[Factor Xa inhibitors in the prevention and treatment of venous thromboembolism in cancer patients]. / Faktor Xa-hemmere til forebygging og behandling av venøs tromboembolisme ved kreft.

Venous thromboembolism is a common complication of cancer. The prevalence varies according to cancer type and increases proportionally with the stage of cancer. In the past 15-20 years, low molecular weight heparin has been recommended as the first-line treatment. New international guidelines now allow for use of direct factor Xa inhibitors both as prophylaxis and treatment for venous thromboembolism. Prophylaxis should as a general rule only be initiated in patients with moderate to high risk. Bleeding risk assessment is important before starting anticoagulation. Both thrombosis and bleeding risk can change and should therefore be assessed on an ongoing basis. In this clinical review, use of anticoagulation therapy in cancer patients is discussed with particular emphasis on the use of direct factor Xa inhibitors.

Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment.

Cancer patients are often encouraged to receive seasonal influenza vaccination. The monoclonal antibody rituximab is widely used in treatment of non-Hodgkin lymphoma. This results in a prolonged depletion of normal B cells, which might impair humoral responses. The aim of the present study was to investigate whether lymphoma patients undergoing rituximab-containing treatment regimens or having received such regimens within the past 6 months were able to mount protective antibody responses to the influenza A(H1N1) 2009 virus vaccine Pandemrix during the 2009 "swine flu" pandemic. Contrary to the control group, where 82% responded adequately to the vaccine, none of the 67 patients achieved protective antibody titers, suggesting that lymphoma patients receiving rituximab-containing regimens might not benefit from this vaccine. It is important that doctors who care for such patients are aware that they may fail to respond not only to the influenza vaccine, but also to other common vaccines.

Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

The Norwegian experience with penicillin G plus an aminoglycoside as initial empiric therapy in febrile neutropenia; a review.

BACKGROUND: The occurrence of antibiotic resistance and the use of broad-spectrum antibiotics are relatively low in Norway. The national recommendation in febrile neutropenia (FN) is prompt initial therapy with penicillin G plus an aminoglycoside. We sought to evaluate the evidence behind this recommendation. METHODS: We did a literature search in Medline and EMBASE with search terms penicillin, aminoglycoside and febrile neutropenia. RESULTS: Seven Norwegian studies (six adult and one pediatric) conducted over the last 25 years were identified. They all conclude that penicillin G plus an aminoglycoside are effective and safe initial empiric antibiotic therapy in FN provided the regimen is modified if the clinical response is unsatisfactory. Overall 40-50% of the patients required only penicillin G and an aminoglycoside during their FN episode. The overall fatality rate was similar in the Norwegian and in international studies. CONCLUSION: Many countries use a broad-spectrum ß-lactam as initial therapy in FN. International experts are sceptic towards the Norwegian recommendations. We discuss the arguments for and against penicillin G plus an aminoglycoside in FN. The main arguments to continue the Norwegian treatment tradition are the satisfactory clinical results and the reason to believe that it contributes to the low levels of antibiotic resistance in Norway.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

[Penicillin and aminoglycoside in febrile neutropenia]. / Penicillin og aminoglykosid ved febril nøytropeni.

BACKGROUND: Fever in patients with neutropenia may indicate a serious/lethal underlying bacterial sepsis. In Norway, penicillin G in combination with an aminoglycoside is the therapy of choice for this indication. In most countries, empiric monotherapy starts with a broadspectrum betalactam antibiotic. MATERIAL AND METHODS: Review of the literature and expert opinion identified five Norwegian studies evaluating therapy with penicillin in combination with an aminoglycoside in febrile neutropenia. These studies are presented and assessed. RESULTS: Mortality in febrile neutropenia is approximately 5 % both in the Norwegian studies and in larger international trials. Therapy which starts with penicillin and an aminoglycoside needs to be modified more frequently(60 %) than when it starts with broadspectrum betalactam monotherapy (40 %). The Norwegian studies span 20 years. Clinical blood culture isolates from this group of patients show stable resistance patterns. INTERPRETATION: In spite of methodological weaknesses, all the studies have the same conclusion: penicillin G in combination with an aminoglycoside is an effective and safe initial empiric therapy provided it is modified when the clinical course is unsatisfactory.

Pneumocystis jirovecii pneumonia in B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen.

We report six cases of Pneumocystis jirovecii pneumonia (PCP) verified by immunoflourescence/polymerase chain reaction of bronchoalveolar fluid among 46 lymphoma patients (13%) who received rituximab-CHOEP-14 at our institution. PCP prophylaxis should be standard management for this group of patients and also considered for patients treated with rituximab-CHOP-14, CHOP-14 or CHOEP-14.

