This study is to determine the concentrations of IL-6, TNF α, and C reactive protein (CRP) in women with severe preeclampsia, and compare with those of gestational age- matched normotensive pregnant women and to correlate CRP levels with markers of organ damage in women with preeclampsia.This was a case control study of fifty women with severe preeclampsia and fifty gestational age matched pregnant women with normal blood pressure. The women were drawn from The Antenatal Clinic of The Lagos University Teaching Hospital. Severe pre eclampsia was defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg and ≥2+ of proteinuria. After obtaining an informed consent, each participant completed a structured questionnaire. The questionnaire sought information on socio-demographic and clinical data. From each participant, mid-stream urine was collected for urinalysis and culture, and blood sample was collected for biochemical analysis. Comparisons of continuous variables and categorical variables were done using the Student's t test and Chi square test respectively. Correlation analysis was used to determine the associations between variables. Statistical significance was set at PThe women were similar in their socio demographic characteristics. There was a statistically significant difference in the systolic blood pressure (p < 0.0001), diastolic blood pressure ( p < 0.0001), uric acid ( p < 0.0001), AST ( p < 0.0001), ALP ( p < 0.0001), creatinine ( p < 0.0013), GGT ( p < 0.005), IL 6 ( p < 0.021), CRP ( p < 0.0002), and TNF α ( p < 0.023), between the group with severe preeclampsia and the group with normal blood pressure. This study also reports a significant association between CRP and systolic blood pressure, diastolic blood pressure, uric acid AST and ALP (pThe inflammatory cytokines, IL6, TNF α and CRP are elevated in severe preeclampsia and may mediate some of the clinical manifestations of the disorder. A role may exist for anti inflammatory agents in the management of women with preeclampsia. A complex relationship exists between immunity, inflammation and disease. This relationship is played out in pregnancy, from the adaptation in immune responses necessary for the mother to tolerate the immunologically different foetus throughout the period of pregnancy to the role of inflammation in abnormal pregnancy outcome such as preeclampsia and pre term birth.Immune adaptation in normal pregnancy has been associated with a decrease in the T helper 1 cytokines: interleukin 2 (IL2), interferon gamma (IF γ) and transforming growth factor beta (TGF β), which are involved in cellular immunity and mediate immune rejection of the foetus; and an increase in the T helper 2 cytokines: interleukins 4, 5, 6 and 13, which mediate humoral immunity, suppress cellular immunity and thereby prevent immune rejection of the foetus [An abnormality in this delicate immunologic balance has been implicated in the pathology of preeclampsia . The defThe study took place during the period of July 2012 to August 2013. The cases and controls were drawn from women attending The Ante natal Clinic at Lagos University Teaching Hospital, Lagos Nigeria. This observational case control study consisted of fifty women with severe preeclampsia who were recruited as cases and fifty pregnant women with normal blood pressure who were recruited as controls.Case definition: The cases consisted of pregnant women in whom a diagnosis of severe preeclampsia had been made. These women were in their third semesters of pregnancy. Severe preeclampsia was defined as systolic blood pressure ≥ 160 mmHg and/ or diastolic blood pressure ≥ 110mmHg and ≥ 2+ of proteinuria [teinuria .Control definition: the controls were chronological and gestational age matched pregnant women whose blood pressures have remained normal during pregnancy; ≤120mmHg systolic blood pressure and ≤80mmHg diastolic blood pressure. Gestational age was calculated from the last normal menstrual period and/or by an early obstetric ultrasonography.Inclusion criteria: the Inclusion criteria included absence of labour, absence of premature rupture of membranes and febrile illness in pregnancy.Exclusion criteria: the exclusion criteria included multiple gestation, diabetes mellitus, sickle cell disease and HIV infection. Before recruitment, an informed consent was obtained from each study participant. The institutional review board/ Ethics committee of the Lagos University Teaching Hospital, Lagos, Nigeria, approved the study protocol.Mid stream urine specimen and blood was collected for analysis. Specimen with positive urine culture and elevated white cell count, were excluded. Blood was centrifuged at 4000 RPM for 10 minutes and stored at -800C in aliquots till analysis. Freeze thaw cycles were avoided. Plasma creatinine, urea and uric acid were estimated from lithium heparin plasma using reagent from Biolabo laboratories, 02160, Maizy, France. Serum levels of aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatise (ALP) and gamma glutamyl transferase (GGT) were estimated from lithium heparin plasma using reagents from Randox Laboratories Limited, Antrim, UK, BT 29 4QY. Spectrophotometric methods were employed for the biochemical analysis on semiautomatic biochemistry analyser BS3000P-Sinnowa Medical Science and Technology Company limited, Nanjing, China (211135).Plasma levels of IL6, TNF α and CRP were determined from EDTA plasma using reagents from Biovendor Laboratories, 62100 Brno, Czech Republic by an enzyme linked immunoassay technique  on AcureThe data were analyzed using the IBM SPSS version 19.0 package. Independent student's t test was used to test the differences in the mean values for the continuous variables. Chi square test was used to test the differences in proportion of the catergorical variables. Correlation analysis was used to determine the association between variables. Statistical significance was set at p < 0.05.The group with severe preeclampsia and the normotensive pregnancy control group did not differ in their socio demographic characteristics. Forty – nine percent (49%) of the group with severe preeclampsia were of the Yoruba tribe, forty –two (42%) were Igbo and nine percent (9%) were from other tribes. In the normotensive pregnancy control group, forty-eight percent (48%) were Yoruba, forty three percent (43%) were Igbo and nine percent (9%) were from other tribes. Ninety –eight percent (98%) of the group with severe preeclampsia were married and two percent (2%) were unmarried. In the normotensive pregnancy control group, ninety –five percent (95%) were married and five percent (5%) unmarried. Comparing educational status, five percent (5%) of the cases had only primary school education while twenty four percent (24%) and seventy one percent (71%) had secondary and tertiary education respectively. In the control group, twenty percent (20%), thirty one percent (31%) and forty nine percent (49%) of the women had primary, secondary and tertiary education respectively. The study participants did not differ in age distribution. The mean age of the cases was 31.90± 6.3 years and 32.33±5.8 years for the controls (p = 0.82). The mean gestational age of the cases was 30.95±3.79 weeks and 31.23±4.77 weeks for the controls (p = 0.84)This study reports a statistically significant difference in the levels of the pro inflammatory cytokines, IL 6 and TNF α and in CRP levels in the women with severe preeclampsia, compared with women with normotensive pregnancy. Similar increases in the plasma levels of these markers were also reported by Teran et al;  and HentThe finding of significantly increased levels of IL 6 and TNF α and CRP in the women with severe preeclampsia from our study was corroborated by findings from a meta-analysis by Cui Xie et al;  who concThe cytokines, IL6 and TNF α, are proteins produced principally by activated lymphocytes and macrophages but also by endothelial, epithelial and connective tissues that function by modulating the function of other cell types. TNF α and IL 6 mediate immunologic, inflammatory and reparative host responses . In preeHigh levels of IL 6, and TNF α induce the systemic acute phase response stimulating the liver to synthesize CRP . C-reactPreeclampsia is a multisystem disorder with greatest effects on the central nervous system, the liver, the kidney and the coagulation system , with reSevere pre-eclampsia and eclampsia cause hepatocellular dysfunction reflected by elevation of serum transaminases and/or alkaline phosphatise . GrosslyThis study reports a significant relationship between CRP and increasing blood pressure, uric acid, ALP and AST suggesting that inflammation is involved in the tissue damage that occurs in preeclampsia. The association of CRP with disease severity in preeclampsia has been reported by other authors –34. DuriThe reduced uterine perfusion pressure and resultant placental ischemia in preeclampsia induces the release of cytokines that mediate immunologic, inflammatory and reparative host responses that contribute to the widespread endothelial damage and resultant hypertension and organ dysfunction in preeclampsia , 19.A role has been suggested for inflammatory mediators in the pathogenesis and pathology of preeclampsia. This study reports increased levels of the inflammatory cytokines, IL6, TNF α and the marker of inflammation, CRP in severe preeclampsia. This study also reports an association between CRP and markers of vascular and organ damage in severe preeclampsia. There may be a place for anti inflammatory agents in the management of women who develop preeclampsia.


