Effective therapy for Burkitt's lymphoma: High-dose cyclophosphamide + high-dose methotrexate with coordinated intrathecal therapy

Summary A new treatment for Burkitt's lymphoma (BL) has been devised with coordinated intrathecal (IT) methotrexate (MTX) + high-dose intravenous (IV) MTX with citrovorum factor (CF) rescue and high-dose Cytoxan (CYT). Six patients have been entered on the study. Five patients continue in complete remission at 13+–31+ months (median, 29+ months). One died of septicemia during myelosuppression. Only minor toxicity was seen in four patients. Two patients had severe metabolic disturbances following initial CYT therapy; one of these patients also had reversible, moderately severe hepatorenal MTX toxicity. No neurotoxicity was observed. Results of therapy are impressive in this limited patient group, four of whom were poor-prognosis (Stage C or D) and two of whom were good-prognosis patients (Stage B or AR). The potential for severe toxicity is great; adherence to the criteria for drug administration and close surveillance of the patient in the post-treatment period are mandatory.Plasma and cerebrospinal fluid (CSF) MTX pharmacokinetics were studied in three patients. CSF MTS levels exceeded 10^-6 M with coordinated IT-IV MTX (150 mg/kg body wt.) With MTX infusions at the 200 mg/kg level, therapeutic concentrations were maintained in the CSF for approximately 60 h. Plasma MTX concentrations exceeded 10^-6 M at all infusion dose levels, the duration of the therapeutic concentration increasing with the dose level. Priming IT MTX followed in 24 h by IV MTX, 200 mg/kg assured therapeutic concentrations in plasma and CSF of sufficient duration to cover two generation times of the BL cell.     

Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.

An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours. This pattern of induction is distinct from that caused by agents such as endotoxin, muramyl dipeptide or Corynebacterium parvum. The induction of NOS (iNOS) in the tumour was more persistent (maximal at 3 days) than in other tissues (maximal at 12 h). Immunohistochemical staining suggested that iNOS was located in macrophages and endothelial cells within and around the tumour. Treatment with 5,6-MeXAA also caused substantial increases in plasma nitrite and nitrate (NOx) concentrations that peaked at 8-12 h after 5,6-MeXAA. The increase in plasma NOx was prevented by a NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), indicating that it was due to enhanced production of NO. Tumour-bearing mice were more responsive than controls to 5,6-MeXAA both in their plasma NOx increase and in their lower maximally tolerated dose. L-NIO was unable to prevent the complete tumour necrosis and regression caused by 5,6-MeXAA at a dose that substantially inhibited the increase of plasma NOx. In conclusion, the experimental anti-tumour agent 5,6-MeXAA induced NO synthesis in tumour-associated macrophages and in immunologically active tissues in parallel with its effects on tumour growth. The experiments with a non-selective NOS inhibitor L-NIO, however, suggest that NO is not a significant component in the mechanism of the anti-tumour action of 5,6-MeXAA in this particular model.     

Psychological Problems among Head and Neck Cancer Patients in Relation to Utilization of Healthcare and Informal Care and Costs in the First Two Years after Diagnosis

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients. Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses. Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs. Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.     

Single fresh and frozen-thawed blastocyst transfer using hyaluronan-rich transfer medium

The purpose of this prospective randomized study was to evaluate use of a hyaluronan-rich transfer medium in fresh and frozen-thawed single blastocyst transfer. The study included 279 single blastocyst transfers in women aged<37 years in their first, second or third treatment cycle. According to the type of single blastocyst transfer (fresh elective or frozen-thawed) the women were divided into two study and two control groups. In both study groups (n=130) transfers were performed using hyaluronan and in the control groups (n=149) a conventional transfer medium was used. The results indicate that fresh elective single blastocyst transfer with hyaluronan results in significantly higher pregnancy rates in a selected subgroup of women; those with >or=2 blastocysts developed to day 5 and a previous implantation failure (55% versus 10%; P=0.012). Overall pregnancy rates after fresh elective and frozen-thawed single blastocyst transfer were similar in both study and control groups.     

Orthostatic hypotension in internal medicine wards

Objectives: Most studies of orthostatic hypotension (OH) have focused on community-dwelling and institutionalized patient populations. Less is known about OH in hospitalized patients. Moreover, a comprehensive review of OH in internal medicine wards has not been published in the English literature. Our purpose is to provide current information regarding OH in internal medicine inpatients.

Methods: A comprehensive search of medical databases was performed for potentially relevant articles, using the following keywords: postural or orthostatic hypotension, with the combination of hospitalization or internal medicine. Inclusion criteria were: population of patients hospitalized for acute disorders in internal medicine or geriatric wards with a sample size of ≥50 and publication as an original full-length article in the English language. Data from 14 selected studies are reviewed, including: pathophysiology, evaluation, prevalence, manifestations, risk factors, prognosis, and management.

Results: OH is a common and often symptomatic disorder in elderly internal medicine patients. The prevalence of OH in this population ranges from 22–75%. There are substantial discrepancies between the studies reviewed regarding definitions and means of evaluating OH. OH in internal medicine wards is largely non-neurogenic and multifactorial. The main predisposing factors for OH are prolonged bed rest, hypertension, and heart failure. OH in internal medicine wards is managed mainly with non-pharmacologic interventions, and is frequently reversible.

Conclusions: In internal medicine inpatients, OH warrants attention because this disorder is common, potentially dangerous, and treatable. In the hospital setting, OH should be routinely assessed on ambulation, following the current guidelines for OH definition and meaning.     

The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns.