[Cryptococcal meningitis]. / Kryptokokkmeningitt.

BACKGROUND: Cryptococcus neoformans causes systemic disease in patients with immunodeficiency. The incidence of cryptococcal meningitis has increased in parallel with that of HIV infection. Cancer is also a known predisposing factor. MATERIAL AND METHODS: We present two case reports and a review of the literature concerning the epidemiology, diagnostics and treatment of cryptococcal meningitis. RESULTS: The incidence of cryptococcal meningitis in Scandinavia seems to be lower than in other parts of the world. Clinical signs and symptoms are often uncharacteristic. Detection of antigen in spinal fluid is a sensitive and fast test. INTERPRETATION: Cryptococcal meningitis is a rare disease, often with uncharacteristic symptoms. Patients with haematological malignancies have a higher risk of contracting this disease. It is a differential diagnosis when neurological symptoms occur in these patients.

A large outbreak of Listeria monocytogenes infection with short incubation period in a tertiary care hospital.

OBJECTIVES: Listeria monocytogenes is a foodborne pathogen with a high mortality rate. We report a large, nosocomial outbreak of Listeria monocytogenes infection. METHODS: Patients with L. monocytogenes isolated from a sterile site, or from faeces when diarrhoea and fever were present, were included. Clinical data were collected from the patient records. The incubation period was calculated as the time between exposure and start of symptoms. RESULTS: Seventeen patients (11 women, median age 64 years) were infected of whom 15 patients were at increased risk for listeriosis. Eleven patients received empiric antibiotic treatment, eight of them with cephalosporins. Three patients died with a resulting mortality rate of 18%. The source of the outbreak was a Camembert cheese made from pasteurised milk containing up to 360 million colony forming units per portion. The median incubation period was 3-4 days. CONCLUSIONS: The incubation period in this outbreak was significantly shorter than previously reported, a fact that may be due to the high number of ingested bacteria. Furthermore, food restrictions in hospitals seem warranted, as do treatment with antibiotics effective against L. monocytogenes in at-risk populations.

Tobramycin once versus three times daily, given with penicillin G, to febrile neutropenic cancer patients in Norway: a prospective, randomized, multicentre trial.

OBJECTIVES: Penicillin G with an aminoglycoside is the standard initial empirical treatment in febrile neutropenia in Norway. It has been argued that giving the aminoglycoside once daily to neutropenic patients with Gram-negative bacteraemia may be hazardous when penicillin G is the beta-lactam antibiotic. We questioned this argument and hypothesized that tobramycin once daily was as efficacious as three times daily. METHODS: We conducted a randomized prospective multicentre study, comparing the efficacy of tobramycin 6 mg/kg once (arm A) versus three times (arm B) daily, plus penicillin G 5 million IU x 4, in febrile neutropenic cancer patients. PRIMARY OUTCOME: modification of the antibiotic regimen. RESULTS: One hundred and seventy-four patients were evaluable for intention-to-treat analyses. One hundred and fifty-five patients had lymphoma or leukaemia as the underlying cancer diagnosis. In arm A, 35 of 88 patients and in arm B, 34 of 86 patients, that is 40% in both arms had no modification of the antibiotic regimen. No patients died while participating in the study. Upon modification of the antibiotic regimen, all patients were successfully treated. The increase in serum creatinine was modest and similar in the two treatment groups. CONCLUSIONS: When administered with penicillin G, tobramycin given once daily was as efficacious and safe as tobramycin given three times daily in cancer patients with febrile neutropenia in Norway, provided the regimen was modified according to the clinical response.

Invasive fungal infections at The Norwegian Radium Hospital 1998-2003.

The study evaluates the clinical and microbiological data from patients with documented invasive fungal infections at a comprehensive cancer centre in Norway. Relevant microbiology and pathology databases were screened and medical records were reviewed. 17 yeast infections, including 1 case of cryptococcal meningitis, and no mould infections were found. Diagnostically, in 30% of the positive blood cultures Candida only grew in the Mycosis IC/F bottle. Half of the patients had febrile neutropenia, and 30% had undergone complicated abdominal or pelvic surgery. 12 out of 13 positive blood cultures were Candida albicans. 30% of the patients died of acute septic candidiasis. Within 14 months 90% of the patients were dead from their underlying diseases. A diagnosis of invasive fungal infection is an ominous sign for the patient's overall prognosis.