Vascular endothelial dysfunction is involved in macrovascular disease progression in type 2 diabetes mellitus (T2DM). We reported previously that blood glucose fluctuations, as evaluated by continuous glucose monitoring (CGM), correlate with vascular endothelial function, serving as a marker of vascular endothelial function. However, the use of CGM is limited, suggesting the need for another marker of vascular endothelial function. Here, we investigated the relationship between vascular endothelial dysfunction and blood levels of 1,5-anhydro-D-glucitol , a marker of both postprandial hyperglycemia and fluctuations in blood glucose.In 32 inpatients with T2DM and HbA1c less than 8.0%, the reactive hyperemia index (RHI), an index of vascular endothelial function, was determined by peripheral arterial tonometry. The relationships between RHI and 1,5-AG, blood glucose, lipid metabolism markers, and blood pressure, were examined.There was a strong correlation between 1,5-AG and natural logarithmic-scaled RHI (L_RHI) . However, there was no correlation between L_RHI and HbA1c, fasting blood glucose, IRI, LDL-C, HDL-C, TG, systolic blood pressure, or diastolic blood pressure. Multivariate analysis identified blood 1,5-AG levels to be the only significant and independent determinant of L_RHI.In T2DM with HbA1c <8.0%, low 1,5-AG levels were associated with vascular endothelial dysfunction, suggesting it is a potentially useful marker for vascular endothelial dysfunction.UMIN000015317 Atherosclerosis causes vascular endothelial dysfunction even at an early stage , and is The level of 1,5-anhydro-D-glucitol  in peripheral blood is considered a useful marker of glycemic control  and a usThe present cross-sectional study included 32 patients with T2DM admitted to the University of Occupational and Environmental Health Hospital and Wakamatsu Hospital of the University of Occupational and Environmental Health between January 2012 and November 2013. All patients satisfied the following inclusion criteria: (1) age 20 years and above; (2) HbA1c <8.0%; (3) serum creatinine (Cre) <2.0 mg/dl; and (4) the absence of arrhythmias. Patients with diabetic ketoacidosis, nonketotic hyperosmolar coma, infection, or acute coronary syndrome were excluded from the study. The study protocol was approved by the Human Ethics Review Committee and a signed consent form was obtained from each subject.in vivo stimulated by vascular shear stress, was measured automatically by PAT . HbA1c (%) was measured by HPLC using Tosoh HLC-723 G8 , and expressed as National Glycohemoglobin Standardization Program (NGSP) values by adding 0.4% to HbA1c values expressed as the conventional Japanese standard substance (JDS) values . The 1,5p < 0.05. SPSS Statistical Software 21.0  was used for all statistical analyses.All values were expressed as mean ± SD. The Kolmogorov-Smirnov normality test demonstrated that natural logarithmic-scaled RHI (L_RHI), 1,5-AG, HbA1c, FPG, LDL-C, TG, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were normally distributed, whereas IRI and HOMA-IR showed skewed distribution. For intergroup comparisons, the unpaired t-test was used for normally distributed data, the Mann–Whitney U test for data with skewed distributions. To assess potential correlations with L_RHI, the Pearson correlation coefficient was used for data with normal distribution pattern, whereas the Spearman rank-correlation coefficient was used for data with a non-normal distribution. Multivariate analysis was carried out employing the step-up procedure, using L_RHI as the dependent variable, and age, sex, body mass index (BMI), disease duration, use of presence/absence of treatment with α-glucosidase inhibitor treatment or insulin treatment, use of antihypertensive drugs, use of antihyperlipidemic drugs, history of cardiovascular disease (CVD), LDL-C, HDL-C, TG, SBP, DBP, HbA1c, 1,5-AG, and FPG as independent variables. The level of significance was set at Table The relationship between L_RHI and clinical markers of glycemic control is shown in Table In the next step, we compared the relationship between L_RHI and treatment with and without sulfonylurea, pioglitazone, metformin, α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor, and insulin. There was no relationship between L_RHI and treatment with and without sulfonylurea , pioglitazone , metformin , and dipeptidyl peptidase-4 inhibitor treatment . On the other hand, L_RHI was significantly higher in the α-glucosidase inhibitor-treated group  than -untreated group  (P = 0.042), and significantly lower in the insulin-treated group  than -untreated group  (P = 0.006).2 = 0.277, standardization coefficient β = 0.548, t = 3.149, P = 0.001) (Table Multivariate analysis, using L_RHI as the dependent variable and age, sex, BMI, disease duration, use of presence/absence of treatment with α-glucosidase inhibitor treatment or insulin treatment, use of antihypertensive drugs, use of antihyperlipidemic drugs, history of CVD, LDL-C, HDL-C, TG, SBP, DBP, HbA1c, 1,5-AG, and FPG as the independent variables, identified 1,5-AG as the only significant and independent determinant of L_RHI (adjusted multiple RBecause the incidence of cardiovascular events is reportedly increased significantly in patients with L_RHI of ≤0.4 , the subThe main finding of the present study was that vascular endothelial function parameter L_RHI correlates significantly with 1,5-AG in T2DM patients with HbA1c <8.0%.In fact, 1,5-AG blood level correlate with postprandial hyperglycemia in patients with HbA1c <8.0%, in both type 1 diabetes mellitus  and T2DMBlood 1,5-AG level is a marker of glycemic control and accurately reflects rises and falls in urinary glucose excretion. When 1,5-AG leaks into the urine along with excessive excretion of glucose, the result is a decreased concentration in the blood. In other words, blood glucose levels correlate inversely with those of 1,5-AG . BecauseL_RHI is mainly an index of vascular endothelial function that reflects vasodilatory responses to NO, an endothelium-dependent vasodilatory factor . Vascula2 being equal to 0.277 in multivariate analysis. The sample size was relatively small, and therefore the obtained results require further confirmation in a larger number of patients.This study has several limitations. First, this study did not include control subjects free of diabetes mellitus. Second, we did not evaluate the relationship between vascular endothelial function with either oxidative stress or inflammation. Third, about half of the subjects were on treatment intended to improve lipid metabolism. Although a relationship between L_RHI and blood pressure or the ratio of TC to HDL-C was found in a large-scale cohort study , no relaThe present study demonstrated that low levels of 1,5-AG, a marker of fluctuations in blood glucose level, are associated with vascular endothelial dysfunction in patients with HbA1c <8.0%.1,5-AG: 1,5-anhydro-D-glucitol; CGM: Continuous glucose monitoring; CVD: Cardiovascular disease; DBP: Diastolic blood pressure; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model of assessment insulin resistance; IRI: Immunoreactive insulin; JDS: Japanese standard substance; L_RHI: Natural logarithmic-scaled reactive hyperemia index; LDL: Low-density lipoprotein; MAGE: Mean amplitude of glycemic excursions; PAT: Peripheral vascular arterial tonometry; RHI: Reactive hyperemia index; SBP: Systolic blood pressure; T2DM: Type 2 diabetes mellitus; TG: Triglycerides.The authors declare no conflict of interest.All authors listed on the manuscript participated in the design of the study and in writing the manuscript. KT performed the statistical analysis. All authors read and approved the final manuscript.


