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Biomedical subjects

H L Janssen

Publications and source records attributed to H L Janssen.

At least 19 recordsLinked to original sources
PubMed2005

Hypoxia in head and neck cancer: how much, how important?

BACKGROUND: Hypoxia develops in tumors because of a less ordered, often chaotic, and leaky vascular supply compared with that in normal tissues. In preclinical models, hypoxia has been shown to be associated with treatment resistance and increased malignant potential. In the clinic, several reports show the presence and extent of tumor hypoxia as a negative prognostic indicator. This article reviews the biology and importance of hypoxia in head and neck cancer. METHODS: A review of literature was carried out and combined with our own experience on hypoxia measurements using exogenous and endogenous markers. RESULTS: Hypoxia can increase resistance to radiation and cytotoxic drugs and lead to malignant progression, affecting all treatment modalities, including surgery. Hypoxia measurements using electrodes, exogenous bioreductive markers, or endogenous markers show the presence of hypoxia in most head and neck cancers, and correlations with outcome, although limited, consistently indicate hypoxia as an important negative factor. Each hypoxia measurement method has disadvantages, and no "gold standard" yet exists. Distinctions among chronic, acute, and intermediate hypoxia need to be made, because their biology and relevance to treatment resistance differ. Reliable methods for measuring these different forms in the clinic are still lacking. Several methods to overcome hypoxia have been tested clinically, with radiosensitizers (nimorazole), hypoxic cytotoxins (tirapazamine), and carbogen showing some success. New treatments such as hypoxia-mediated gene therapy await proper clinical testing. CONCLUSIONS: The hypoxia problem in head and neck cancer needs to be addressed if improvements in current treatments are to be made. Increased knowledge of the molecular biology of intermediate, severe, and intermittent hypoxia is needed to assess their relevance and indicate strategies for overcoming their negative influence.

Antineoplastic Agents↗
PubMed2001

Is combination therapy with lamivudine and interferon-alpha superior to monotherapy with either drug?

For the treatment of chronic hepatitis B (CHB) two drugs have been licensed world-wide: interferon-alpha (IFN) and lamivudine. Both drugs significantly increase the hepatitis B e-antigen (HBeAg) seroconversion rate, but a sustained treatment response occurs in less than 40% of patients. To explore whether there is an additional benefit of combining these two drugs, we reviewed the literature on lamivudine-IFN combination therapy in comparison to the two monotherapies in compensated, HBeAg-positive, CHB patients. We focussed on two clinically relevant outcome measures: HBeAg seroconversion, and change in liver histology. Candidates for lamivudine-IFN combination therapy were, previously untreated, patients with moderately elevated alanine aminotransferase (ALT). Such regimen should still be considered experimental. Viral kinetics may provide insight into how long therapy should be continued; prolongation of therapy to 52 weeks currently appears a reasonable approach. According to principles of anti-viral therapy today, simultaneously dosing of both drugs is to be preferred, since rapid maximal virus suppression is thought to be essential to prevent drug resistance and enhance seroconversion. From an immunological point of view, pre-treatment with lamivudine or IFN may alter the virus-host balance and set the stage for the other drug to enhance the effect of treatment. Further clinical research on lamivudine-IFN combination therapy appears warranted.

Antiviral Agents↗
PubMed2001

The prognostic value of histology in the assessment of patients with Budd-Chiari syndrome.

BACKGROUND/AIMS: It is unclear whether treatment of patients with Budd-Chiari syndrome (BCS) should be based on liver histology, as large histopathological studies have not been performed. We investigated the relationship between the histopathological findings and survival. METHODS: We studied the clinical features and findings on biopsy specimens in 45 patients with BCS who were admitted to four tertiary referral medical centers. Histological findings, i.e. congestion, necrosis, inflammation and fibrosis, were graded. Survival was assessed in relation to histological findings and clinical features at the time of diagnosis as well as in relation to subsequent treatment with or without portosystemic shunting. RESULTS: Centrilobular congestion, centrilobular necrosis, lobular inflammation and portal inflammation were not significantly related to survival. In addition, there was no association between either pericentral or periportal fibrosis and survival. Univariate analysis revealed that the prothrombin time and Child-Pugh score were significantly related to survival (P = 0.005 and Ptrend = 0.02, respectively). Multivariate analysis yielded the Child-Pugh score, serum alanine aminotransferase (ALT) and treatment with portosystemic shunting as independent prognostic indicators. CONCLUSIONS: We found no evidence for a relationship between early liver pathology and survival. Child-Pugh score, serum ALT and portosystemic shunting appeared to be prognostic indicators for patients with BCS.

