We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol ...is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol.
Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months.
Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days.
High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.
Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared ...with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care.
DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented.
The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint.
These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment.
ClinicalTrials.gov: NCT00627783.
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Early gestational diabetes mellitus (eGDM) is diagnosed when fasting plasma glucose before 24 weeks of gestation (WG) is ≥ 5.1 mmol/L, whilst standard GDM is diagnosed between 24 and 28 WG by oral ...glucose tolerance test (OGTT). eGDM seems to have worse obstetric outcomes than standard GDM. We compared the rates of postpartum glucose metabolism disorders between women with early versus standard GDM in this prospective study on women with GDM from three university hospitals between 2014 and 2016. Patients were included if they were < 24 WG with at least one risk factor for GDM and excluded if they had type 2 diabetes. Patients were assigned to Group 1 (G1) for eGDM according to IADPSG: fasting blood glucose < 24 WG between 5.1 and 7 mmol/L. Group 2 (G2) consisted of patients presenting a standard GDM at 24-28 WG on OGTT results according to IADPSG: T0 ≥ 5.1 mmol/L or T60 ≥ 10.0 mmol g/L or T120 ≥ 8.5 mmol/L. The primary outcome was postpartum OGTT result. Five hundred patients were analysed, with 273 patients undergoing OGTT at 4-18 weeks postpartum: 192 patients in G1 (early) and 81 in G2 (standard). Patients in G1 experienced more insulin therapy during pregnancy than G2 (52.2% versus 32.5%, p < 0.001), but no patients were taking insulin postpartum in either group. G1 patients experienced less preterm labour (2.6% versus 9.1%, p = 0.043), more induced deliveries (38% versus 25%, p = 0.049) and reduced foetal complications (29.2% versus 42.0%, p = 0.048). There was no significant difference in the rate of postpartum glucose metabolism disorders (type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia) between groups: 48/192 (25%) in G1 and 17/81 (21%) in G2, p = 0.58. Thus the frequency of early postpartum glucose metabolism disorders is high, without difference between eGDM and standard GDM. This supports measurement of fasting plasma glucose before 24 WG and the threshold of 5.1 mmol/L seems appropriate until verification in future studies.Trial registration: NCT01839448, ClinicalTrials.gov on 22/04/2013.
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To retrospectively characterize the molecular features of Non-Small Cell Lung Carcinomas (NSCLC) with peritoneal carcinomatosis (PC), clinicopathological data of 12 patients diagnosed with NSCLC and ...PC between 2007 and 2016 were collected. Immunohistochemistry and Next Generation Sequencing (NGS) were performed on cases with available material. PC was the initial presentation of NSCLC in 17% of the cases. Overall, patients with PC displayed a poor median survival of 12 weeks. Histology was adenocarcinoma in 11 cases. 37.5% of cases showed PD-L1 immunostaining positivity (50% cut-off). ALK and ROS1 immunostainings were negative. Using NGS, we identified 17 molecular alterations in 9 genes (TP53, KRAS, STK11, BRAF, EGFR, DDR2, ERBB4, SMAD4, CTNNB1) in 88.9% of adenocarcinomas. To the best of our knowledge, 5 of these variants are not referenced in the literature. In conclusion, PC might be the initial presentation of NSCLC. Molecular profiling of our cases did not find any effective targetable alteration, except from high PD-L1 expression.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary Despite the very good response rate of small cell lung cancer (SCLC) to many anti-cancer agents, survival remains disappointing, particularly in extensive-stage (ES) disease. Many potentially ...beneficial regimens have achieved a median survival of less than 12 months in clinical trials, and so the standard regimen has remained cisplatin plus etoposide. Trials have shown that 3- and 4-drug regimens are no better than 2-drug regimens; alternating agents, dose-dense and high-dose regimens do not improve outcome, and non-platinum-based regimens are not superior to platinum-based regimens. A recent phase II trial demonstrated that pemetrexed/platinum-based doublets are active in ES-SCLC in the first-line setting. In combination with cisplatin or carboplatin, pemetrexed demonstrated a favourable toxicity profile. The ease of administration and convenient schedule of pemetrexed make these regimens attractive. Although further follow-up of patients in this trial is necessary to define response durability and survival, results so far have led to the initiation of phase III trials of pemetrexed-based regimens in ES-SCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Different Patterns of Insulin Resistance in Relatives of Type 1 Diabetic Patients With Retinopathy or Nephropathy