R = 0.68, P < 0.001). All formulas failed to provide a reliable estimate of GFR. In multivariate analysis, Cockcroft-Gault < 52 mL/min and kidney sinus section area < 28 cm2 showed the highest accuracy for the identification of CKD subjects . MDRD and CKD-EPI differed significantly for GFR ≥90 mL/min. Conclusions. Cockcroft-Gault < 52 mL/min was able to discriminate subjects with CKD but all formulas failed to provide a reliable estimate of GFR. The combined use of r-US and Cockcroft-Gault formula improved the ability to discriminate CKD in elderly subjects.We evaluated in elderly subjects (a) the ability of GFR formulas to discriminate chronic kidney disease (CKD), (b) the correlation between renal morphology and function, and (c) the usefulness of combined r-US and GFR formulas to detect CKD. A total of 72 patients were enrolled . Cockcroft-Gault showed the highest sensitivity (78%) and specificity (94%) for CKD and was correlated with kidney volume ( These measurements, however, are not suitable for routine clinical practice because they are expensive, are time-consuming, and require specialized equipment and skills [Only about one-third of the elderly population has a normal glomerular filtration rate (GFR). In these subjects, a reliable estimate of kidney function is of fundamental importance since reduced GFR significantly affects prognosis, drug prescriptions, and dosing . Accurat99mTc-DTPA-GFR [51Cr-EDTA [Several formulas based on serum creatinine (SCr) measurements have been developed and tested. The most used formulas in adults are the Cockcroft-Gault , modifiDTPA-GFR , 9, or 51Cr-EDTA ); howeve1Cr-EDTA . Moreove1Cr-EDTA , MDRD fo1Cr-EDTA ; the dif1Cr-EDTA . No dataUltrasound imaging is an easy and widely available technique to evaluate patients in clinical practice. Ultrasound kidney volume and size are reliable predictors of renal function in patients with chronic renal disease .Few data are available on the relationship between kidney morphology and function in elderly subjects. Renal size decreases with increasing age among subjects >60 years . LongituCross-Sectional Study. Hospitalized elderly subjects with age 65–100 years, catheterized for at least 24 h, were included in this analysis.Exclusion criteria were absence of bilateral kidneys visualization at ultrasound examination, acute renal failure, wasting disease, kidney cysts > 2.5 cm, malignancy, and absence of informed consent.CG, MDRD, and CKD-EPI formulas were tested versus 24 h urinary creatinine clearance (24 h-CrCl). CKD is defined as 24 h-CrCl <60 mL/min.π/6/2).The following kidneys ultrasound parameters were evaluated: mean resistance index (mean-RI), kidney longitudinal diameter (l-diameter), kidney transverse diameter (t-diameter), total kidney volume (t-volume), kidney parenchymal volume (p-volume), parenchymal thickness (mPT), total kidney section area (ASMT), kidney sinus section area (ASMS), and kidney parenchymal section area (ASMP). t-volume was measured by use of the ellipsoid formula  with a MyLab 25 device  paired with a 3.5–5 MHz convex probe in transversal and longitudinal sections. Each measurement was performed twice; the mean of the two measurements was recorded.The study has been conducted in conformity with the ethical guidelines of our institution; an informed consent was obtained from all participants.P < 0.05 was taken as a significant value) to study the relationship between CG, MDRD, and CKD-EPI.All calculations were made using a standard statistical package . Continuous variables were reported using means and standard deviations (SD). Categorical variables were described as counts and percentages. The clinical characteristics of patients were compared using analysis of variance for continuous variables and chi-square test for categorical variables. Spearman's correlation coefficient was calculated  between patients with and without CKD . To obtain a parsimonious model, we selected variables that differed  and theThe study population included 72 patients . Their demographics and characteristics are summarized in The best cut-off of CG, MDRD, and CKD-EPI for 24 h-CrCl <60 mL/min was 52 mL/min, 87 mL/min, and 65 mL/min, respectively.R = 0.70, P < 0.001, The strongest correlation was found between 24 h-CrCl and CG (CG showed a high sensibility (78.0%) in selecting patients with CKD and a very high specificity (93.5%) in detecting patients without CKD. Thirty-one patients had a 24 h-CrCl ≥60 mL/min; yet using the CG equation, thirty-eight patients were determined to have GFR ≥60/mL/min with a PV−  of 76.3%. Predictive performance of GFR formulas for CKD is reported in R = 0.68, P < 0.001; GFR was correlated to kidneys ultrasound parameters . The strR square was 0.44. The correspondent area under the ROC curve (AUC) was 0.86  (CG < 52.8 mL/min had the highest accuracy (among the three equations compared) in correctly identifying cases with 24 h-CrCl <60 mL/min. Cox and Snell < 0.001) . 2;Model 1: CG < 52 mL/min and ASMS < 28 cm Model 2: MDRD < 87 mL/min, age, and t-volume < 124 mL; 2, and t-volume < 124 mL.Model 3: CKD-EPI < 65 mL/min, age, ASMS < 28 cmThe ROC curves illustrated that Model 1 had the highest accuracy (among the three models) in correctly identifying cases with 24 h-CrCl <60 mL/min. Cox and Snell R square was 0.48; the Hosmer-Lemeshow test of the regression analysis was not significant (P = 0.80) indicating that the model is well calibrated. The correspondent AUC was 0.91 . The AUC of each model was reported in In multivariate analysis for 24 h-CrCl <60/mL/min, according to the best cut-off, the following models were selected:Renal function has a significant impact on survival of elderly patients. K-DOQI guideline recommends to estimate the GFR in all subjects >60 years. The reference technique for the evaluation of renal function is the inulin clearance. However, this test is far too complex for regular clinical use. 24 h-CrCl is a robust alternative for the evaluation of renal function in clinical practice but it is difficult to be employed routinely in elderly patients mostly for their low compliance and the need of extra care. Over the years, several equations have been developed for the evaluation of renal function from readily available variables. However, most of these equations, and in particular the recently developed CKD-EPI formula, have not been tested in elderly patients. Therefore, the validation of simple predictive models for CKD, designed to identify patients with 24 h-CrCl <60 mL/min and based on readily available laboratory and morphologic data, may be clinically advantageous in elderly patients.R = 0.70, P < 0.001). These data are in agreement with the data by Gómez-Pavón et al. [In the present study, we evaluated the most frequently applied prediction equations for the evaluation of renal function, the CG, MDRD, and CKD-EPI formula. Two of them (MDRD and CKD-EPI) are independent from the determination of body weight which, albeit simple to obtain, may be not readily available in old and frail patients. To assess the suitability of prediction equations, the variability of renal function was evaluated using the Bland-Altman analysis. This test is currently considered superior to the more widely used regression analysis . Our datn et al.  who repoThe CG equation showed a good sensibility in selecting elderly patients with CKD Se 78%,  and had Our data revealed also a great variability of the estimated renal function between MDRD and CKD-EPI formula for a mean GFR ≥90 mL/min (corresponding to a serum creatinine 0.36–0.64 mg/dL) . This fiR = 0.68, P < 0.001; Ultrasound imaging is a widely available diagnostic procedure that provides much valuable real-time information on the clinical status of elderly patients. A recent study reported a good correlation between total kidney volume evaluated by ultrasound imaging and renal function in patients with chronic kidney disease . In eldeAs intrarenal vascular compliance diminishes and subclinical chronic ischemia ensues, the kidneys become smaller. The ratio of ultrasound determined