Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene

As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole‐exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis‐related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well‐established cancer gene lysine (K)‐specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome‐sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D‐mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

Follicular dendritic cells inhibit human B-lymphocyte proliferation.

In germinal centers, B lymphocytes are intimately associated with follicular dendritic cells (FDCs). It has been hypothesized that FDCs are involved in the regulation of B-cell growth and differentiation through cell-cell interactions. In this study, highly enriched preparations of FDCs were isolated by cell sorting using the FDC restricted monoclonal antibody DRC-1. When irradiated FDCs were cultured with mitogen stimulated B cells, B cell 3H-TdR uptake was inhibited by up to 80%. This inhibitory effect was not seen when paraformaldehyde fixed FDCs were added to B-cell cultures, suggesting that the FDCs needed to be metabolically active. Moreover, supernatants from cultured FDCs were similarly able to inhibit B-cell proliferation. These results demonstrate that FDCs may downregulate the clonal expansion of B cells that occurs within lymphoid follicles as part of the normal physiologic immune response. Potentially, the loss of the inhibitory role of FDCs in vivo may be of importance in certain infectious and neoplastic processes in which germinal centers are affected.     

Is it safe to treat allogeneic stem cell transplant recipients at home during the pancytopenic phase? A pilot trial

After myeloablative treatment and allogeneic stem cell transplantation (ASCT), patients are kept isolated in the hospital to prevent infections during neutropenia. To date, 22 patients have been given the choice of being treated at home. Eleven could not be treated at home, and they served as controls. Most had haematological malignancies. The donors were 12 HLA-compatible unrelated, nine HLA-identical siblings and one twin. In the home care group, three developed bacteraemia, compared to nine in the controls (P < 0.01). Patients in the home care group had fewer days of total parenteral nutrition (median 3 vs 24, P < 0.001), required fewer erythrocyte transfusions (median 4 vs 8, P = 0.01), fewer days on i.v. antibiotics (median 6 vs 13 days), and on analgesics (median 0 vs 15) than the controls (P < 0.05). Days with fever, time to engraftment, days with G-CSF and acute GVHD were the same in the two groups. Seven of 11 patients treated at home were readmitted to the ward for a median of 3 (0-7) days, due to fever or lack of a caregiver at home. Days to discharge to the out-patient clinic were faster in the group treated at home (median 20 vs 35 days, P < 0.01). Patients who were treated at home enjoyed being active and taking a walk when they felt like it. This preliminary report suggests that home care after ASCT is not only safe, but superior to isolation in the hospital.     

Femorotibial rotation and the Q-angle related to the dislocating patella

PURPOSE: To compare the femorotibial rotation, the patellar translation, the hip-knee-ankle angle and the Q-angle in patients with a dislocation of the patella with those of healthy volunteers. Further, the clinically measured Q-angle was compared to that measured by radiography. MATERIAL AND METHODS: A system for measurement of patellar variables was previously developed and applied to 80 healthy volunteers. In the present study, 28 patients (20 women, 8 men) with dislocation of the patella were examined bilaterally. Fourteen patients had habitual dislocations (20 affected knees) and 14 patients traumatic dislocations (17 affected knees). In 20 patients the clinical Q-angle was measured bilaterally by an orthopaedic surgeon and in 9 of these patients also by a second independent orthopaedic surgeon. RESULTS: The most striking finding was that dislocating knees in both groups showed a smaller Q-angle than the healthy knees. Further, the habitual group showed greater relative rotation between the tibia and the femur and an increased patellar translation compared to the traumatic group and to the healthy volunteers. There was a poor correlation between clinical and radiographic measurements of the Q-angle and no correlation was found between two independent clinical measurements. CONCLUSION: Surgical operations aiming at decreasing the Q-angle should be challenged.     

