Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Trends and gaps in climate change and health research in North America.

The Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report (2014) assessed the state of climate change and health knowledge, globally through the Human Health: Impacts, Adaptation, and Co-Benefits Chapter and regionally through chapters, such as the North America Chapter. With IPCC's 6th Assessment Report scheduled to be released in 2021-22, we asked: how has climate change and health research in North America advanced since the IPCC's 5th Assessment Report in 2014? Specifically, we systematically identified and examined trends in the extent, range, and nature of climate-health research conducted in North America. We used a scoping review methodology to systematically identify literature and map publication trends. A search string was used to search five academic databases. Two independent reviewers first screened titles and abstracts, and then the full texts of articles for relevance. Research articles and reviews using systematic methods published since 2013 were eligible for inclusion, and no language restrictions were applied. To be included, articles had to measure and link climatic variables or hazards to health outcomes in North America. Relevant articles were analysed using descriptive statistics to explore publication trends. The number of climate-health articles has significantly increased since the last IPCC Assessment Report. Published research about climate change impacts, heat-related mortality and morbidity, and respiratory illness taking place in urban centres and in the USA continue to dominate the North American climate-health literature, reflected by the high proportion of articles published. Important research gaps on previously neglected climate-sensitive health outcomes, however, are beginning to be filled, including climate change impacts on mental health, nutrition, and foodborne disease. We also observed progress in research that included future projections of climate-health risks; however, projection research is still relatively nascent and under-studied for many climate-sensitive health outcomes in North America, and would benefit from considering social and demographic variables in models. Important research disparities in geographical coverage were noted, including research gaps in Canada and Mexico, and in rural and remote regions. Overall, these publication trends suggest an improved understanding of exposure-response relationships and future projections of climate-health risks for many climate-sensitive health outcomes in North America, which is promising and provides an evidence-base to inform the IPCC 6th Assessment Report. Despite these advancements and considering the urgent policy and practice implications, more research is needed to deepen our understanding of climate-sensitive health outcomes, as well as examine new arising issues that have limited evidence-bases. In particular, transdisciplinary and cross-sector research, that includes the social sciences, examining current and future climate-health adaptation, mitigation, and the adaptation-mitigation nexus should become a top priority for research, given the urgent need for this evidence to inform climate change policies, actions, and interventions.

Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A rare case of Waldenström's macroglobulinaemia-associated cryoglobulinaemia vasculitis.

This case report presents a patient with vasculitis as a presenting symptom of type I cryoglobulinaemia due to lymphoproliferative disease. This is an uncommon cause of vasculitis, but important to recognise, as it influences treatment decisions. We discuss the differential diagnosis and extensive diagnostic approach of vasculitis. Above all, this case emphasizes that even a limited quantity of paraproteins can cause severe symptoms.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Is the 15∆ Base in Prism Test Reliable for Detection of Amblyopia in Anisometropic Patients?

PURPOSE: The 15∆ base in prism test (15∆BIPT) introduced by Gobin is often used in The Netherlands to detect fixation preference, especially in young and preverbal children in whom a reliable measurement of the visual acuity (VA) is difficult. It is assumed that the fixation preference detected by the 15∆BIPT can be used to predict the presence of amblyopia. The aim of this retrospective case note review was to investigate the accuracy of the 15∆BIPT in detection of amblyopia in anisometropic patients. METHODS: Four hundred and twelve files of anisometropic patients visiting the orthoptic department of The Rotterdam Eye Hospital were analyzed. Amblyopia was defined as an intraocular difference in VA of 2 or more Snellen lines. The sensitivity, specificity, and positive and negative predictive values of the 15∆BIPT were calculated and the receiver operating characteristic (ROC) curve was plotted. RESULTS: One hundred and fifty-two patients ranging from 3.3-13.1 years of age (median 5.4 years) met the inclusion criteria. One hundred and two patients were diagnosed with amblyopia. Best-corrected median VA of the best eye was 1.0 (range 0.5-1.2) and the worst eye 0.70 (range 0.05-1.2). Sensitivity of the 15∆BIPT (based on detecting amblyopia) was 34.3%. Specificity was 88.0%. The positive predictive value was 85.4% versus a negative predictive value of 39.6%. The area under the ROC curve (AUC) was 0.65 (95% CI 0.56-0.74). CONCLUSION: The low sensitivity, large number of false negatives and the AUC show that the 15∆BIPT can be considered a poor test for detecting amblyopia in anisometropic patients.

A compensatory mutagenesis study of a conserved hairpin in the M gene segment of influenza A virus shows its role in virus replication.