renal volume to intraparenchymal resistive index as evaluated by Doppler at the level of the intrarenal arteries has been proposed as a way to measure nephroangiosclerosis and has been shown to be useful in identifying patients with preclinical hypertensive renal damage, characterized by reduced kidney volume and increased renovascular stiffness . In the 2) had the highest discriminatory power in identifying CKD patients with an excellent AUC  will improve the ability of CKD-EPI formula to discriminate between elderly subjects with and without CKD providing a good AUC. Alternatively, if data of body weight are available, the use Cockcroft-Gault formula and ASMS (Model 1) will provide an excellent AUC.A possible limitation of the present study is the absence of gold standard techniques for GFR assessment, such as inulin clearance, in the present study. However, even if the use of 24 h creatinine clearance as reference technique to estimate renal function may have theoretically introduced a bias, the major source of error with the use of this technique is the urine collection which may not reflect the real 24 h urine output . In ordeWe tested the Ac and the precision of the most common formulas for the evaluation of renal function in elderly patients and evaluated the role of renal ultrasound imaging to improve the ability of prediction formulas to discriminate elderly patients with CKD.None of the equations reached an acceptable Ac (70%). Cockcroft-Gault provided the best performance (Ac 69%) and had the highest discriminatory power in detecting elderly patients with CKD. The use of renal ultrasound parameters improves the ability of prediction formulas to discriminate between subjects with and without CKD.


Objective. Thyroid-stimulating-hormone (TSH) receptors are expressed in endothelial cells. We investigated whether elevated TSH levels after acute recombinant TSH (rhTSH) administration may result in alterations in blood pressure (BP) in premenopausal women with well-differentiated thyroid carcinoma (DTC). Designs. Thirty euthyroid DTC female patients were evaluated by rhTSH stimulation test (mean age 40.4 ± 8.6 years). A 24 h ambulatory systolic and diastolic blood pressure  monitoring (24 hr ABPM) was performed on days 2-3(D2-3). TSH was measured on day 1(D1), day 3(D3), and day 5(D5). Central blood pressure was evaluated on D3. Twenty-three patients were studied 1–4 weeks earlier . Results. TSH levels were D1: median 0.2 mU/L, D3: median 115.0 mU/L, and D5: median 14.6 mU/L. There were no significant associations between TSH on D1 and D3 and any BP measurements. Median D5 office-SBP and 24 h SBP, DBP, and central SBP were correlated with D5-TSH (P < 0.04). In those where a basal 24 h ABPM had been performed median pulse pressure was higher after rhTSH-test (P = 0.02). Conclusions. TSH, when acutely elevated, may slightly increase SBP, DBP, and central SBP. This agrees with previous reports showing positive associations of BP with TSH. It is well known that thyroid hormones influence cardiovascular function and may modulate the vascular response, the endothelial function, and the arterial blood pressure . Moreove per se, after binding to receptors expressed in the vasculature, may modulate its function and if such effect could be of any clinical importanc, has not been thoroughly investigated.TSH receptors have indeed been recognized in many extrathyroidal tissues such as smooth muscle cells and adipose tissue including endothelial cells –8. FurthTSH has a stimulatory effect on both residual normal thyroid and malignant tissue in patients with well differentiated thyroid carcinoma. Suppression of endogenous TSH levels with thyroxine is the cornerstone of therapy in differentiated thyroid cancer (DTC). Thyroglobulin (Tg) measurement is used to evaluate residual/recurrent disease; this is reliable only when TSH is high. The exogenous administration of recombinant human TSH (rhTSH) results in stimulation of Tg analogous to thyroxine withdrawal  and has Concerning the effect of acute rhTSH administration on blood pressure, only limited data exist: two studies have not found any association of TSH levels with single blood pressure measurements , 16. TheThus, the aim of our study was to investigate whether elevated TSH levels after acute rhTSH administration may result in alterations in blood pressure in a 24-hour ambulatory blood pressure monitoring (ABPM) as well as in central arterial pressure in individuals who had undergone thyroid ablation with radioactive iodine for well differentiated thyroid carcinoma and who have in the reevaluation remission of disease. In a subgroup of these patients a second ABPM and central blood pressure were measured 1–4 weeks before rhTSH administration in order to compare the rhTSH effect on blood pressure with basal measurements.Sixty-three consecutive women visited the endocrine unit of our department from 2009 to 2011 for a scheduled visit, one year after total thyroidectomy, to undergo a rhTSH stimulation test for the evaluation of well differentiated thyroid carcinoma progress (DTC) (papillary or follicular). All patients were receiving TSH suppressive treatment with stable dose of levothyroxine and had fT4 and T3 levels within normal range. For the purposes of the study in order to exclude the influence of sex hormones in the cardiovascular parameters we included only women of reproductive age , 18. BecExclusion criteria were menopausal women, history of known cardiovascular disease (CVD) , diabetes mellitus, and impaired glucose tolerance, as well as alcohol consumption, chronic hepatic or renal disease, and history of pulmonary diseases, vasculitis, or other autoimmune diseases. Obese patients were excluded only when they also had at least one further risk factor for CVD, as it has been shown that metabolically healthy obese subjects without risk factors for CVD appear to have the same risk for CVD as the nonobese -[HDL]-[(TG/5)] .Office blood pressure measurements  and heart rate (HR) were recorded during each visit on D1, D3, and D5 by means of an automated sphygmomanometer (OMRON 705IT). Blood pressure measurements were obtained twice at a sitting position, after 15 min rest. The mean was calculated.The 30 women finally participating in the study underwent 24-hour ambulatory blood pressure measurements (24 h ABPM) after the second administration of rhTSH (D2-D3). As already mentioned, 23 women had undergone a further ABPM, 1–4 weeks before rhTSH administration .The 24 h ABPM was performed on a usual working day for the patients. Readings were taken every 15 minutes starting at 12:00-13:00 am, after the central blood pressure measurements. The median 24-hour, daytime and nighttime, systolic BP (SBP), and diastolic BP (DBP) were recorded with an oscillometric Spacelabs 90207  device. Additionally, the standard deviation (SD) of the above mentioned BP parameters was calculated. The median 24 h, daytime and nighttime, pulse pressure (PP) was estimated as the difference between SBP and DBP. None of our patients was hospitalized during the recording. Examination was valid if at least three recordings were available during an hour.Central blood pressures (systolic and diastolic) were evaluated the day after the second administration of rhTSH (D3) in all participants as well as 1–4 weeks before the rhTSH stimulation in 23 subjects . The study protocol was performed in a dark, quiet examination room after a 20 min rest for the patients. All data were collected in the morning during 8:30–11 a.m.We used radial artery tonometry to analyze the pulse waveform of the aorta  as has been previously described . The meat-test was used for data not normally distributed and the Mann-Whitney rank-test for nonparametric factors. A paired t-test was performed to assess the differences between arterial blood pressure before and during rhTSH stimulation test in each participant in the study for parameters normally distributed otherwise Wilcoxon signed ranks test was used for nonparametric factors accordingly. A P value of <0.05 was taken