Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis in Finland.

OBJECTIVE: A systematic review found that an average of 27% of rheumatoid arthritis (RA) patients using tumour necrosis factor (TNF) inhibitors discontinue their treatment within 1 year. The aim of this study was to assess drug survival on TNF inhibitors among patients with RA. METHODS: Patients were identified from the National Register for Biologic Treatment in Finland (ROB-FIN), which is a longitudinal cohort study established to monitor the effectiveness and safety of biologic drugs in rheumatic diseases. Inclusion was limited to TNF-inhibitor treatments started as the patient's first, second, or third biologic treatment between 2004 and 2014. Follow-up was truncated at 36 months. The results of a time-dependent Cox proportional hazards model were reported as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of the 4200 TNF-inhibitor treatment periods identified from ROB-FIN, 3443 periods from 2687 patients met the inclusion criteria. Twenty-seven per cent of the patients discontinued their treatment within 12 months. Infliximab (HR 1.8, 95% CI 1.3-2.5) and certolizumab pegol (HR 1.7, 95% CI 1.2-2.3) had lower drug survival compared to golimumab. A similar trend was seen with adalimumab (HR 1.2, 95% CI 0.90-1.7) and etanercept (HR 1.2, 95% CI 0.87-1.6). Concomitant use of methotrexate (MTX) was associated with improved drug survival (HR 0.76, 95% CI 0.64-0.90) in comparison with TNF-inhibitor monotherapy. CONCLUSIONS: Golimumab was better in terms of drug survival than infliximab or certolizumab pegol and at least as good as adalimumab and etanercept. Concomitant use of MTX improved drug survival on TNF inhibitors.

Night-time bioavailability of levodopa/carbidopa/entacapone is higher compared to controlled-release levodopa/carbidopa.

OBJECTIVE: Controlled-release levodopa/carbidopa (CR-LC) is often used to provide prolonged control of night-time motor symptoms in patients with Parkinson's disease (PD). Levodopa/carbidopa/entacapone (LCE) provides higher bioavailability of levodopa compared with levodopa/carbidopa formulations and has been shown to be effective in PD patients with wearing-off symptoms. The aim of this study was to compare the bioavailability of levodopa after a single evening dose (administered at 10 p.m.) of LCE 200 or CR-LC 200. METHODS: This was an open-label, randomized, crossover study in healthy subjects. The main pharmacokinetic (PK) parameters were AUC, Cmax, C6h and t1/2 of levodopa. RESULTS: A single evening dose of LCE 200 was associated with significantly better bioavailability compared with CR-LC 200. In line with increased bioavailability of levodopa, LCE 200 induced more nausea. CONCLUSIONS: The results of this study demonstrate that a single bedtime dose of LCE 200 provides higher bioavailability of levodopa compared to CR-LC 200.

Anaerobic digestion of grass silage in batch leach bed processes for methane production.

Anaerobic digestion of grass silage in batch leach bed reactors, with and without a second stage upflow anaerobic sludge blanket (UASB) reactor, was evaluated. Sixty six percent of the methane potential in grass was obtained within the 55 days solids retention time in the leach bed-UASB process without pH adjustment, whereas in the one-stage leach bed process 20% of the methane potential in grass was extracted. In two-stage operation, adjustment of the pH of influent to the leach bed reactor to 6 with HCl led to inhibition of both hydrolysis/acidogenesis and methanogenesis. In the leach bed-UASB process 39% of the carbohydrates and 58% of the acid soluble lignin were solubilised within the 49 days of operation, whereas Klason lignin was most recalcitrant. The methane potential of the digestates varied from 0.141 to 0.204 m3 CH4 kg(-1) added volatile solids.

Late non-relapse mortality among adult autologous stem cell transplant recipients: a nation-wide analysis of 1,482 patients transplanted in 1990-2003.

