remissions. Transient icterus, elevation of aminotransferases and delayed bromsulfalein excretion have been reported, particularly in patients with complete Still's syndrome, and indicate impairment of liver function. Liver biopsies have been performed only rarely and show nonspecific infiltrations of portal fields with lymphocytes and, in a few cases, "autoimmune" hepatitis and even cirrhosis with portal hypertension. Plasma cell hepatitis with affection of joints can be readily differentiated from juvenile rheumatoid arthritis: the synovitis is merely transiet and disappears with institution of steroid therapy. As in the adult, severe liver dysfunction leads to remission of arthritis. Amyloidosis should be considered in every case of long-lasting hepatomegaly.     

Humoral immune reaction in chronic liver diseases

In 60 patients with a morphologically ascertained chronic liver disease and 40 hepatologically examined patients with a healthy liver of a control group the quantitative determination of the immunoglobulin and the immunofluorescence-serological determination of antibodies against nuclei, smooth musculature and mitochondria were carried out. Only in one female patient with a chronic active hepatitis out of 51 patients with morphologically ascertained liver cirrhosis or chronic active hepatitis antibodies against nuclei and smooth musculature in a level of the titre of more than 1 : 40 and only in 2 female patients with a primary biliary cirrhosis antibodies against mitochondria could be proved in a level of the titre of more than 160. Titres of antibodies lying below were found in the group of patients with liver diseases and the control group in the same frequency, so that an autoimmune form of the cryptogenic cirrhosis could not be differentiated. The proof of antibodies against nuclei and smooth musculature of a high titre in connection with an isolated increase of the IgG is of special diagnostic importance for the autoimmune form of the chronic active hepatitis; the same is the case in the proof of antibodies against mitochondria of a high titre in connection with an isolated increase of IgM.     

Compomers and glass ionomers: bond strength to dentin and mechanical properties

Twenty-six patients with newly diagnosed ALL (age range 15-49 years, median 32 years) received treatment comprising: cycles 1 and 2: adriamycin 30 mg/m2 days 1-3, vincristine: 2 mg days 1, 8, and 15, with prednisolone 40 mg daily, given until complete remission (CR). L-asparaginase 10000 units/m2, days 1-14, was given only with the first cycle. Cycle 3 consisted of 100 mg/m2 etoposide orally, days 1-5, and 1 gm/m2 bd cytosine arabinoside (ara-C) days 1-5. Cycles 1-3 were then repeated. Intrathecal methotrexate (MTX) 12.5 mg was given on day 1 of each treatment cycle. The first 12 consecutive patients received this chemotherapy alone, the subsequent 14 received, in addition, 3 micrograms/kg GM-CSF subcutaneously, from day 4 of cycles 1,2,4 and 5 (and from day 6 of cycles 3 and 6) until the absolute neutrophil count had reached 0.5 x 10(9)/1. All patients in whom CR was achieved then received prophylactic cranial irradiation. With the exception of those with T-ALL, this was followed by oral maintenance therapy consisting of 6-mercaptopurine, MTX, and cyclophosphamide for 3 years. Patients receiving GM-CSF did not have shorter intercycle times or a lower incidence of documented infections than those who did not receive it. The CR rate was 89% overall-uninfluenced by GM-CSF, but higher than that achieved previously at St Bartholomew's Hospital in an equivalent age-group.     

Combination chemotherapy of Hodgkin's disease in children

Forty-five children with advanced Hodgkin's disease (stages III and IV) received combination chemotherapy in three schedules: MOPP (mustargen, Oncovin, procarbazine, prednisolone); COPP (cyclophosphamide was substituted for mustargen); and CVPP (cyclophosphamide, vinblastine, procarbazine, prednisone). The results showed the efficacy of all drug combinations (93% complete and partial remissions). However, the superiority of the MOPP program in prolonging the duration of the complete remission rate was demonstrated. Of 29 patients who showed complete response, 24 continued in complete remission from 8 to 53 months (median duration, 21 months). The other five patients relapsed within 2 to 6 months. Thirty-six of the 45 treated patients are still alive after an average period of follow-up of 19 months. The nine patients who died were followed for an average of seven months. The histologic type, prior chemotherapy, and the age of the patients influenced the results of treatment. The role of maintenance therapy is not discussed in this series     