RNA structures are increasingly recognized to be of importance during influenza A virus replication. Here, we investigated a predicted conserved hairpin in the M gene segment (nt 967-994) within the region of the vRNA 5' packaging signal. The existence of this RNA structure and its possible role in virus replication was investigated using a compensatory mutagenesis approach. Mutations were introduced in the hairpin stem, based on natural variation. Virus replication properties were studied for the mutant viruses with disrupted and restored RNA structures. Viruses with structure-disrupting mutations had lower virus titers and a significantly reduced median plaque size when compared with the wild-type (WT) virus, while viruses with structure restoring-mutations replicated comparable to WT. Moreover, virus replication was also reduced when mutations were introduced in the hairpin loop, suggesting its involvement in RNA interactions. Northern blot and FACS experiments were performed to study differences in RNA levels as well as production of M1 and M2 proteins, expressed via alternative splicing. Stem-disruptive mutants caused lower vRNA and M2 mRNA levels and reduced M2 protein production at early time-points. When the RNA structure was restored, vRNA, M2 mRNA and M2 protein levels were increased, demonstrating a compensatory effect. Thus, this study provides evidence for functional importance of the predicted M RNA structure and suggests its role in splicing regulation.

Human metapneumovirus in haematopoietic stem cell transplantation recipients: a case series and review of the diagnostic and therapeutic approach.

Human metapneumovirus (hMPV) is a paramyxovirus that causes respiratory tract infections ranging from mild upper airway infection to severe pneumonia. Patients with haematological disease, especially haematopoietic stem cell transplantation (HSCT) recipients, are more likely to develop more severe infections. We describe three cases of hMPV infection in HSCT patients. The most reliable diagnostic procedure for hMPV is multiplex ligation-dependent probe amplification (MLPA) on a nasopharyngeal swab. Sensitivity and specificity of MLPA to detect hMPV is high and time to diagnosis is short. A number of other respiratory pathogens can be tested in one test run. Treatment is mainly supportive and only a few antiviral agents are available for treating paramyxovirus infections. Ribavirin and immunoglobulins were reported to be effective in cases of HSCT patients with hMPV pneumonia but their efficacy has not been studied in randomised trials.

Pure orbital blowout fractures reconstructed with autogenous bone grafts: functional and aesthetic outcomes.

The purpose of this study was to investigate the ophthalmic clinical findings following surgical reconstruction with autogenous bone grafts of pure blowout fractures. A retrospective review of 211 patients who underwent surgical repair of an orbital fracture between October 1996 and December 2013 was performed. Following data analysis, 60 patients who were followed up over a period of 1 year were included. A solitary floor fracture was present in 38 patients and a floor and a medial wall fracture in 22 patients. Comparing preoperative findings between these two groups, preoperative diplopia and enophthalmos were almost twice as frequent in the group with additional medial wall fractures: diplopia 8% and 14% and enophthalmos 18% and 55%, respectively. One year following surgery there was no diplopia present in either group. In the solitary floor fracture group, 3% still had enophthalmos. It can be concluded that at 1 year following the repair of pure orbital floor fractures using autogenous bone, good functional and aesthetic results can be obtained. In the group with both floor and medial wall fractures, no enophthalmos was found when both walls were reconstructed. When the medial wall was left unoperated, 29% of patients still suffered from enophthalmos after 1 year.

Inter-examiner variability and agreement of the alternate prism cover test (APCT) measurements of strabismus performed by 4 examiners.

PURPOSE: To investigate the inter-examiner variability and agreement of the alternate prism cover test (APCT) measurements of strabismus at near and distance fixation performed by 4 examiners. METHODS: Forty-one participants (median age 12 years, range 3-74) with horizontal strabismus completed APCT measurements at near (1/3 m) and distance (5 m) fixation. Each participant was assessed by 4 masked experienced orthoptists on the same visit. Bland-Altman plots and inter-examiner variability (1.96xSD of the difference) were used to determine a clinical value suggestive of real change. RESULTS: The inter-examiner variability was ±10 prism diopters (PD) at near and ±9 PD at distance fixation. The mean difference between measurements per examiner pair for near fixation ranged between -3 and 1.5 PD, with inter-examiner variability ranging between ±6.9 and ±12.5 PD, and mean difference for distance fixation between -0.8 and 1.6 PD, with inter-examiner variability ranging between ±7.5 and ±11.7 PD. Larger variability was found between some examiner pairs than others. Magnitude of the deviation, test distance, and age had no significant influence on the variation in APCT measurement. CONCLUSION: A variation in APCT measurement between 4 examiners of less than 10 PD for both near and distance fixation is likely to be due to inter-examiner variability. Changes of 10 PD or more are suggestive of a real change and may be employed as a management threshold.

A method for the determination of antibody affinity using a direct ELISA.

Antibody affinity is of major significance in immunoassays. Since affinity may be influenced by the immunoassay methodology it is important to determine this parameter under the conditions of the assay used. Here a method is described for the determination of binding constants (K) in a direct ELISA with the use of the computer program LIGAND. Five of the antibodies studied bound to their antigen with two classes of antigen binding site, while all the other antibodies studied reacted with only a single class of antigen binding site. The accuracy of the method and the implications for antigen-antibody reactions are discussed.

