Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients.

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients' outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder characterized by myalgia, exercise intolerance, and rhabdomyolysis. We evaluate the efficacy of bezafibrate (BZ), a hypolipidemic drug, as a treatment for this form of CPT2 deficiency. A pilot trial was conducted with BZ in six patients for 6 months. There was a follow-up period of 3 years. The oxidation rates of the long-chain fatty acid derivative palmitoyl-CoA, measured in the mitochondria of the patients' muscles, were markedly lower than normal before treatment and increased significantly (+39 to +206%; P = 0.028) in all patients after BZ treatment. The evaluation of the therapeutic effects by the patients themselves (using the Short Form Health Survey (SF-36)), as well as by the physicians, indicated an improvement in the condition of the patients; there was an increase in physical activity and a decline in muscular pain. The results suggest that BZ has a therapeutic effect in the muscular form of CPT2 deficiency.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

Stress myocardial scintigraphy and dobutamine echocardiography in the detection of coronary disease in asymptomatic patients with type 2 diabetes.

OBJECTIVE: The aims of this prospective study were: (1) to compare stress thallium-201 single photon emission computed tomography (SPECT) and dobutamine echocardiography (DE) in the detection of silent myocardial ischemia (SMI) in asymptomatic high risk diabetic patients; (2) to analyse long-term outcome after intensive care of SMI in these patients. METHODS: SPECT was performed in 100 high risk diabetic patients and DE in the first 75 patients. Coronary angiography was realized in patients with SMI, with revascularization for suitable lesions. Intensive treatment of atherosclerosis risk factors was performed in all patients. Patients were followed 2 +/- 0.5 years for the subsequent occurrence of cardiac death, myocardial infarction and revascularization. RESULTS: SMI was detected by SPECT in 62% and by DE in 10% of the patients (p < 0.0001), whereas significant coronary stenosis at angiography was detected by SPECT in 26% and by DE in 5% of the patients (p < 0.02). Independent predictive factors of significant coronary stenosis were male gender (p < 0.03) and peripheral arterial disease (p < 0.007). Nonfatal acute coronary syndrome occurred during follow-up in 2 patients (2%). Subsequent revascularization procedure was needed in 9 patients. Baseline patients' characteristics, as well as SMI, were not predictive of cardiac event during follow up. CONCLUSION: SPECT seems more accurate than DE to detect significant coronary stenosis in high risk asymptomatic diabetic patients. In this population, aggressive treatment of SMI with systematic revascularization combined with intensive care of risk factors is associated with a favorable long-term prognosis, similar in diabetic patients with and without initial SMI.

Cumulative adverse effects of diabetes mellitus and hypertension on coronary flow velocity reserve.

BACKGROUND: this study aimed to assess the hypothesis that essential hypertension (EH) may increase coronary microcirculation dysfunction in patients with type 2 diabetes mellitus (DM). Microvascular dysfunction has been reported in patients with DM or EH. Discordant results have been reported on cumulative adverse effects of the simultaneous presence of DM and EH on coronary flow velocity reserve (CFR). METHODS: CFR were compared in 13 hypertensive diabetics (group 1), 12 normotensive diabetics (group 2), 11 hypertensive non diabetics (group 3) and 29 normotensive non diabetic patients (group 4). CFR was calculated using an intracoronary Doppler-tipped flow wire. RESULTS: CFR was significantly lower in patients with both DM and EH (2.2 +/- 0.4 in group 1 vs 2.8 +/- 0.5, 2.8 +/- 0.6 and 2.9 +/- 0.7 in groups 2, 3 and 4 respectively, p<0.01). The presence of hypertension reduced CFR in diabetic patients with angiographically abnormal but unobstructed coronary arteries (2.1 +/- 0.3 in hypertensive vs 3.1 +/- 0.2 in normotensive diabetic patients, p<0.02). No cumulative adverse effect was observed in diabetics with angiographically normal coronary arteries (2.3 +/- 0.6 in hypertensive vs 2.6 +/- 0.5 in normotensive diabetic patients, NS). Multivariate analysis revealed that combination of DM and EH (p<0.007) was independently related to CFR. CONCLUSIONS: the presence of hypertension appears to worsen coronary microangiopathy in diabetic patients with unobstructed coronary artery disease. The cumulative effect of EH and DM on CFR impairment has consequences for decision-making during coronary angioplasty and could identify patients at risk for cardiomyopathy.

Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabète Insuline Orale group.

BACKGROUND: Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. METHODS: We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy. Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. FINDINGS: Baseline C-peptide and haemoglobin A1c concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A1c concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. INTERPRETATION: At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function.

Life table analysis of the risk of type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study.

To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2-29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p less than 10(-5)) than HLA-identity (10% and 7%, respectively, p less than 0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p less than 0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p less than 10(-7)). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4+ subjects had the highest risk (70% after 8 years, predictive value 58%, p less than 10(-7)) compared with islet cell antibody-positive DR3,4- (37% and 20%, respectively) and islet cell antibody-negative DR3,4+ (5% and 3.6%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between first-phase insulin secretion and age, HLA, islet cell antibody status, and development of type I diabetes in 220 juvenile first-degree relatives of diabetic patients.

OBJECTIVE: To assess the adequacy of the first-phase insulin response for predicting development of insulin-dependent diabetes. RESEARCH DESIGN AND METHODS: Determinations were made of 1- and 3-min insulin responses to glucose (0.5 g/kg i.v.), islet cell antibodies (ICAs), insulin autoantibodies (IAAs), and HLA. We studied 220 first-degree relatives (aged 3-29 yr) of diabetic patients; 75 underwent two or more tests. RESULTS: At the first test, insulin responses correlated with age in ICA- children less than or equal to 11 yr old (r = 0.46, p less than 0.001). Individual responses varied widely in all ages, and low values were common (5th percentile: 108 pM in children less than 5 yr old, 180 pM thereafter). No correlation was found between insulin responses and IAAs or HLA. The responses of 15 ICA+ subjects were not significantly different from those of ICA- subjects after excluding the influence of age. At subsequent tests, ICA+ and ICA- subjects displayed distinct changes; the mean +/- SE insulin response increased in ICA- subjects from 619.2 +/- 40.8 to 716.4 +/- 50.4 pM (P less than 0.001) but declined in ICA+ subjects from 403.2 +/- 91.8 to 313.8 +/- 67.2 pM (P less than 0.02). During follow-up, 5 of 9 (56%) consistently ICA+ siblings developed diabetes or impaired glucose tolerance compared with 1 of 54 (2%) consistently ICA- subjects. The sensitivity and specificity of two or more low insulin responses (300 pM) for predicting progression to diabetes were 60 and 96%, respectively; the predictive value was 43%. The highest predictive value (75%) was achieved by the combination consistently ICA+, consistently low insulin response, and HLA-DR3/4. However, in no subject could the time of onset of diabetes be deduced from the decline of the insulin response. CONCLUSIONS: Consecutive intravenous glucose tolerance tests are a useful complement for predicting progression to diabetes but not its onset.

[Decrease of early insulin secretion, risk factor of insulin-dependent diabetes. Prospective study in families with diabetic children]. / Diminution de l'insulinosécrétion précoce, facteur de risque de diabète insulinodépendant. Etude prospective dans les familles d'enfants diabétiques.

In order to study the capacity of the first phase insulin response (FPIR) for predicting insulin-dependent diabetes (IDDM), we have performed one or more intravenous glucose tolerance tests (IVGTT) and determined islet-cell antibodies (ICA) and HLA-types in 220 first degree relatives of IDDM patients (194 siblings, 26 offsprings) aged 2 to 29 years. They were prospectively followed for periods ranging from 18 months to 8 years. The immunological and metabolic changes in 9 subjects who have developed IDDM or impaired glucose tolerance during the study and in 3 ICA-positive non-diabetic subjects were compared to those in ICA-negative subjects. Although the mean FPIR (1 + 3 min. plasma insulin) was significantly lower in ICA-positive compared with ICA-negative subjects, a unique low FPIR had no predictive value at the individual level. At repeated tests, the two groups followed distinctive evolutive patterns: ICA-negative subjects usually had higher FPIRs at a 2nd test, while FPIRs remained low or still decreased in ICA-positive subjects. Follow-up of subjects at high risk showed good concordance between the different predictive factors: among the 9 subjects who have developed IDDM, 7 had persisting ICA, 8 were HLA-DR3, DR4; the FPIR was consistently low in 3 and low at least once in 4. Progressive loss of the FPIR allowing to predict the time of onset of IDDM, was not observed.