as statistically significant. Due to the small sample size partial correlations have been performed in order to avoid the possibility of overfitting multivariate models. All nonparametric factors included in partial correlations were log transformed.The SPSS  statistical package was used to perform all the statistical analysis. Descriptive data are shown as range as well as mean ± standard deviation (SD) for data normally distributed and median  when not normally distributed. The linear regression model was used for correlations between continuous variables . For the comparison of the means the unpaired n = 30) had a mean age 40.4 ± 8.6 years (19–51 years) and mean BMI 24.4 ± 4.0 kg/m2 (17.4–35.9). One patient had BMI = 35.9 kg/m2 with no other risk factors for CVD. We performed the analysis both including as well as excluding this patient and no differences in the results were observed. Thus, this patient was finally included. Thus 30 women underwent 24-hour ambulatory blood pressure measurements (24 h ABPM) and central blood pressure measurements during rhTSH stimulation test and of those 23 women had already undergone a further basal ABPM and basal central blood pressure measurements, 1–4 weeks before rhTSH administration.The studied female subjects (P < 0.001). All patients had fT4 and total T3 within the normal range .Mean fasting glucose (FFG) levels were 85.5 ± 6.7 mg/dL, total cholesterol 162.2 ± 21.9 mg/dL, triglycerides 82.4 ± 17.9 mg/dL, low density cholesterol (LDL) 86.5 ± 12.8 mg/dL and high-density cholesterol (HDL) levels 56.0 ± 9.0 mg/dL. In all subjects Tg levels remained <0.5 ng/mL before and after rhTSH stimulation test consistent with absence of residual disease. The TSH range on D1 (before the rhTSH administration) was 0–2.6 mU/L , on day D3 62.0–178.1 mU/L  and on D5 2.9–24.1 mU/L  five patients were found with blood pressure levels outside the normal limits according to the criteria mentioned above . The offr = 0.541, P < 0.008, Spearman's correlation). No significant association was found between diastolic arterial pressure and D5-TSH levels .No significant associations between office arterial pressure measurements and the respective TSH levels on D1 and D3 were found. However, a positive correlation between day 5 office systolic arterial pressure and D5-TSH levels was observed .Concerning the 24 h ABPM measurements, no significant associations between any of the arterial pressure measurements and TSH levels on D3 were found. However, a positive correlation between Standard Deviation of SBP (SD-SBP) with D3 TSH levels was found  as well as between nighttime SBP, DBP, and D5-TSH .A significant positive association of 24 h SBP and DBP with D5-TSH levels was found  remained significant when these confounding variables were taken into account as  account .r = 0.503, P = 0.04), while no significant association was found between central diastolic blood pressure and D3 or D5 TSH levels . In a similar manner, the observed significant correlations between BP parameters and D5-TSH also provided sufficient power ranging from 80.8% to 90% .In our study we examined whether elevated TSH levels after acute rhTSH administration may result in alterations in arterial blood pressure, both peripheral and central, in DTC patients without residual disease. This is the first study in which a 24-hour monitoring of blood pressure is performed in DTC patients during a TSH stimulation test in order to examine in a more detailed manner a possible effect of acute TSH elevation on arterial pressure.Our first important finding concerns the possible influence of rhTSH on blood pressure levels; we found that the 24 hour, daytime and nighttime, SBP, and DBP measurements in 24 h ABPM were positively associated with the increased TSH levels on day 5. We further showed that D5-TSH levels are associated with D5-office systolic blood pressure. These associations remained significant when confounding cardiovascular risk factors were taken into account in partial correlations. As the 24 h ABPM method allows the investigation of blood pressure variations even during the night, the influence of exogenous factors such as the stress of a medical procedure can be reduced or even eliminated.Furthermore, the 24 h standard deviation (SD) of SBP was positively associated with TSH levels on D3, independently of the various confounding factors in partial correlations. This is of importance as it has been previously reported that increased blood pressure variability is an independent predictor for target-organ-damage and cardiovascular mortality , 30.Finally, we found significant positive correlation of D5-TSH levels with central systolic arterial pressure. There are no previous reports in the literature about a possible association between acute increase of TSH levels and central arterial pressure. Central pressures have been proven to be a better marker than peripherally obtained blood pressures to estimate cardiovascular risk .There are possible explanations concerning the association of D5-TSH levels with blood pressures obtained on day 3. First, TSH levels at D3, which are the highest, have little variations that do not allow us to observe any significant relationships during the statistical analysis. Moreover, it is possible that the increase in blood pressure levels recorded on D3 might be associated with the overall increase of TSH and not with the exact TSH levels measured on D3. Thus, a moderate TSH increase may have similar effect on blood pressure with a very high TSH level. TSH values on D5 might be more stabilized and thus they could reflect the longer exposure effect of TSH on blood pressure. Another speculation is that blood vessels reactivity could be more obvious after a prolonged exposure to higher TSH levels. Thus, it seems that the acute increase may have no immediate significant effect in blood pressure; the increase in office blood pressures observed on D5 could also point to the same direction.Regarding the subgroup of 23 patients in which a basal 24-hour monitoring of blood pressure was performed, pulse pressure, a significant independent predictor of cardiovascular risk  was signConflicting results concerning associations of TSH with blood pressure during rhTSH stimulation test have been rarely reported in the literature , 16. It  per se on blood pressure in vivo. As many factors can influence blood pressure, our patients were strictly selected: they had no risk factors for cardiovascular disease and they had no residual thyroid disease which in theory, via the production of cytokines, could alter the blood pressure levels [Our results are in the same line with previous findings where slight increases of TSH levels even within the normal range are associated with increased blood pressure measurements in humans , 38. Thue levels .The most important limitation of our study is the relatively small number of participating patients. However our sample was highly selected and homogeneous, as mentioned before. We included only apparently healthy women of reproductive age, while the measurements were performed in the same phase of the menstrual cycle so as to exclude any possible effect of sex hormones in vascular parameters. As the effect of TSH on blood pressure appears to be limited to a few mmHg and our sample was small, such effect may be difficult to be demonstrated.Another limitation is the fact that not all patients underwent measurements before rhTSH administration. Thus, it is possible that we may have lost some significant findings.The results of this study suggest that TSH, when acutely elevated, may have a prolonged direct effect on peripheral and central arterial pressures; however, this effect is only mild and temporary and probably with no clinical significance.The significant differences in ambulatory pulse pressure, an accurate marker of arterial stiffness, between basal and after rhTSH administration measurements also supports the view that rhTSH when acutely elevated could temporarily affect blood pressure levels, albeit at a very mild degree.