Adolescent↗
PubMed2001

Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis.

BACKGROUND AND AIMS: The bleeding tendency of patients suffering from cirrhosis is in part ascribed to accelerated fibrinolysis. In this study, the role of the recently discovered inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI) in cirrhosis was examined. METHODS: In 64 patients with cirrhosis of varying severity, TAFI antigen levels were measured by enzyme-linked immunosorbent assay and compared with TAFI levels in control subjects. Furthermore, a plasma-based fibrinolysis assay was performed in the presence and absence of a specific inhibitor of activated TAFI. RESULTS: TAFI levels were decreased in cirrhosis. Mean TAFI levels were 66% in Child's A, 55% in Child's B, 47% in Child's C cirrhosis, and 26% in acute liver failure. Decreased TAFI antigen levels were highly correlated with antithrombin and alpha(2)-antiplasmin activity levels. Clot lysis times and clot lysis ratio (defined as ratio between clot lysis time in the absence and presence of a specific inhibitor of activated TAFI) of cirrhotics were not significantly different from healthy controls. CONCLUSIONS: Despite decreased levels of TAFI and other components of the fibrinolytic system, no evidence of increased plasma fibrinolytic potential in cirrhosis is observed using the plasma-based assay of this study. The reduction of antifibrinolytic factors in cirrhosis is compensated by the concomitant reduction in profibrinolytics.

Antigens↗
PubMed2001

Extrahepatic portal vein thrombosis: aetiology and determinants of survival.

BACKGROUND: Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS: To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984-1997 in eight university hospitals. RESULTS: Mean follow up was 3.9 years (range 0.1-13.1). Overall survival was 70% (95% confidence interval (CI) 62-76%) at one year, 61% (95% CI, 52-67%) at five years, and 54% (95% CI, 45-62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87-98%), 89% (95% CI 78-94%), and 81% (95% CI 67-89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION: We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension.

Adolescent↗
PubMed2001

Interferon-alpha therapy for chronic hepatitis B: early response related to pre-treatment changes in viral replication.

Chronic hepatitis B patients with low pre-treatment HBeAg (and HBV-DNA) levels are more likely to respond to interferon-alpha therapy. In retrospect, this low level of HBeAg may have been reached just before the start of therapy. Pre-treatment changes in HBeAg levels were studied in 121 patients undergoing interferon-alpha 2B therapy. HBeAg was monitored by the AxSYM HBe 2.0 Quantitative (Abbott Laboratories) and HBV-DNA by liquid hybridisation (Abbott Laboratories). At the end of treatment (week 16) 24 patients had responded (HBeAg and HBV-DNA below the level of detection). Response was significantly (P = 0.007) related to a decrease in HBeAg level before the start of therapy. Eight of the 24 (33%) responding patients exhibited a > 50% decrease in HBeAg level just before the start of therapy compared to 7 of the 97 (7%) non-responding patients. The geometric mean titre of HBeAg decreased significantly (P < 0.005; 8-week period before start) among responding patients (271 ( 98 PEI U/ml) in contrast to non-responding patients (737 ( 724 PEI U/ml). Planning the start of interferon treatment just after a spontaneous decrease in HBV replication may increase the response rate for interferon-alpha therapy.

DNA, Viral↗
PubMed2000

Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.