Data on the incidence and causes of late (>100 d) non-relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited. We have analysed NRM in a cohort of 1,482 adult patients who received ASCT in 1990-2003 in six Finnish transplant centres. The most common diagnoses included non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (n = 132); Hodgkin's lymphoma (HL) (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Until September 2005, 646 patients (44%) have died. Late NRM was observed in 68 patients (4.6% of ASCT recipients; 11% of all deaths). There were 38 males and 30 females with a median age of 58 yr (20-69) at the time of ASCT. The median time to NRM was 27 months from ASCT (3-112). The risk of NRM was highest in patients with CLL (9.5%) and those with HL (8.1%) followed by MM and NHL (4.9% and 4.8%, respectively). The risk of late NRM was comparable in patients who received total body irradiation (TBI) and those who received chemotherapy-only regimens (6.7% vs. 4.3%). Another malignancy was the most common cause of late NRM (24 patients, 35% of late NRM). Twelve patients (0.8% of ASCT recipients) have died due to secondary haematological malignancy. Altogether 22 patients (32% of late NRM) died from infectious causes. Malignancies and late infections are important causes of NRM after ASCT. These facts point out the importance of prolonged follow-up in ASCT recipients.

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients.

OBJECTIVES: To evaluate early (<100 d) treatment-related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. PATIENTS: Altogether 1482 adult patients received ASCT in six Finnish centres 1990-2003. The most common diagnoses were non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkin's lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). RESULTS: Forty-two patients (2.8%) died from treatment-related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0-99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). CONCLUSIONS: This nation-wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.

Direct observation of Josephson capacitance.

The effective capacitance has been measured in the split Cooper-pair box (CPB) over its phase-gate bias plane. Our low-frequency reactive measurement scheme allows us to probe purely the capacitive susceptibility due to the CPB band structure. The data are quantitatively explained using parameters determined independently by spectroscopic means. In addition, we show in practice that the method offers an efficient way to do nondemolition readout of the CPB quantum state.

Outcome of progressive disease after autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a nation-wide survey.

OBJECTIVES: To analyse outcome and prognostic factors in non-Hodgkin's lymphoma (NHL) patients who progress after autologous stem cell transplantation (ASCT). PATIENTS: Altogether 115 consecutive NHL patients transplanted in 1991-2000 were studied. Histology included diffuse large B cell (n = 52), follicular (n = 26), mantle cell (n = 15), T cell (n = 16) and other subtypes (n = 6). The median time from ASCT to the progression was 7 months. Ninety-six patients (83%) received salvage treatment. RESULTS: Twenty-four patients (25%) achieved complete remission and 30 (31%) partial remission. The median overall survival was 8 months (range 0-98+) and the projected 4-year survival 21%. In multivariate analysis factors predicting treatment response after the progression included the use of rituximab (P = 0.036), histology other than diffuse large B cell (P = 0.001) and International Prognostic Index < or =2 at progression (P < 0.001). Normal lactate dehydrogenase (LDH) at progression (P = 0.002), response to salvage treatment (P < 0.001) and time from ASCT to progression > or =7 months (P = 0.022) were predictors for overall survival. CONCLUSIONS: Although the prognosis of patients who progress after ASCT is generally poor, many patients will respond to current therapies, and some may experience prolonged survival. Normal LDH at time of disease progression and longer time to progression after ASCT were the most powerful predictors for a promising outcome.

Invasive fungal infections in autologous stem cell transplant recipients: a nation-wide study of 1188 transplanted patients.

UNLABELLED: Based on small single-centre series, the risk of invasive fungal infections (IFI) has been considered small in autologous stem cell transplant (ASCT) recipients. PURPOSE: To analyse epidemiological and clinical features of (IFI) among ASCT recipients in Finland 1990-2001. PATIENTS: During the study period, 1188 adult patients received high-dose therapy supported by ASCT in six centres. Altogether, 1112 patients (94%) received blood progenitor cells. The graft was CD34+ selected in 261 patients (22%). The major diagnostic groups were non-Hodgkin's lymphoma (n = 417), multiple myeloma (n = 395), breast cancer (n = 132) and Hodgkin's lymphoma (n = 53). RESULTS: Eighteen patients (1.5%) with IFI were identified. The incidence of proven or probable invasive aspergillosis was 0.8%, followed by candidaemia with an incidence of 0.3%. The median time to the diagnosis of IFI was 35 d (6-162) from the progenitor cell infusion. In fourteen patients (78%) IFI was diagnosed during lifetime and they were treated with antifungal therapy for a median of 50 d. Nine patients (64%) were cured. CONCLUSIONS: IFI appears to be a rare event after ASCT and Aspergillus infections seem to be predominant. These epidemiological features have an impact in planning prophylactic and empirical antifungal strategies in ASCT recipients.