Hypertensive crisis  is very rare during operation except pheochromocytoma, but it can be a fatal and embarrassing to surgeons and anesthesiologists. The right adrenal gland can be electrocauterized during a right hemi-hepatectomy. We report a case of hypertensive crisis during right hemi-hepatectomy in which the right adrenal gland was stimulated by monopolar electrocautery in a patient with normal neuroendocrine function.A 73-year-old man with hepatocellular carcinoma was scheduled to undergo right hemi-hepatectomy. Three hours into the surgery, the patient’s blood pressure increased abruptly from 100/40 to over 350/130 mmHg . The surgeon had cauterized the right adrenal gland using monopolar electrocautery to separate the liver from the adrenal gland immediately prior to the event. Approximately 3 minutes after suspending the operation, blood pressure returned to baseline levels. After the event, the operation was successfully completed without any complication. Hormonal studies and iodine-123 meta-iodobenzylguanidine scintigraphy revealed no neuroendocrine tumor such as a pheochromocytoma.Operations such as hepatectomy that stimulate the adrenal gland may lead to an unexpected catecholamine surge and result in hypertensive crisis, even if neuroendocrine function of the adrenal gland is normal. Intraoperative hypertension is common during general anesthesia, but it is usually well managed without serious complications. However, severe hypertension can cause cardio-cerebrovascular complications such as myocardial ischemia, arrhythmia, cerebral hemorrhage, or aortic dissection during the perioperative period. Although controlling blood pressure has become easier to accomplish due to the development of anesthetic techniques and antihypertensives, severe hypertension still remains a challenging issue , 2. In pThe adrenal gland stores and discharges catecholamines into the blood stream by activation of the sympathetic nervous system. Surgical manipulation of the adrenal gland, especially in the catecholamine producing tumors such as pheochromocytoma and paragangliomas, may cause a catecholamine surge resulting in hypertensive crisis intraoperatively , 6. FurtWe report a case of abrupt and severe hypertension, with systolic blood pressures over 350 mmHg, during a right hemi-hepatectomy in which the normal neuroendocrine functioning adrenal gland was electrically stimulated by monopolar electrocautery to separate the liver from the adrenal gland.A 73-year-old man with a 10-year history of hypertension and diabetes mellitus presented with hepatocellular carcinoma and complicated cyst in the liver. The patient was scheduled to undergo right hemi-hepatectomy. Hypertension was controlled with an angiotensin II receptor antagonist. Diabetic neuropathy was diagnosed in autonomic function test. Magnetic resonance imaging of the abdomen revealed a 2.6 × 2.6 sized hepatocellular carcinoma in segment VII and a 3.2 × 3.2 sized atypical complicated cyst in segment VIII. The patient had no abnormal findings in the adrenal gland, spleen, and pancreas, except for a simple renal cyst.Initial blood pressure was 150/80 mmHg and heart rate was 65 beats per minute in the operating room. Anesthesia was induced with thiopental 300 mg, rocuronium 60 mg, and continuous infusion of remifentanil (effect site concentration 3 ng/ml) using a target controlled infusion system . After endotracheal intubation, anesthesia was maintained with 1-3% of sevoflurane and remifentanil 2–4 ng/ml effect site concentration. The left radial artery was cannulated for direct blood pressure monitoring using a pressure kit . The right subclavian vein was catheterized for fluid management and central venous pressure monitoring.From the start of the operation, blood pressures ranged from 100/40 to 150/70 mmHg with heart rates 55 to 70 beats per minute for three hours. Three hours into the surgery, systolic blood pressure abruptly increased from 100 to over 350 mmHg, the maximum measurable pressure of the monitor incorporated with anesthesia workstation . Diastolic blood pressure increased from 40 to 130 mmHg and heart rate increased from 75 to 95 beats per minute. The anesthesiologist checked the delivery system of the anesthetics, which was functioning normally. No drug was injected at that time. Anesthesia was deepened and labetalol 10 mg was administered.The operation was stopped immediately. Although a vasopressor such as epinephrine was not injected in the surgical field, the right adrenal gland had been cauterized by monopolar electrocautery to separate the liver from the adrenal gland. Approximately 3 minutes after suspending the operation, blood pressure and heart rate returned to baseline levels, which were maintained until the end of the operation. After the event, the right liver was resected successfully without any complication.123I-MIBG) scintigraphy revealed no neuroendocrine tumors such as pheochoromocytoma. The postoperative course was uneventful, and the patient was discharged without any sequelae.Postoperatively, the patient was transferred to the intensive care unit for hemodynamic monitoring and neurologic examination. Neurologic examination performed by a neurologist was within normal limits, and the patient remained hemodynamically stable during recovery. Hormonal studies were performed to investigate an undetected pheochromocytoma or paraganglioma. However, urine metanephrine, vanillylmandelic acid, and homovanillic acid levels were 0.3 mg/day , 2.3 mg/day (0–8 mg/day) and 2.8 mg/day (1.4-8.8 mg/day), respectively. Iodine-123 meta-iodobenzylguanidine (Severe hypertension is defined as an increase in systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg without end-organ damage. Hypertensive emergency is defined as rapidly evolving end-organ damage associated with hypertension of diastolic blood pressure > 120 mmHg [123I-MIBG scintigraphy revealed no neuroendocrine tumor such as a pheochromocytoma or paragalglioma.Paix et al.  reportedChini et al.  reportedIn summary, intraoperative stimulation of the adrenal gland has the potential risk of unexpected catecholamine surge, resulting in severe hypertension even if the neuroendocrine function of the adrenal gland is normal.Written informed consent was obtained from the patient for publication of this Case Report. A copy of the written informed consent is available for review by the Editor of this journal.


