High incidence of complications after 2-chloro-2’-deoxyadenosine combined with cyclophosphamide in patients with advanced lymphoproliferative malignancies

The combination of purine analogs with alkylating agents is able to produce a synergistic antitumoral effect. However, the addition of immunosuppressive and DNA-targeting agents might increase purine analog-related complications. The risk for serious complications was evaluated in 38 patients treated with 2-chloro-2-deoxyadenosine (CDA) and cyclophosphamide (CP). The diagnoses were chronic lymphocytic leukemia (CLL) in 15, Waldenströms macroglobulinemia in 4, mantle cell lymphoma in 6, follicular non-Hodgkins lymphoma (NHL) in 10, and other low-grade NHL in 3 patients. All patients were pretreated (median: 2 lines, range: 1–5) and 23 (61%) were refractory. The patients received a median of two courses (range: 1–5) of 5.6 mg/m² CDA, followed by a median of 200 mg/m² CP, for 3 days. The response rate was 51% [complete remission (CR): 14%, partial remission (PR): 38%]. Grade 3/4 infections occurred in 16 (42%) patients. Dose-limiting cytopenias were seen in 22 (58%) patients. In 12 (32%) patients, autoimmune manifestations developed requiring treatment in most of them. Second cancers arose in five (13%) patients (myelodysplastic syndrome/acute myelocytic leukemia in three, lung cancer in two). Multivariate analysis showed that cytopenias, gender (F), prior radiotherapy, and age (>65 years) predicted for the complications seen after CDA-CP. To conclude, because of the high incidence of complications, caution is warranted in selecting patients with advanced lymphoid malignancies for the CDA-CP protocol.     

Association of plasma soluble α-klotho with pro-endothelin-1 in patients with type 2 diabetes

Objectives

To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).

Subjects and methods

In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.

Results

Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8 ± 148.1 vs. 494.6 ± 134.3 pg/ml, p = 0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho = −0.410, p < 0.0001) but not in non-diabetic controls (Rho = 0.091, p = 0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.

Conclusions

Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.     

Longterm visual prognosis of patients with ocular Adamantiades-Behçet's disease treated with interferon-alpha-2a

OBJECTIVE: Relapsing ocular involvement is one of the major manifestations in Adamantiades-Beh?et's disease (ABD). Combining systemic corticosteroids with cyclosporin A is currently the treatment of choice. Interferon-alpha (IFN-alpha) has proven to be effective in mucocutaneous ABD and has been reported to improve ocular lesions. We examined the longterm effects of IFN-alpha-2a in a case series of 45 patients with ocular involvement. METHODS: Since 1988, 45 patients (79 eyes of 90 eyes) with ocular involvement in ABD have been treated with IFN-alpha (3 x 6-9 Mio IU per wk). In the initial acute phase of the disease, patients additionally received short-term corticosteroids (oral prednisolone 100 mg/day), tapered to a maintenance dose of 10 mg/day within 2 weeks. IFN-alpha-2a was administered as longterm therapy with a mean duration of 30 months (range 1.1-101 mo). RESULTS: IFN-alpha-2a/prednisolone treatment was effective against vasculitis, optic nerve neuropathy, and iritis. Sixty-four eyes had no recurrence under therapy. To date, recurrences have been seen in 26 eyes under IFN-alpha treatment. Flu-like symptoms were recorded in nearly all patients (n = 43). Further side effects were dose-dependent reversible thrombocytopenia (n = 1), psychosis (n = 3), depression (n = 13), thyroiditis (n = 1), and reversible diffuse alopecia (n = 7). In our series, 92% of all eyes showed stable or improved visual acuity in longterm followup. CONCLUSION: Longterm remission of ocular inflammation can be achieved with the combination of IFN-alpha and low-dose corticosteroids.     