Autologous stem cell transplantation in adult patients with peripheral T-cell lymphoma: a nation-wide survey.

Limited experience is available on the feasibility and efficacy of high-dose therapy (HDT) supported by autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphoma (PTCL). Therefore, a nation-wide survey was conducted in adult patients transplanted for PTCL in Finland during 1990-2001. After histopathology review, 37 patients were identified. The median age was 46 years (16-68) at the time of ASCT. Histology included PTCL not otherwise specified in 14 patients, anaplastic large cell lymphoma (ALCL) in 14 patients, and other in nine patients. Disease status at the time of ASCT was CR/PR1 in 18 patients; CR/PR2 in 14 patients, and other in five patients. HDT consisted of either BEAC (N=22) or BEAM (N=15), supported by blood stem cells in 34 patients (92%). Early transplant-related mortality was 11%. With a median follow-up of 24 months from HDT, 16 patients (43%) have relapsed or progressed. The estimated 5-year overall survival (OS) was 54%. Patients with ALCL had superior OS when compared with other subtypes (85 vs 35%, P=0.007). OS at 5 years was 63% in patients transplanted in CR/PR1 vs 45% in those transplanted in other disease status (P=NS). Prospective studies are needed to define the role of ASCT in this lymphoma type.

A randomised dose-finding phase II study on ifosfamide in metastatic hormone-refractory prostate cancer (HRPC).

The palliative efficacy and toxicity of single-ifosfamide chemotherapy were investigated in patients with progressive metastatic hormone-refractory prostate cancer (HRPC). Thirty patients were randomised to receive ifosfamide by a 24-hour infusion on day 1 or a 3-hour infusion on days 1-4 at three week intervals until renewed disease progression or a total of six chemotherapy cycles. Response was analyzed according to the guidelines of the Prostate-Specific Antigen Working Group (1999). All 30 patients were included in the final analysis. 1 (3%) PSA normalization, 8 (27%) partial responses, 3 (10%) stabile diseases and 18 (60%) progressive diseases. The mean time to progression was 2.4 months, (range 0 -17) months and the median survival time was 13.6+ months, (range 2 -52). The treatment was well tolerated. No severe gr III-IV hematotoxicities were observed. In conclusion ifosfamide is effective and well tolerated as a single-agent in the treatment of HRPC. Further studies including ifosfamide in combination chemotherapy of HRPC are in progress.

A reversible neuronal antibody (anti-Tr) associated paraneoplastic cerebellar degeneration in Hodgkin's disease.

Paraneoplastic cerebellar degeneration (PCD) has been associated with a variety of neoplasms, most commonly with gynecologic tumors, breast cancer, small cell lung cancer, and Hodgkin's disease (HD). In some patients PCD is associated with circulating antineuronal antibodies like anti-Hu, anti-Yo or anti-Ri. Previously, only 5 patients with a new antineuronal antibody called anti-Tr, proposed to be specific for HD, have been reported. We describe 1 further patient with HD and reversible PCD with a decline in anti-Tr antibody titers in cerebrospinal fluid and serum corresponding to the improvement of clinical symptoms. At the present time the immunoreactive pattern observed in rat cerebellum is the only way to identify anti-Tr antibodies and differentiate them from other antibodies that immunoreact with the Purkinje cells.

Serological evidence of an association between chlamydial infections and malignant lymphomas.