Objectives: To determine the risk factors associated with persistent airflow limitation in patients with asthma.Methods: This study was designed and carried out in the department of respiratory medicine, fourth People’s Hospital of Jinan City, Shandong province, China between Jan 2012 and Dec 2012. Three hundred and six asthma patients participating in the study were divided into persistent airflow limitation group (PAFL) and no persistent airflow limitation group (NPAFL). The patients participated in pulmonary function tests and sputum induction examination. The clinical data including age, gender, onset age, disease course, smoking history, family history, regular corticosteroid inhalation, hospitalization history and presence of atopy were collected.Results: In 306 patients, 128 (40.5%) were included in PAFL group and 178(59.5%) in NPAFL group. Multivariate analysis demonstrated smoking , longer asthma duration (≥ 20years) , absence of regular corticosteroid inhalation  and neutrophil in induced sputum≥65%  were independent risk factors for PAFL.Conclusions: Smoking, longer asthma duration and increased neutrophil in induced sputum are risk factors for PAFL, while regular corticosteroid inhalation is protective factor. Smoking cessation and regular corticosteroid inhalation may play an important role in preventing the occurrence of persistent airflow limitation group (PAFL). In the study of 1017 patients from Lee, 612 patients (60%) showed evidence of PAFL, and in the study of 136 patients from ten Brinke,Asthma is a common inflammatory disease of airways characterized by reversible airflow obstruction.Some authors suggest that specific factors might accelerate this progressive decline in lung function and promote the occurrence of PAFL. In the study of 152 patients with severe asthma, ten Brinke advocated PAFL is associated with adult onset of the disease, airway hyper responsiveness and sputum eosinophilia.Therefore, in the current study, we consecutively recruited 306 out-patients with asthma in pulmonary departments of our hospital. The objective of the current study was: (1) To analyze the clinical characteristics of patients with PAFL; (2) To determine the risk factors for PAFL, and help physicians make treatment strategies.This study was designed and carried out in the department of respiratory medicine, fourth People’s Hospital of Jinan City, Shandong province, China, between Jan 2012 and Dec 2012. In the study, we consecutively recruited the out-patients who met the inclusion criteria from the department of respiratory medicine of our hospital.The inclusion criteria was patients with bronchial asthma history for more than three months, and asthma was defined according to the American Thoracic Society criteria. The patients with other pulmonary disease such asbronchiectasia, pulmonary tuberculosis, pulmonary infection, malignant neoplasm and serious heart failure were excluded. The current study was approved by the ethical committee of our hospital and performed according to the principles of Helsinki Declaration. All the included patients gave informed consent.Procedures: At the time of patients’ entry into the study, the clinical characteristics including age, gender, onset age, asthma duration, smoking history, family history, regular corticosteroid inhalation, hospitalization history and presence of atopy were documented according to a detailed structured questionnaire.   3 1,7 No PAFL was defined when an FEV1/FVC ratio > 0.7 was proved on at least one pulmonary function test.      4 The included patients underwent three pulmonary function tests under stable conditions without asthma exacerbation at the time of enrollment (baseline) and at 3 and12 months after enrollment, among which at least one test was performed both before and after inhalation of 200 microgram of albuterol.,Sputum induction examination were performed according to previous studies.8Statistical analysis: Statistical analysis was performed using SPSS17.0 .The comparison of age, cell counting, asthma duration between two groups was performed using independent 2-sample t test. The comparison of categorical variables including gender, family history, hospitalization history, smoking history and atopy between two groups was carried out using Chi-Square test. Univariate analysis and multivariate logistic regression analysis were performed to find the correlation between variables and PAFL. Variables showing a significant correlation were included in the multivariate logistic regression analysis to determine the independent risk factors associated to PAFL. A p value less than 0.05 was considered to indicate statistical significance.In the current study, 306 patients with asthma were included. PAFL group consisted of 128 patients (40.5%) and NPAFL group consisted of 178(59.5%).The clinical characteristics of two groups are shown in The cell classification in induced sputum in two groups was listed in The risk factors associated with PAFL was listed in In the present study, the FEV1 value was 49.61% predicted in PAFL group, but the value was 82.79% in NPAFL group. This indicates that most cases with PAFL belongs to severe asthma.,Up to date, the mechanism of PAFL is still not completely clear. Many factors may be correlated closely to its occurrence, while some viewpoints are contradictory and controversial. Airway remodeling is regarded as an important mechanism of PAFL. Airway remodeling results in thickening of the airway wall and leads to a component of fixed airway narrowing and airflow obstruction.4,Moreover, we found the longer asthma duration is the risk factor associated with PAFL. While, Vonk suggested the development of irreversible airflow obstruction is caused by a longer delay in treatment rather than by a longer duration of the disease.13,In addition, in the cell count in induced sputum, there was no significant difference in monocyte, lymphocyte and eosinophil between the two groups, but neutrophil in PAFL group is significantly higher than those in NPAFL group. Also, the logistic regression analysis demonstrate that the increasing cell count in neutrophil is one of the risk factors to cause PAFL, our result is similar to Shaw’s study,3In conclusion, we found the identifiable clinical and demographic characteristics including smoking, longer asthma duration and increased neutrophil in induced sputum are risk factors for PAFL, while regular corticosteroid inhalation is protective factor. Subsequently, smoking cessation and regular corticosteroid inhalation may play an important role in preventing PAFL.


KIT or platelet-derived growth factor receptor α-activating mutations. This deep molecular understanding has allowed the correct classification into risk groups with implications regarding prognosis, essential use in the development of targeted therapies and even response prediction to this drugs. Treatment has been evolving and an update to include lessons learned from recent trials in advanced disease as well as controversies in the adjuvant setting that are changing daily practice, is reviewed here. An effort from the Spanish Group for Sarcoma Research with investigators from the group has been undertaken to launch this third version of the GIST guidelines and provide a practical means for the different disciplines that treat this complex disease.Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. Correct diagnosis with thorough use of pathologic and molecular tools of GIST mutations has been of the foremost importance. GIST are usually (95 %) KIT positive and harbor frequent  KIT or PDGFRA [Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors originating in the digestive tract. They have a characteristic morphology, are generally positive for CD117 (c-kit) and are primarily caused by activating mutations in the GIST have become a model of multidisciplinary work in oncology: the participation of several specialities  has allowed advances in the understanding of this tumor and the consolidation of a targeted therapy, imatinib, as the first molecular treatment that is effective in solid tumors. Following the introduction of this drug, median survival of patients with advanced stage GIST has increased from 18 to more than 60 months. Additionally, sunitinib is another targeted drugregistered as second-line treatment for metastatic GIST.Radiological diagnosis of GIST is similar to that of other digestive-tract tumors. In barium studies, GIST appear as submucosal lesions  and in uA computerized tomography (CT) scan and magnetic resonance imaging (MRI) are the first choice to study location and extension . A CT wiIn a CT, tumors appear as well-circumscribed exoluminal masses that, after the contrast, show heterogeneous enhancement, especially large tumors, which may have necrotic-hemorrhagic areas or degenerative components .An MRI is useful for the local study of tumors located in the pelvic area  as well The technique