Radiographic measurement of femorotibial rotation in weight-bearing. The influence of flexion and extension in the knee on the extensor mechanism and angles of the lower extremity in a healthy population

PURPOSE: A system for examination and measurement of the weight-bearing knee was developed earlier on examination equipment used for QUESTOR Precision Radiography (QPR), adapted to computed radiography and to a picture archiving and communication system. In this study the same system was used to develop a method to define "patellar variables" including measurements of the rotation of the femur and the tibia and the patellar translation, between semiflexion and extension, as well as the Q-angle. The aim of this study was to evaluate the reproducibility of these patellar variables and also to establish "normal" reference values for both the patellar variables and the variables in the original QPR system. MATERIAL AND METHODS: For evaluation of the reproducibility 10 volunteers with healthy knees were examined twice. To obtain the reference values, 80 volunteers with healthy knees, 10 females and 10 males within each decade between 20 and 59 years of age, were examined. RESULTS AND CONCLUSION: The reproducibility of the rotation of the femur and the tibia and of the Q-angle was 2--3 degrees (SD) and of the patellar translation about 3 mm (SD). The result from the healthy volunteers will be a useful tool for evaluation of disorders in the knee joint.     

Fatty acid content of plasma lipid fractions, blood lipids, and apolipoproteins in children fed milk products containing different quantity and quality of fat

BACKGROUND: Differences in fatty acid content of plasma lipid fractions and serum lipid concentrations were investigated among young children fed different milk diets composed to achieve a recommended saturated fat intake. METHODS: Thirty-eight healthy children were randomly assigned to one of four feeding groups at 12 months: 1) low-fat milk (1.0 g/dL cow's milk fat); 2) standard-fat milk (3.5 g/dL cow's milk fat); 3) partially vegetable fat milk (3.5 gtat/dL fat; 50% vegetable fat: rapeseed oil); and 4) full vegetable-fat milk (3.5 gtat/dL fat; 100% vegetable fat: palm, coconut, and soy oil). Plasma fatty acids, blood lipids, and apolipoproteins were analyzed at 15 months, and dietary intakes at 12, 15, and 18 months. RESULTS: There were significantly lower percentage contributions of saturated fatty acids in plasma triglycerides in children fed low-fat milk or milk with 50% or 100% vegetable fat than in children fed standard-fat milk. Plasma polyunsaturated fatty acid levels were significantly higher in children fed milks with vegetable fat than in children fed standard-fat milk. Plasma saturated and polyunsaturated fatty acids in triglycerides most closely reflected dietary intake. Blood lipid concentrations were lower in children fed milk with 50% vegetable fat. CONCLUSIONS: Children fed milk with 50% or 100% vegetable fat, together with high vegetable-fat and low milk-fat dairy products have lower percentages of plasma saturated fatty acids and higher percentages of polyunsaturated fatty acids than children fed standard- or low-fat milk and dairy products.     

Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer – A randomized trial from the South Sweden Breast Cancer Group

PurposeTo study long term loco-regional and distant recurrence rate and survival after post-mastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer.Study designA three-armed randomized multicenter phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT + C) and 3) Oral cyclophosphamide only (C).Radiotherapy was administered, in 20 fractions, to 48 Gy to the axilla and parasternal lymph nodes, 45 Gy to infra- and supraclavicular fossae and 38 Gy to the chest wall. Cyclophosphamide was prescribed as 12 courses of 130 mg/m² od for14 days every 4 weeks.Patients and methods367 patients from 15 surgical departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978–1983. Median age was 47 years, median tumour size was 25 mm, and 33% of the patients were lymph node negative. Median follow-up time was 24 years.ResultsRT reduced the risk at twenty years for loco-regional recurrence in C-treated patients at twenty years with 75% (13.9% vs. 3.5%). The risk reduction was highly significant in both N0 and N+ patients. No reduction in systemic disease or mortality was observed.ConclusionPost-mastectomy radiotherapy reduced loco-regional recurrences in this premenopausal population, but no effect was seen on mortality with 20 years follow-up.