Enhanced proliferation in colorectal epithelium of patients with type 2 diabetes correlates with β-catenin accumulation

Aimsβ-Catenin accumulation promotes proliferation. However, the correlation between proliferation of colorectal epithelium and β-catenin in type 2 diabetes mellitus (DM) patients remains unclear.MethodsColorectal epithelium samples from distal ends of colorectal adenocarcinomas without histological aberrances were divided into two groups: DM patients with type 2 DM for more than 1 year (n = 27) and non-DM patients without hyperglycemia (n = 20). Samples from patients without colorectal epithelial disease or hyperglycemia served as a control group (n = 6). Proliferative index was calculated as the percentage of proliferating cell nuclear antigen positive cells. Wnt/β-catenin signaling was assessed immunohistochemically and phosphorylation of β-catenin was assessed by immunofluorescence.ResultsCompared with the non-DM or control group, the proliferative index and expression of lactate dehydrogenase A and Wnt/β-catenin signaling were significantly higher in the DM group (all p < 0.01). The proliferative index correlated positively with β-catenin expression (Spearman correlation coefficient = 0.55; p < 0.01). Reduced phosphorylation at serine 33/37 and increased phosphorylation at serine 675 of β-catenin were detected in the DM group (all p < 0.01).ConclusionsEnhanced proliferation, accompanied by increased aerobic glycolysis, was detected in colorectal epithelium of patients with diabetes. β-Catenin accumulation with altered phosphorylation correlated with the proliferative changes.     

Extension of Aβ2M amyloid fibrils with recombinant human β2-microglobulin

In order to elucidate the pathogenesis ofAβ2M amyloidosis, we established an experimental system to study the mechanism of amyloid fibril formation or degradation in vitro. We compared the kinetics of Aβ2M amyloid fibril (fAβ2M) extension with native β2microglobulin (n-β2M) purified from the urine of a patient suffering from renal insufficiency, with that with recombinant β2M (r-β2M) in vitro. n-β2M and r-β2M were incubated with fβ32Mpurifiedfrom synovial tissues excised from Aβ2M amyloidosis patients. The fA β2M extension reaction could be explained by a first-order kinetic model in both β2Ms. The extension reaction was greatly dependent on the pH of the reaction mixture and maximum around pH 2.5-3.0 in both p2Ms. ThefAβ2M extended with both p2Ms assumed the similar helical filament structure, although the fibrils extended with r-β2M were slightly wider than those extended with n-β2M and the former fibrils assumed a helical structure more clearly as compared to the latter. In order to obtain pure, unmodifiedfAβ2M, we next extendedfA β2M repeatedly by the algorithmic protocol with r-β2M. As the generation of the extended fibrils proceeded, the initial rate of the extension reaction increased. The ultrastructure of fibrils was completely preserved throughout the repeated extension steps. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting revealed that f A P2M extended repeatedly with r-β2Mwere composed solely ofr-β2M. The use of these r-β2M and fAβ2M will be advantageous to assess the effects of several amyloid-associated molecules in the formation or degradation offAβ2M in vitro.     

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Background and objectives

CKD–mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.

Design, settings, participants, & measurements

Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2–4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.

Results

Patients were followed for 2.6 (interquartile range, 1.4–3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43–1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39–1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58–2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33–15.21]; P=0.02).

Conclusions

In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.     

Serum γ-glutamyl transferase is associated with plasma total homocysteine in Japanese patients with type 2 diabetes

Serum γ-glutamyl transferase (γ-GT), a marker of oxidative stress, predicts morbidity and mortality from cardiovascular disease. Plasma total homocysteine (tHcy), a pro-oxidant and also an independent risk factor for cardiovascular disease, correlates with γ-GT among some populations. It is not known whether tHcy correlates with γ-GT among type 2 diabetic patients in whom oxidative stress is increased and implicated for the development of diabetic complications. In the present study, we analyzed the association between γ-GT, tHcy and related vitamins cross-sectionally among patients with type 2 diabetes without overt nephropathy (age range 17–76 years; n = 110). In a univariate regression analysis model, γ-GT (logarithm) was positively associated with tHcy (β = 0.288, P = 0.002) but not with folate or vitamin B₁₂. The association between tHcy and γ-GT (logarithm) remained significant in a multivariate analysis model including age, lifestyle factors, folate, vitamin B₁₂, creatinine, HbA_1c and medical history (β = 0.219, P = 0.027). These results suggest that tHcy generates oxidative stress among type 2 diabetic patients and may partly explain the reported association between γ-GT and cardiovascular disease.     

