Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation

In 2-8% of patients with mental retardation, small copy number changes in the subtelomeric region are thought to be the underlying cause. As detection of these genomic rearrangements is labour intensive using FISH, we constructed and validated a high-density BAC/PAC array covering the first 5 Mb of all subtelomeric regions and applied it in our routine screening of patients with idiopathic mental retardation for submicroscopic telomeric rearrangements. The present study shows the efficiency of this comprehensive subtelomere array in detecting terminal deletions and duplications but also small interstitial subtelomeric rearrangements, starting from small amounts of DNA. With our array, the size of the affected segments, at least those smaller than 5 Mb, can be determined simultaneously in the same experiment. In the first 100 patient samples analysed in our diagnostic practice by the use of this comprehensive telomere array, we found three patients with deletions in 3p, 10q and 15q, respectively, four patients with duplications in 9p, 12p, 21q and Xp, respectively, and one patient with a del 6q/dup 16q. The patients with del 3p and 10q and dup 12p had interstitial rearrangements that would have been missed with techniques using one probe per subtelomeric region chosen close to the telomere.     

Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia

Journal of Thrombosis and Thrombolysis - Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab...     

Systemic bevacizumab as salvage therapy for persistent severe bleeding and anemia in heyde syndrome following aortic valve replacement

Journal of Thrombosis and Thrombolysis - Heyde syndrome is characterized by the co-occurrence of aortic stenosis and bleeding gastrointestinal angiodysplasias, often with acquired von Willebrand...     

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumor s and hematologic malignancies

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy treatment delays, dose reductions, and discontinuation. There is no US Food and Drug Administration (FDA)-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at four US centers. The primary outcome was achievement of a romiplostim response (median on-romiplostim platelet count ≥75x10⁹/L and ≥30x10⁹/L above baseline). Secondary outcomes included time to platelet count ≥100x10⁹/L and rates of the following: platelet count <100×10⁹/L, platelet count <75x10⁹/L, platelet count <50x10⁹/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. A total of 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of four (range: 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays, and 89% avoided platelet transfusions. Median per-patient platelet count on romiplostim was significantly higher than baseline (116x10⁹/L vs. 60x10⁹/L; P<0.001). Bone marrow (BM) tumor invasion, prior pelvic irradiation, and prior temozolomide exposure predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays/bleeding; intracycle dosing had an incidence rate ratio (IRR) for dose reduction/treatment delay of 3.00 (95%CI: 1.30-6.91; P=0.010) and an IRR for bleeding of 4.84 (95%CI: 1.18-19.89, P=0.029) compared with weekly dosing. Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with BM involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.     

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9^Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9^Q152H variation. We report that PCSK9^Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9^Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9^Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.     

The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in postmenopausal women with type 2 diabetes mellitus

Type 2 diabetes mellitus is frequently accompanied by hypercoagulability and hypofibrinolysis. Both are related to increased cardiovascular risk, but possibly with endothelial injury as well. Studies with nondiabetic persons indicate that unopposed oestrogen replacement therapy (oERT) decreases cardiovascular risk, possibly mediated in part by effects on coagulation and fibrinolysis. In a double-blind, randomised placebo-controlled trial, we assessed the effect of oral 17 beta-oestradiol daily during 6 weeks on indicators of coagulation and of fibrinolysis in postmenopausal women with type 2 diabetes mellitus. We observed significant increases of Factor VII (FVII) and von Willebrand factor (vWF) after oERT and no change in the already high fibrinogen. Prothrombin fragment 1 + 2 (F1 + 2) increased after oERT, whereas thrombin-antithrombin (TAT) complexes was unchanged, but increments of F1 + 2 and TAT correlated. Soluble fibrin (SF) levels remained stable. In fibrinolysis, a clear reduction in plasminogen activator inhibitor 1 (PAI-1) was observed, but no significant change in tissue-type plasminogen activator antigen (t-PA-Ag) or activity was found, although fibrinolytic activity assessed as t-PA activity (t-PA-Act) tended to increase after oERT. Indicators of fibrinolytic activity (plasmin-antiplasmin complexes and fibrin degradation products) however did not change. oERT increased C-reactive protein (CRP) but none of the coagulation or fibrinolysis changes significantly associated with the CRP changes. It is concluded that oERT increases the coagulation potency as well as the fibrinolytic potency raising the question of the net effect in their balance. Increase in F1 + 2 suggests that in diabetic women oERT effectively increases the chronic, continuous activation of coagulation, which appears to be compensated for or not effective in the blood compartment as judged from the unchanged levels of SF. Suspected increased fibrin formation in the vascular wall is at least not followed by increases in fibrinogen degradation products (TDP), which suggests the possibility of accumulation and increased cardiovascular risk. The results indicate that specific attention should be paid to fibrin turnover in studying other categories of women and the effects of the addition of progesterone.     

Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery

Most patients treated for single or multiple brain metastases die from progression of extracranial tumor activity. This makes it uncertain whether the combination of neurosurgery and radiontherapy for treatment of single brain metastasis will lead to better results than less invasive treatment with radiotherapy alone. The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 faractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs. stable). Survival as such and functionally independent survival (FIS; defined as world Health Organization performance status ≤ 1 and neurological funcition ≤ 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p =0.04) and a longer FIS (p=0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12vs 7 mo; median FIS 9 vs 4 Mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgial excision and radiotherapy than after radiotherpy alone. Patients older than 60 years had a hazard ratio of dying of 2.74(p=0.001) compared with younger patients, but in both age groups the combined treatment did better then radiotherapy alone. We coclude that patients with single brain metastasis and stable extracranial tumor activity should be treated with surgical excision and radiotherapy. For patients with progressive extracranial disease during the previous 3 months, radiotherapy alone appears to be sufficient. After treatment of single brain metastasis, parients remain functionally independent until a few months before death.