In a collaborative multicenter case-control study, we investigated the effect of factor V Leiden mutation, prothrombin gene mutation, and inherited deficiencies of protein C, protein S, and antithrombin on the risk of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). We compared 43 BCS patients and 92 PVT patients with 474 population-based controls. The relative risk of BCS was 11.3 (95% CI 4.8-26.5) for individuals with factor V Leiden mutation, 2.1(95% CI 0.4-9.6) for those with prothrombin gene mutation, and 6.8 (95% CI 1.9-24.4) for those with protein C deficiency. The relative risk of PVT was 2.7 (95% CI 1.1-6.9) for individuals with factor V Leiden mutation, 1.4 (95% CI 0.4-5.2) for those with prothrombin gene mutation, and 4.6 (95% CI 1.5-14.1) for those with protein C deficiency. The relative risk of BCS or PVT was not increased in the presence of inherited protein S or antithrombin deficiency. Concurrence of either acquired or inherited thrombotic risk factors was observed in 26% of the BCS patients and 37% of the PVT patients. We conclude that factor V Leiden mutation and hereditary protein C deficiency appear to be important risk factors for BCS and PVT. Although the prevalence of the prothrombin gene mutation was increased, it was not found to be a significant risk factor for BCS and PVT. The coexistence of thrombogenic risk factors in many patients indicates that BCS and PVT can be the result of a combined effect of different pathogenetic mechanisms.

Adult↗
PubMed2000

Budd-Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability.

A young female, who had been in excellent health and had used third-generation oral contraceptives, was admitted to hospital because of abdominal pain and ascites. Budd-Chiari syndrome (BCS) was diagnosed by radiographic and histological examination. Tests for myeloproliferative disease, deficiency of coagulation inhibitors and paroxysmal nocturnal haemoglobinuria were negative. DNA investigation showed a double heterozygous defect: the Arg506Gln mutation in the factor V gene (factor V Leiden) and G20210A nucleotide substitution in the prothrombin gene. This double defect was also found in the patient's father, who had never experienced an episode of venous thromboembolism. Genetic and acquired thrombogenic risk factors are being detected increasingly in patients with BCS. With the discovery of new genetic defects leading to hypercoagulabiulity an increasing number of patients with serious thrombotic manifestations, such as BCS, will exhibit concurrence of hereditary and acquired risk factors for thrombosis.

Adolescent↗
PubMed2000

Interferon-alpha therapy in chronic hepatitis B: early monitoring of hepatitis B e antigen may help to decide whether to stop or to prolong therapy.

Hepatitis B e antigen (HBeAg) was quantified before, during and after interferon-alpha administration in a trial of 162 chronic hepatitis B patients treated for 16 or 32 weeks. In 139 of these patients we examined the prognostic value of the pretreatment level of HBeAg and the reduction in HBeAg level at weeks 4 and 8 for response at week 16. Multivariate analysis showed that the HBeAg pretreatment level is a highly significant predictor of response (judged as HBeAg and hepatitis B virus [HBV] DNA negativity), followed by a decrease in HBeAg from the start of therapy to week 8. During the first 8 weeks of therapy, a decrease in HBeAg of less than 40%, as observed in 30% of the patients, consistently resulted in non-response. After 16 weeks of treatment, non-responding patients were randomly assigned to receive no further treatment (n=57) or prolonged treatment for another 16 weeks (n=61). In both groups, changes in the HBeAg level from the start of (the first) therapy to week 8, but not the pretreatment HBeAg level itself, were significantly related to the response at week 52 (the end of follow-up). Changes in the HBV DNA level had no additional predictive value for response at weeks 16 or 52. Therefore, instead of sequential HBV DNA assessment, we recommend monthly monitoring of HBeAg during IFN-alpha therapy.

Antiviral Agents↗
PubMed2000

Aspergillus osteomyelitis after liver transplantation: conservative or surgical treatment?

We report on a liver transplant recipient who developed coxarthritis and lumbar spondylodiscitis due to Aspergillus flavus. He was treated with high-dose liposomal amphotericin B for 2 months followed by itraconazole. Because of intractable pain and severe, irreversible damage of the left hip, a Girdlestone resection was performed. The spondylodiscitis was treated successfully with anti-fungal agents only, which indicates that, in the absence of neurological impairment, good clinical outcome can be achieved without surgery. This case demonstrates that surgical therapy, which is often proclaimed as unavoidable for the treatment of Aspergillus osteomyelitis, should be considered in particular in the case of intolerable pain due to irreversible joint damage or involvement of vital organs.

Adult↗
PubMed2000

Changing perspectives in portal vein thrombosis.