Chronic infections may predispose to malignant growth. Recently, serological markers of chronic Chlamydia pneumoniae infection have been associated with lung cancer. Our aim was to study the possible association between chronic chlamydial infections and malignant lymphomas. The present case-control study involved 72 patients with lymphoma (31 females and 41 males) and matched controls. 53 patients had non-Hodgkin's lymphoma (NHL) and 19 had Hodgkin's disease. The sera, collected at the time of diagnosis, were tested for IgG antibodies and immune complexes to C. pneumoniae and C. trachomatis by a microimmunofluorescence method and ELISA and for IgG antibodies and immune complexes to Helicobacter pylori by ELISA. The serological markers suggesting chronic chlamydial infection were associated with malignant lymphoma. The association was most evident for the presence of C. pneumoniae-specific immune complexes in NHL (OR = 7.3, 95% CI 2.2-25) and appeared to be limited to men. No association between H. pylori antibodies or immune complexes and malignant lymphomas could be demonstrated. Our study provides seroepidemiological evidence of an association between chronic chlamydial infections and lymphomas.

Common and emerging infectious causes of hematological malignancies in the young.

Comparative epidemiological studies have for a long time suggested a link (or links) between infectious agents and hematological malignancies in the young. Identification of Epstein-Barr virus (EBV) as the major cause of specific subtypes of Burkitt's lymphoma and Hodgkin's disease 20 and 10 years ago, respectively, and the recent involvement of human T-cell leukemia virus in non-Hodgkin's lymphomas of the T-cell lineage in young adults in Jamaica have given further credit to early presumptions that these diseases have an infectious etiology. The spectrum of possibly involved viruses: old, EBV, and new, herpesviruses 6, 7 and 8, and unknown retroviruses - as well as the list of partially or totally unresolved disease entities: Hodgkin's disease in adolescents, non-Hodgkin's lymphomas in the immunocompromised, and acute lymphocytic leukemia - is rapidly expanding. Both direct and indirect transforming effects of the above-mentioned viruses are being rapidly disclosed. However, the complex interaction between the different viruses and other causes of hematological malignancies in the young guarantees that many things remain to be discovered also in the future.

Type 1 cytokine response and treatment outcome of genital HPV lesions.

OBJECTIVES: To determine the role of type 1 cytokines as predictors of response to treatment of genital HPV lesions with laser ablation with or without adjuvant systemic interferon alpha 2b (IFN-alpha). METHODS: Measurement of serum interleukin 2 (IL-2), IL-2 soluble receptor alpha (sIL-2 alpha), interferon gamma, and human papilloma virus (HPV) DNA in patients undergoing treatment of genital HPV lesions with carbon dioxide laser and systemic IFN-alpha. A randomised, placebo controlled study of 92 cases with 6 months of follow up. RESULTS: High IL-2/sIL-2 alpha was associated with 60% to 70% protection against recurrences both in the IFN-alpha and placebo groups (OR = 0.4, 90%, CI 0.1-2.5; OR = 0.3, 90% CI 0.0-1.8, respectively). Diagnostic phase serum IL-2 predicted favourable outcome (OR = 0.2, 90% CI 0.0-1.0) in women with high load of HPV DNA or HPV 16/18 DNA regardless of the adjuvant therapy. CONCLUSIONS: Serum IL-2 determinations may identify women with good prognosis following laser ablation of genital HPV lesions.

Serum p53 accumulation and altered antibody responses to Epstein-Barr virus proteins precede diagnosis of haemopoietic malignancies of lymphoid origin.

We analysed antibodies to Epstein-Barr virus nuclear antigens (EBNAs 1, 2, 5 and 6) and the presence of serum p53 in 100 individuals, 37 of whom has developed a haemopoietic malignancy during a 12-year follow-up of 39,000 Finnish adults. Serum p53 was detectable in six of the 63 (10%) matched controls and in 13/31 (42%) patients who developed a malignancy of lymphoid origin approximately 7 years after serum withdrawal. Six patients who developed a malignancy of myeloid origin were negative for p53. The presence of p53 alone was associated with a highly significant increased risk of lymphoid malignancies (relative risk (RR)p53 = 6.7, 95% confidence limits (CL) 1.9, 24) whereas high levels of antibody to EBNA2 seemed to be inversely related to the risk (RREBNA2 = 0.1, CL 0.0, 1.1). Among lymphoid malignancies, a combination of serum p53 and high EBNA1 antibody levels gave a greater than expected risk (RRp53 and EBNA1 = 14, CL 1.4, 130; RRexpected = 4.4), whereas interaction with high levels of EBNA5 antibody gave an expected risk (RRp53 and EBNA5 = 19, CL 1.7, 220; RRexpected = 17). Thus detectable levels of p53 appear early in the development of lymphoid malignancies, and high EBNA1 antibody levels, and accumulated p53 may both be synergistic risk indicators for lymphoid malignancies, whereas high EBNA5 antibody levels and accumulation of p53 seem to raise the RR independently of each other.