AIMS: The metabolic syndrome (MetS) is defined as a clustering of cardiovascular risk factors characterized by insulin resistance. We investigated the relationship of the MetS and its single components, defined by all six different criteria, with coronary heart disease (CHD), cardiovascular disease (CVD), and all-cause mortality in a prospective population-based study. METHODS AND RESULTS: The MetS was defined according to the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the National Cholesterol Education Program (NCEP), the American College of Endocrinology (ACE), the International Diabetes Federation (IDF), and the American Heart Association (updated NCEP) criteria. We investgated the relationship of the MetS defined by aforementioned six criteria with CHD, CVD, and all-cause mortality with Cox regression analyses in a non-diabetic Finnish population of 1025 subjects, aged 65-74 years, during the 13-year follow-up. The MetS defined by all aforementioned criteria was associated with a statistically significant risk for CVD mortality when adjusted for all confounding variables (Hazards Ratios, HRs from 1.31 to 1.51). The MetS defined by the WHO, ACE, and IDF criteria was associated with an increased risk of CHD mortality (HRs from 1.42 to 1.58). There was no association between the MetS by any criteria and all-cause mortality. Of the single components of the MetS, the following predicted CVD mortality in multivariable models: impaired fasting glucose by the WHO, NCEP, and ACE criteria (HR 1.34) and by the IDF and updated NCEP criteria (HR 1.29); impaired glucose tolerance by the WHO and ACE criteria (HR 1.55); low HDL cholesterol by the EGIR criteria (HR 1.50) and by the NCEP, IDF, and updated NCEP criteria (HR 1.29); and microalbuminuria according to the WHO definition (HR 1.86). CONCLUSION: The MetS defined by all six current criteria predicts CVD mortality in elderly subjects. However, of the single components of the MetS, IFG, IGT, low HDL cholesterol, and microalbuminuria predicted CVD mortality with equal or higher HRs when compared with the different definitions of the MetS. Therefore, our study suggests that the MetS is a marker of CVD risk, but not above and beyond the risk associated with its individual components.     

New legal requirements for submission of product information to poisons centres in EU member states

Introduction: In the past eight years, the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) has been intensively involved in a European Commission led process to develop EU legislation on the information of hazardous products that companies have to notify to EU Poisons Centres (or equivalent “appointed bodies”). As a result of this process, the Commission adopted Regulation (EU) No 2017/542, amending the CLP Regulation by adding an Annex on harmonised product submission requirements.

Harmonised mixture information requirements: Detailed and consistent information on the composition of the hazardous product will become available to EU Poisons Centres (PC). The information will be submitted by companies to PCs (or equivalent “appointed bodies”) using a web-based software application or in-house software. Two new important features are introduced. Firstly, to be able to rapidly identify the product formula, a Unique Formula Identifier (UFI) on the product label links to the submitted information. Secondly, for better comparability of reports on poisonings between EU member states, a harmonised Product Categorisation System will specify the intended use of a product. Rapid product identification and availability of detailed composition information will lead to timely and adequate medical intervention. This may lead to considerable reduction in healthcare costs.

Additionally, for companies trading across the EU, costs of submission of this information will be reduced significantly.

Next steps: From 2017, an implementation period has started, consisting of a three-year period for stakeholders to implement the new requirements, followed by a gradual applicability for consumer products (2020), professional products (2021) and industrial use-only products (2024). Technical tools to generate the electronic format and the UFI together with guidance documents are expected to be made available by the end of 2017 by the European Chemicals Agency (ECHA). Guidance on interpretation of legal text and ECHA helpdesk support are planned to be ready at the end of 2018.     

Suppression of pro-inflammatory cytokine release by selective inhibition of inducible nitric oxide synthase in mucosal explants from patients with ulcerative colitis

BACKGROUND: In ulcerative colitis (UC), inflammatory damage is associated with increased production of pro-inflammatory cytokines and nitric oxide through the inducible nitric oxide synthase (iNOS) pathway. In an animal model of acute experimental colitis we have previously shown amelioration of inflammation with the highly selective iNOS inhibitor 1400W. The aim of the present study was to investigate the effects of selective iNOS inhibition on the production of pro-inflammatory cytokines by the colon mucosa in UC. METHODS: Inflamed and uninflamed mucosa from patients with severe UC were incubated with a highly selective iNOS inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W), with a relatively selective cNOS inhibitor N(G)-nitro-L-arginine-methyl-esther (L-NAME), or with an NO-donor, S-nitroso-acetylpenicillamine (SNAP). Cytokine concentrations in the incubation medium were quantitated with ELISA. RESULTS: Compared to uninflamed mucosa there was an increase in iNOS protein and nitrotyrosine levels in inflamed mucosal samples. Immunolocalization of iNOS and nitrotyrosine showed their expression in inflammatory cells in the lamina propria. Expression of iNOS was also found in the epithelial brush border. Selective inhibition of iNOS suppressed the release of tumour necrosis factor alpha (TNF-alpha, by 66%) and interleukin-6 (IL-6, by 27%). The NO-donor, SNAP, augmented the secretion of TNF-alpha, IL-6 and IL-1-beta (by 62%, 52% and 175%, respectively) and decreased the release of IL-1 receptor antagonist (IL-1Ra, by 34%) by the inflamed mucosa. Moreover, in uninflamed samples, 1400W suppressed the production of TNF-alpha (by 69%) and incubation with SNAP decreased IL-6 concentrations by 48%. The cNOS over iNOS selective inhibitor L-NAME had no significant effects on the accumulation of cytokines. CONCLUSION: Selective inhibition of iNOS suppresses mucosal TNF-alpha and IL-6 release in active UC, whereas NO seems to exacerbate the inflammatory response. These results suggest that selective iNOS inhibition may have therapeutic promise in the treatment of UC.