The aetiology of portal vein thrombosis (PVT) is heterogeneous. Important primary risk factors for PVT are cirrhosis, hepatobiliary malignancies and pancreatitis. Newly discovered thrombotic risk factors, such as latent myeloproliferative disorders and prothrombotic genetic defects, have also been identified as major risk factors for PVT. At least one-third of PVT patients demonstrate a combination of thrombotic risk factors. PVT, which does not have a detrimental effect on liver function, usually becomes manifest as a variceal haemorrhage in the oesophagus months to years after the development of thrombosis. Owing to intact coagulation variceal bleeding has a better prognosis among patients with PVT than cirrhotics. Endoscopic sclerotherapy or band ligation is the primary therapeutic option for variceal bleeding in patients with PVT. It is questionable whether anticoagulant therapy should be started, since it has not proven beneficial for most PVT patients. Therapy with anticoagulants is only recommended for those with acute PVT (especially in association with mesenteric vein thrombosis), those who recently underwent a portosystemic shunt procedure, and those with other thrombotic manifestations, particularly in case of proven hypercoagulability. Mortality of patients with PVT may be associated with concomitant medical conditions which lead to the PVT or with manifestations of portal hypertension, such as variceal haemorrhage. Multivariate analysis of a large Dutch PVT population has shown that age, malignancy, ascites and the presence of mesenteric vein thrombosis are independently related to survival. Death due to a variceal haemorrhage is rare. Poor outcome of PVT thus appears to be associated primarily with concomitant diseases which lead to PVT, and not the complications of portal hypertension. It is therefore uncertain whether surgical portosystemic shunting affects survival favourably.

Anticoagulants↗
PubMed1999

[Portal vein thrombosis: causes and treatment].

Portal vein thrombosis (PVT) has a heterogeneous aetiology. Recently discovered thrombotic risk factors such as latent myeloproliferative disorders and prothrombotic genetic defects are important in the aetiology of PVT. At least one-third of the PVT patients exhibit a combination of thrombotic risk factors. Treatment with anticoagulant drugs has not proved beneficial for most PVT patients. Therapy with anticoagulants is only recommended in those with acute PVT, in those who recently underwent a portosystemic shunt procedure and in those with other thrombotic manifestations, particularly in case of proved hypercoagulability. Due to intact coagulation, oesophageal varices bleeding in patients with PVT has a better prognosis than in cirrhotics.

Acute Disease↗
PubMed1999

[Chronic hepatitis-b-virus infections: new options for antiviral therapy].

The possibilities for antiviral treatment of patients with chronic hepatitis B virus (HBV) infections have been in flux for the last few years. Apart from interferon alpha, oral nucleoside analogues are given a place. The treatment focuses on the group of patients with active virus multiplication (hepatitis B e antigen (HBeAg) and HBV DNA are demonstrable), abnormal liver enzyme values and histologically demonstrated inflammatory activity in the liver. For the individual patient the pros and cons of protracted virus inhibition should be weighted by means of an orally administered nucleoside analogue such as lamivudine, immunostimulation with injections of interferon alpha or a combination of these two.

Antiviral Agents↗
PubMed1999

Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).

Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

Adolescent↗
PubMed1999

Severe hepatitis and pure red cell aplasia in adult Still's disease: good response to immunosuppressive therapy.

Adult-onset Still's disease is a systemic inflammatory disorder with a highly variable clinical course. Mild hepatitis and anemia are common manifestations. We describe a patient with adult Still's disease who developed a severe hepatitis and a life-threatening pure red cell aplasia. The hepatitis developed after treatment with NSAIDs was started. The patient was successfully treated with a combination of prednisone, cyclosporin, and methotrexate. Physicians should be aware that severe hepatitis and pure red cell aplasia can occur in adult Still's disease. We recommend a careful monitoring of liver functions in patients with adult Still's disease who are being treated with NSAIDs.

Adult↗
PubMed1998

Fatal cerebral oedema associated with primary dengue infection.

Encephalopathy associated with dengue fever is considered to be a rare condition in adults. We describe a patient with a primary dengue infection who, in the absence of overt signs of dengue shock syndrome, died due to progressive cerebral oedema. Autopsy findings demonstrated loss of integrity of cerebral vascular endothelium and involvement of complement activation.

Adult↗