Sister chromatid exchanges, hyperdiploidy and chromosomal rearrangements studied in cells from melanoma-prone individuals belonging to families with the dysplastic nevus syndrome.

Cytogenetic investigations were performed on 25 individuals belonging to six melanoma-prone families with multiple melanocytic lesions (the dysplastic nevus syndrome, DNS). Patients having DNS with or without a history of melanoma were compared with clinically normal relatives and unrelated normal controls. The results indicate normal frequencies of hyperdiploidy and spontaneous sister chromatid exchanges in the fibroblasts of all individuals studied. Karyotypic analyses were carried out on the members of one family. The patients with DNS had a normal constitutional karyotype. In lymphocytes or fibroblasts from five patients, however, increased frequencies of cells with random chromosomal rearrangements were observed. These abnormalities, mainly translocations and inversions, were not found in two of the patients' spouses and in six clinically normal relatives. In the fibroblast cultures considerable clonal selection of cytogenetically abnormal cells occurred.

Growth and differentiation of pluripotent embryonal carcinoma cells in the Snell dwarf mouse.

To investigate the influence of hormones on the process of cellular differentiation the growth and differentiation of a transplantable tumour, induced by inoculation of pluripotent mouse embryonal carcinoma (EC) cells have been studied in athymic nude mice and, normal and hypopituitary Snell dwarf mice. All athymic nude mice developed tumours independent of the numbers of cells inoculated. In contrast, the tumour percentage in normal Snell mice was lower, showing a dose-dependent increase of takes. In dwarfs tumour percentage was comparable with that observed in normal Snell mice. The morphological differentiation of teratocarcinomas grown in athymic nude mice, normal and dwarfed Snell mice shows derivatives of all three germ layers next to undifferentiated embryonal carcinoma cells. This suggests that the pituitary hormonal deficiencies of the dwarfs (growth hormone, thyroid stimulating hormone and prolactin) did not influence the tumour induction nor the development of the different tissues present in this type of tumour.

Developmental characteristics of somatic cell hybrids between totipotent mouse teratocarcinoma and rat intestinal villus cells.

Hybrids between mouse PCC4-azal teratocarcinoma cells and rat epithelial intestinal villus cells (PCI hybrids) are phenotypically teratocarcinoma cells. They express several teratocarcinoma-specific traits but do not express functions specific for differentiated cells. Tumour formation is partially or completely suppressed. Some of the hybrids show more extensive differentiation both in vitro and in vivo than the PCC4-azal parental line. The hybrids are capable of endoderm formation in monolayer cultures and of the formation of embryoid bodies in suspension cultures. Two of the tumour-forming hybrids generate derivatives of all three germ layers, whereas differentiation in the PCC4-azal tumours is restricted to the formation of primitive neuronal tissues.

Cell survival in canine aortic heart valves stored in nutrient medium.

For transplantation of viable aortic valves a period of preservation will generally be needed. To maintain cell viability during this preservation period valves can be stored in nutrient medium after sterilisation in an antibiotic solution. To obtain quantitative data about the survival of aortic valve fibroblasts after preservation, we determined the number of viable fibroblasts in canine aortic valves after several weeks of preservation. The results shows that after storage of 1 week in nutrient medium cell survival is about 80%, after 2 weeks cell survival has declined substantially, while after 3 weeks survival is already unacceptably low. Storage for periods over 4 weeks results in almost completely non-viable aortic valves. These results show that only valves preserved for 1 to 2 weeks in nutrient medium can be considered as viable aortic valves.

The uptake of R-type cobalamin-binding protein by isolated rat liver cells.

The uptake of R-type cobalamin-binding protein from human granulocytes and plasma by isolated parenchymal rat liver cells has been studied. When [57Co] cyanocobalamin-saturated granulocyte-binding protein or transcobalamin III was incubated with the liver cells in a concentration of 500 pM, more than 80% of the vitamin was taken up in 1 h. Vitamin B-12 bound to plasma transcobalamin I, however, was not taken up unless the protein was desialylated by neuraminidase from Vibrio cholerae. The uptake of iodinated pure granulocyte-binding protein, saturated with cobalamin, reached 100% and was accompanied by increasing intracellular proteolytic degradation of the binding protein. EGTA and asialo-orosomucoid completely inhibited this process of uptake and degradation, whereas partial inhibition was caused by chloroquine and colchicine. These observations provide evidence that these (asialo)-R-type cobalamin-binding proteins are taken up by the cell through the plasma membrane receptor for asialoglycoproteins by means of endocytosis followed by proteolysis of the binding protein in the lysosomes.