The Genesis France-Belgium Study
Samy Hadjadj , MD, PHD 1 2 ,
Franck Péan , PHD 2 ,
...Yves Gallois , PHD 3 ,
Philippe Passa , MD 4 ,
Robert Aubert , PHD 2 ,
Laurent Weekers , MD 5 ,
Vincent Rigalleau , MD, PHD 6 ,
Bernard Bauduceau , MD 7 ,
Amine Bekherraz , MD 8 ,
Ronan Roussel , MD, PHD 2 8 ,
Bernard Dussol , MD 9 ,
Michel Rodier , MD 10 ,
Richard Marechaud , MD 1 ,
Pierre J. Lefebvre , MD, PHD 5 ,
Michel Marre , MD, PHD 2 8 and
for the Genesis France-Belgium Study
*
1 Department of Endocrinology and Diabetology, University Hospital, Poitiers, France
2 Laboratoire de Nutrition Humaine, Faculté de Médecine X Bichat, Paris, France
3 Department of Biochimie, Faculté de Médecine d’Angers, Angers, France
4 Department of Endocrinology and Diabetology, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
5 Diabetes Division, Nutrition and Metabolic Disorders, Department of Medicine, Centre Hospitalier Universitaire Sart Tilman,
Liege, Belgium
6 Department of Nutrition and Diabetology, Centre Hospitalier Universitaire Groupe Sud, Pessac, France
7 Department of Diabetology, Begin Military Hospital, Saint Mandé, France
8 Department of Endocrinology, Diabetology and Nutrition, Bichat Hospital, Assistance Publique des Hôpitaux de Paris, Paris,
France
9 Department of Nephrology, Sainte Marguerite Hospital, Marseille, France
10 Department of Endocrinology, University Hospital, Nimes, France
Address correspondence and reprint requests to Michel Marre, Department of Endocrinology, DiabetologyNutrition, Bichat Hospital,
Assistance Publique des Hôpitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail: michel.marre{at}bch.ap-hop-paris.fr
Abstract
OBJECTIVE —Insulin resistance may be a risk factor for diabetic microangiopathy, which may have a familial component. We carried out
a family-based study to determine which components of the insulin resistance syndrome are associated with diabetic retinopathy
and nephropathy in type 1 diabetes.
RESEARCH DESIGN AND METHODS —The Genesis France-Belgium Study is a multicenter binational study designed to investigate the genetic factors involved in
the microvascular complications of type 1 diabetes using a family-based design. Probands were type 1 diabetic patients with
diabetic retinopathy (classified as background, preproliferative, or proliferative) and possibly diabetic nephropathy (absent,
incipient, established, or advanced). The insulin resistance score of their first-degree relatives was calculated according
to their BMI and history of arterial hypertension, lipid disorders, and type 2 diabetes.
RESULTS —The insulin resistance score of relatives was positively correlated with the albumin excretion rate ( P = 0.0009) and fasting plasma glucose ( P = 0.0003) and HbA 1c ( P < 0.0001) concentrations. This score was higher in the relatives of probands with than in those without diabetic nephropathy
( P = 0.0370). Similarly, it was higher in relatives of subjects with proliferative diabetic retinopathy than in those of probands
without, even after controlling for subjects with versus without diabetic nephropathy ( P = 0.0379). However, the components of the insulin resistance score in relatives differed according to the severity of diabetic
retinopathy or nephropathy in the probands. Obesity and history of arterial hypertension were most common in relatives of
probands with proliferative diabetic retinopathy, whereas obesity and history of lipid disorders were most common in the relatives
of probands with diabetic nephropathy.
CONCLUSIONS —Familial insulin resistance segregates with diabetic complications: lipid disorders and obesity segregate with diabetic nephropathy,
whereas arterial hypertension and obesity segregate with diabetic retinopathy.
AER, albumin excretion rate
HOMA-IR, homeostasis model assessment of insulin resistance
SBP, systolic blood pressure
UAE, urinary albumin excretion
WHO, World Health Organization
Footnotes
*
↵ * A complete list of Genesis France-Belgium Study members can be found in the appendix.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted August 10, 2004.
Received January 14, 2004.
DIABETES CARE
Abstract Background Treatment of non–clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial ...growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. Methods We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan–Meier method. Results 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0–13.9). Median OS was 37.9 months (95% confidence interval CI: 21.4–46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2–10.9) and 22.9 months (95% CI: 17.8–49.2) versus 1.9 months (95% CI: 1.0–6.0) and 3.2 months (95% CI: 2.3–not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55). Conclusion We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot,
randomized, double-blind, placebo-controlled study.