The disease associations of the antibody response against the Epstein-Barr virus transactivator protein ZEBRA can be separated into different epitopes.

The BamHI-Z-encoded Epstein-Barr virus (EBV) replication activator (ZEBRA) is a key mediator of the switch from latency to productive cycle in EBV virus. Antibodies against ZEBRA are a marker of EBV reactivation and are regularly found among patients with infectious mononucleosis (IM) or nasopharyngeal carcinoma (NPC), but are only rarely found among healthy EBV-seropositive donors. In order to define the serologically reactive epitopes in the ZEBRA protein, we synthesized a set of overlapping peptides and tested them for reactivity with serum samples from EBV-seronegative persons, patients with NPC, IM, chronic fatigue syndrome, lymphoma or from healthy donors. Three major EBV-specific epitopes were found. These epitopes were further defined and optimized using substitution or truncation analogues of the peptides. Reactivity with epitope number 22 was found in 63% of NPC patients' sera, with < 2% of healthy donors' sera being positive. Serological reactivity with epitope number 19 was associated with IM (57% positive, 5% healthy donors positive). Serum antibodies against epitope 1 were found among healthy donors, but were significantly elevated among patients with NPC, IM or lymphomas. In conclusion, different serologically reactive epitopes in the ZEBRA protein associate with different EBV-associated diseases.

Antibody response to adenovirus E1b-derived synthetic peptides and serum levels of p53 in patients with gastrointestinal and other malignant lymphomas.

Serum levels of p53 and antipeptide antibody levels to adenovirus type 12 (Ad12) E1b protein were measured in a case-control study of 62 newly diagnosed patients with malignant lymphoma. While patients with gastrointestinal lymphoma did not differ from their matched controls, p53 positive lymphoma patients had significantly (P < 0.04) increased antipeptide IgG antibody levels to the Ad12 E1b. Concomitant detection of serum p53 and antipeptide antibodies to Ad12 E1b was associated with an increased risk (OR = 17.0, 95% confidence limits 1.5, 58.5) of malignant lymphoma suggesting synergism between expression of Ad12 E1b and accumulation of p53 in patients with malignant lymphoma.

Follicular dendritic cells have prognostic relevance in Hodgkin's disease.

The authors' previous study showed the presence of follicular dendritic cell (FDC) networks--though altered--in neoplastic areas, not only in the nodular lymphocyte predominance type, but also in other types of Hodgkin's disease. The present retrospective study was performed on 102 patients to determine whether the presence or absence of FDC networks, or parts of them, in neoplastic areas has prognostic relevance in Hodgkin's disease. Follicular dendritic cells were visualized with the monoclonal antibody Ki-FDC1P, which selectively stains FDCs in paraffin-embedded tissues. Univariate statistical analysis, in which nodular sclerosis (NS) and mixed cellularity (MC) types were combined, showed three prognostically different groups: the best prognosis was associated with nodular lymphocyte predominance cases; the worst with FDC-negative NS or MC cases; and an intermediate prognosis with FDC-positive NS or MC cases. In the NS group, the prognosis of FDC-positive cases was better than that of FDC-negative cases. After multivariate analysis, stepwise modeling identified three prognostic factors at diagnosis: stage (P = .001), FDC status (P = .001), and age (P = .06). The authors conclude that in the most common types of Hodgkin's disease (nodular lymphocyte predominance, NS, and MC), FDC status in the neoplastic area(s) bears prognostic relevance, a positive FDC status predicting a favorable prognosis and a negative FDC status an unfavorable one.