Serum globulin levels and activities of daily living in centenarians

Serum globulin levels in 101 centenarians (77 women, 24 men) were analyzed by zonal electrophoresis and immunoglobulin assays. Six subjects showed an M band in electrophoretograms. Five M bands were immunoglobulin G (IgG) type and one was IgA. One subject was suspected to suffer from IgG-type multiple myeloma, and the others were thought to have essential (benign) monoclonal gammopathy. The relationship between serum globulin levels and activities of daily living (ADL) was studied in remaining 95 subjects. There were 21 rank-J (free-living), 25 rank-A (unable to go outside without help), 23 rank-B (bedridden but able to sit on the bed), and 26 rank-C (completely bedridden) centenarians. The mean serum alpha 1-, alpha 2-, and beta-globulin level in the rank-J centenarians was at the upper limit of the normal adult range. The mean alpha 1-globulin levels in rank-B (3.3 +/- 0.4%) and C (3.4 +/- 0.5%) subjects were significantly higher than those in rank-J (2.9 +/- 0.3%) centenarians. The mean serum gamma-globulin level of rank-J centenarians (16.9 +/- 3.7%) was within the normal range. The mean gamma-globulin levels in rank-B (21.0 +/- 2.7%) and C (22.8 +/- 4.9%) subjects were significantly higher than that in rank-J centenarians. The mean immunoglobulin G concentrations in rank-B (1.620 +/- 304 mg/dl) and C (1.720 +/- 392 mg/dl) subjects were significantly higher than those in rank-J centenarians (1.320 +/- 361 mg/dl) and in normal adults (1.150 +/- 235 mg/dl). IgA concentrations in all centenarians were higher than in normal controls. There was no significant difference in IgA or IgM concentration between rank-J subjects and those in other ranks. Serum globulin levels measured with electrophoresis, and the immunoglobulin concentrations, can be valuable indicators of the ability to perform activities of daily living, and may be useful predictors of subclinical diseases or morbidity in centenarians.     

Therapy for the maintenance of remission in sixty-five patients with generalized Wegener's granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole

OBJECTIVE: To compare the efficacy of low-dose intravenous (IV) methotrexate (MTX; 0.3 mg/kg once weekly), both with and without concomitant prednisone, versus daily oral trimethoprim/sulfamethoxazole (T/S; 160 mg of trimethoprim + 800 mg of sulfamethoxazole twice a day), with and without prednisone, in maintaining remission in patients with generalized Wegener's granulomatosis (WG). METHODS: In this study, 65 patients with generalized WG whose disease had entered remission with cyclophosphamide (CYC) and prednisone therapy were started on one of the following remission-maintenance regimens: MTX alone (group A; n = 22), T/S alone (group B; n = 24), MTX plus concomitant prednisone (group C; n = 11), and T/S plus concomitant prednisone (group D; n = 8). Clinical, radiographic, and seroimmunologic data were evaluated to assess the efficacy of the 4 regimens and to seek possible predictive factors concerning outcome in each group. RESULTS: Partial or complete remission was maintained in 86% of the patients in group A, but in only 58% of those in group B (P < 0.05). In group C, 91% of patients remained in remission, which is in sharp contrast to group D, in which all patients experienced a relapse after a median of 14.5 months (P < 0.005). Side effects occurred twice as often with MTX (n = 12) as with T/S (n = 6) treatment and could usually be resolved by supplemental folinic acid. Two patients taking MTX and 3 patients taking T/S were withdrawn from the study medication because of side effects. In none of the patients were the adverse effects life threatening. No statistically significant factors predictive of poor outcome emerged in any group. CONCLUSION: Low-dose MTX was found to be superior to T/S for the safe and effective maintenance of remission in patients with generalized WG. The use of concomitant prednisone was not associated with a worse outcome with MTX treatment. Since T/S, especially with concomitant prednisone, seemed to increase the chance of relapse, neither T/S alone nor T/S plus prednisone can be recommended for the maintenance of remission in patients with generalized WG.