J L Richard ,
C ...Parer-Richard ,
J P Daures ,
S Clouet ,
D Vannereau ,
J Bringer ,
M Rodier ,
C Jacob and
M Comte-Bardonnet
Department of Dietetics and Diabetology, Centre Medical, Le Grau du Roi, France.
Abstract
OBJECTIVE--To assess the efficacy and safety of topical human recombinant basic fibroblast growth factor (bFGF) on the healing
of diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS--Seventeen diabetic patients suffering from chronic neuropathic
ulcer of the plantar surface of the foot entered a pilot, randomized, double-blind study comparing local application of bFGF
with placebo. Main inclusion criteria were a typical neuropathic ulcer of Wagner grade I-III, more than 0.5 cm in the largest
diameter, with an abnormally high vibration perception threshold in the absence of significant peripheral vascular disease
or wound infection. bFGF or placebo was applied daily during the 6 weeks as inpatients then twice a week for 12 weeks. Evolution
of ulcer size was assessed through weekly clinical examination and computerized photographs. RESULTS--In the bFGF group, three
of nine ulcers healed compared with five of eight in the placebo group (NS). The weekly reduction in ulcer perimeter and area
was identical in both groups, as was the rate of linear advance from entry to the 6th week of treatment (bFGF: 0.053 +/- 0.048
mm vs. placebo: 0.116 +/- 1.129 mm): the same result was obtained at the 11th week. Moreover, percent healed area at the end
of the study did not differ significantly. No side effects were observed during bFGF application. CONCLUSIONS--Topical application
of bFGF has no advantage over placebo for healing chronic neuropathic diabetic ulcer of the foot. Because diabetes causes
significant wound-healing defects, we hypothesized that using a single growth factor might be insufficient to accelerate wound
closure of diabetic ulcers.
TeleDiab‐2 was a 13‐month randomized controlled trial evaluating the efficacy and safety of two telemonitoring systems to optimize basal insulin (BI) initiation in subjects with inadequately ...controlled type 2 diabetes (HbA1c, 7.5%‐10%). A total of 191 participants (mean age 58.7 years, mean HbA1c 8.9%) were randomized into three groups: group 1(G1, standard care, n = 63), group 2 (G2, interactive voice response system, n = 64) and group 3 (G3, Diabeo‐BI app software, n = 64). The two telemonitoring systems proposed daily adjustments of BI doses, in order to facilitate the achievement of fasting blood glucose (FBG) values targeted at ~100 mg/dL. At 4 months follow‐up, HbA1c reduction was significantly higher in the telemonitoring groups (G2: −1.44% and G3: −1.48% vs. G1: −0.92%; P < 0.002). Moreover, target FBG was reached by twice as many patients in the telemonitoring groups as in the control group, and insulin doses were also titrated to higher levels. No severe hypoglycaemia was observed in the telemonitoring groups and mild hypoglycaemia frequency was similar in all groups. In conclusion, both telemonitoring systems improved glycaemic control to a similar extent, without increasing hypoglycaemic episodes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims/hypothesis Infection of diabetic foot ulcers is common; at early stages it is difficult to differentiate between non-infected ulcers (or those colonised with normal flora) and ulcers infected ...with virulent bacteria that lead to deterioration. This pilot study aimed to assess the diagnostic accuracy of inflammatory markers as an aid to making this distinction. Methods We included 93 diabetic patients who had an episode of foot ulcer and had not received antibiotics during the 6 months preceding the study. Ulcers were classified as infected or uninfected, according to the Infectious Diseases Society of America-International Working Group on the Diabetic Foot classification. Diabetic patients without ulcers (n = 102) served as controls. C-reactive protein (CRP), orosomucoid, haptoglobin and procalcitonin were measured together with white blood cell and neutrophil counts. The diagnostic performance of each marker, in combination (using logistic regression) or alone, was assessed. Results As a single marker, CRP was the most informative for differentiating grade 1 from grade 2 ulcers (sensitivity 0.727, specificity 1.000, positive predictive value 1.000, negative predictive value 0.793) with an optimal cut-off value of 17 mg/l. In contrast, white blood cell and neutrophil counts were not predictive. The most relevant combination derived from the logistic regression was the association of CRP and procalcitonin (AUC 0.947), which resulted in a significantly more effective determination of ulcer grades, as shown by comparing receiver operating characteristic curves. Conclusions/interpretation Measurement of only two inflammatory markers, CRP and procalcitonin, might be of value for distinguishing between infected and non-infected foot ulcers in subgroups of diabetic patients, to help ensure the appropriate allocation of antibiotic treatment. Nevertheless, external validation of the diagnostic value of procalcitonin and CRP in diabetic foot ulcers is needed before routine use can be recommended.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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