Prognostic factors for survival in patients with advanced renal cell carcinoma treated with interleukin-2 and interferon-α

A group of 73 patients with advanced renal cell carcinoma, treated in different phase II trials with interferon and/or interleukin-2, have been evaluated to identify potential baseline prognostic factors predicting their survival. The eligibility criteria were very similar across studies and included ECOG performance status 2, measurable or evaluable disease and no CNS metastases. The overall response rate was 8%. The overall survival was 33% at 2 years and 18% at 1 year. In the univariate analysis three prognostic factors were correlated with disease outcome: ECOG performance status (0 versus 1), time from diagnosis to treatment (12 months versus >12 months) and number of metastatic sites (1 versus 2). Multivariate analysis identified ECOG performance status and number of metastatic sites as important prognostic factors for survival. The true impact on patient survival of the selection of patients rather than the treatment itself should be evaluated in controlled trials.Abbreviations IFN interferon - IL interleukin - RCC renal cell carcinoma - PS performance status     

A Novel Variant with Positive Natural Selection Influenced Hb A2 Levels in Chinese Individuals with β-Thalassemia

β-Thalassemia (β-thal) is the most common inherited hemolytic anemia worldwide. Elevated Hb A₂ is a mark of β-thal carriers. The aim of this study was to identify the pathogenic variants associated with the Hb A₂ levels. One thousand and thirty β-thal carriers were recruited for this study. Using positive natural expression quantitative trait loci (eQTL) analysis, a significant variant was selected. Genotyping for the rs231841 polymorphism was performed by the Sequenom MassARRAY IPLEX platform. All genetic association analyses were performed with the PLINK program. The linear regression analysis showed that rs231841 in the intron region of the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene on chromosome 11p15 was significantly associated with Hb A₂ levels. The presence of the C allele was associated with elevated Hb A₂ levels. Our results suggest that rs231841 on the KCNQ1 gene with positive natural selection is related to Hb A₂ levels in Chinese β-thal carriers, and KCNQ1 is probably associated with the expression of the β-like globin gene cluster.     

Is parity associated with earlier diagnosis of type 2 diabetes?

AIM: Whether parity promotes the development of diabetes has been a subject of controversy. Earlier population studies have produced discrepant findings. The aim of the current study was to investigate this question by examining the relationship between parity and the age of diagnosis of diabetes. METHODS: A retrospective analysis from a diabetes database was conducted. Data for 2102 women with type 2 diabetes (T2DM), including date of birth, age at diagnosis, parity, body mass index (BMI), and family history were extracted. A multivariate linear regression model was applied to ascertain if there was an association between parity and the age of diagnosis of diabetes. RESULTS: With correction for the year of birth, there was a significant association between parity and the age of diagnosis of diabetes (beta = -0.25 +/- 0.08, P = 0.002, where beta is the regression coefficient). That is, for an increase in parity by one, the age of diagnosis decreased by 0.25 years. When further adjustments were made for the other variables in the data set, the effect on the overall cohort disappeared, but it persisted in subjects born before 1950 (beta = -0.17 +/- 0.1, P = 0.09), or with a parity >5 (beta = -0.60 +/- 0.25, P = 0.02). CONCLUSIONS: There is an association between parity and the age of diagnosis of diabetes, suggesting that pregnancy may promote the development of diabetes. However, the magnitude of the effect is small, and unlikely to be of great clinical significance in society today.