of choice for providing histological diagnosis is echoendoscopy-guided biopsy or a CT-guided percutaneous biopsy when the first option is not possible. Although FNA (fine-needle aspiration) endoscopy could be performed on esophagogastric tumors, this technique does not usually provide sufficient material to carry out a proper, definitive histological diagnosis, thus a biopsy would also be called for. If the biopsy become complex, a laparoscopic incision or laparotomy is required in order to obtain diagnosis. However, the use of biopsy forceps for polypectomy increases the risk of perforation and should be avoided and performed in exceptional cases only .Preoperative endoscopic biopsy is not necessary when a lesion is considered suspicious, resectable or operable. On the other hand, it would be appropriate for patients with disseminated disease or in locally advanced cancers when considering neoadjuvant therapy .Samples should be fixed in formaldehyde and not in Boiun’s solution as it may alter results in subsequent studies.KIT o PDGFRA mutations [GIST are the most common mesenchymal tumors originating in the digestive tract. They have characteristic morphological features and are generally positive for CD117 (c-kit) and have active Most common sites They are usually found in stomach (60 %), small intestine, jejunum and ileum (30 %), duodenum (5 %), rectum (2–3 %), colon (1–2 %). They are much less frequent in the esophagus (<1 %). In some cases, there is presence of disseminated tumor with unknown primary tumor and a small number of them, and the tumor originates in the omentum, mesentery and retroperitoneum [ritoneum , 10. MetMorphology The size of GIST is variable (up to 38 cm). Most measure around 5 cm at the time of diagnosis. They typically originate in the digestive tract and can be submucosal, intramural or subserosal. They are rarely invasive and there is often ulceration of the mucous membrane with poor prognosis [rognosis . Necrotirognosis . They arrognosis  in familrognosis . Its grorognosis .fusiform cells (77 %), epithelioid cells (8 %) and mixed (15 %) (1). The epithelial type is more frequently observed in stomach and epiplon [Three histological types can be distinguished according to the cellular appearance: nd mixed  % (1). T2), should be standardized given its prognostic relevance. Strict criteria should be followed as pyknosis and karyorrhexis must not be overlooked. The mitotic index should be graded as follows: low ≤5/50hpf and high >5/50hpf [The number of mitosis can vary substantially, between 0 and over 150 mitoses per 50 high-power fields (hpf). Most show a low or very low mitotic index (≤5 mitosis/50 hpf). The method for counting mitoses in the most active areas, in a total of 50 hpf (corresponding to an area 10 mm>5/50hpf .Over 95 % of GSIT have CD117 (c-kit) expression with diffuse cytoplasmic staining pattern but also rarely in the membrane or Golgi apparatus. There is intense staining in 75 % of cases. Moreover, 70–90 % also express CD34, 20–30 % actin, 8–10 % S-100 and desmin in 2–4 % , in whicThe main differential diagnosis in fusiform GIST comprises smooth muscle tumors (leiomyoma and leiomyosarcoma); schwannoma and malignant peripheral nerve sheath tumor; inflammatory myofibroblastic tumor; solitary fibrous tumor, sarcomatoid carcinoma; inflammatory fibroid polyp and desmoid fibromatosis. Differential epithelioid GIST diagnosis includes poorly differentiated carcinomas; endocrine cancers and variants of epithelioid leiomyosarcoma and malignant peripheral nerve sheath tumor. Luckily, morphological features together with an adequate immunohistochemical panel allow proper diagnosis .Between 4 and 5 % of GIST with typical morphological features are negative for CD117 , 20. ThoKIT and PDGFRA mutation, being mindful that there is a small percentage of GIST with typical morphology, negative for CD117 and DOG1 and wild type for KIT and PDGFRA genotype [KIT or PDGFRA mutations should not be classified as GIST.Kit-negative GIST present a true diagnostic challenge. It is recommended to extend the immunohistochemical panel with other markers such as DOG1 and a mandatory study for genotype . Cases mPathologic diagnosis is based on both unique microscopic features and ancillary techniques , which are very important to confirm diagnosis.2) counted in the most active regions; and margins status.The pathology report must include tumor size; number of mitoses per 50 HPF  [KIT mutations are found in 60–85 % of GIST tumors, while PDGFRA mutations are found in 5–10 %. Approximately 10–15 % of GIST do not have detectable mutations in any of these receptors (GIST wild type), suggesting that other molecular routes can also be involved in the pathogenesis of these tumors [GIST are characterized by activating mutations in II (RTC) , 12. KITe tumors –26.Mutations found in GIST mainly affect exons which codify functional domains of KIT and PDGFRA receptors. Among the main types of mutation, we find the following: deletions, point mutations, duplications, insertions and complex mutations .KIT, and exons 18, 12 and rarely affects 14 of PDGFRA). Meanwhile, mutations detected during treatment, which are to a large degree responsible for resistance to TK inhibitors, are known as secondary mutations  [Mutation detection before tyrosine kinase (TK) inhibitor therapy such as imatinib is known as primary mutation  , 26.KIT mutations affect exon 11 (juxtamembrane domain). Approximately 70 % of GIST present some type of mutation in this exon [The most common his exon , 27. Thehis exon , 28–30.extracellular domain), only duplication of residues 502–503 have been described and is present in 9–20 % of cases depending on the study. This mutation is mainly associated with GIST of small bowel location and greater malignant potential [In exon 9  encoded by exon 12; in TK domain (6 %) encoded by exon 18, DD842 V mutation being the most frequent (65–75 %); and very rarely in exon 14 (0.1 %) [Overall, the estimated frequency rate of s 5–10 % , 25, 33,s 5–10 % , 33. Mut (0.1 %) , 33.KIT and PDGFRA mutations [Around 12–15 % of adult GIST and 90 % of pediatric GIST lack utations . Moleculutations . Besidesutations  and mutautations .KIT or PDGFRA [KIT and PDGFRA mutations is not entirely clear considering that current diagnosis is performed by exclusion [KIT and PDGFRA, to confirm GIST diagnosis, especially in CD117/DOG1 negative cases [Approximately 5 % of GIST are c-kit negative, leading to diagnostic difficulties. Between 30 and 50 % of these tumors present mutations in  PDGFRA , 37–39, xclusion . Furtherve cases .wild-type GIST [Carney Triad: characterized by gastric GIST, paraganglioma, pulmonary chondroma, which may develop in any age group, making it difficult to discard this condition in pediatric ype GIST .Neurofibromatosis Type1: usually marked by a wild-type GIST predominantly located in the small intestine and quite possibly a multicenter study [er study .Carney–Stratakis syndrome: characterized by germline mutations in some subunits of the succinate dehydrogenase enzyme  producing a dyad of GIST and paraganglioma [anglioma , 44.At present, there are many syndromes associated with GIST, among them:The last multidisciplinary ESMO consensus  recommenwildtype [Patients with an exon 11 KIT mutation have a better chance of responding, a longer time to progression (TTP) overall survival (OS) versus those with exon 9 mutations or ildtype –47. Moreildtype .In the above-mentioned meta-analysis, it was found that mutations in exon 9 were the only predictive factor for imatinib response with greater benefit, statistically significant for PFS patients who received high doses of imatinib. A 31 % lower risk of death was observed in favor of 800 mg, although it did not reach statistical difference . These fp = 0.0005) or wild type  regarding those with exon 11 mutations (5.1 months). A significantly greater OS was obtained, comparing those with exon 9 mutations,  for wild type, as opposed to those with exon 11 mutations (12.3 months) [Sunitinib inhibits multiple receptor tyrosine kinases  and has a higher receptor binding affinity than imatinib. Data obtained from Phase I/II clinical trials of 78 patients (out of 97) treated with sunitinib as second line and with preimatinib genotype information showed that patients with exon 9 mutations and wild-type tumor were associated with a more favorable outcome  compared with those with exon 11 mutations. Furthermore, the median PFS was significantly higher in patients with primary exon 9 mutation  .It is acknowledged that secondary resistance observed in patients with metastatic GIST is mostly developed due to the appearance of secondary mutations. Interestingly, no secondary mutations were found in initially wild type and resistant patients .In vivo data obtained from biopsies carried out at the time of progression to imatinib provide important information on secondary mutations identified in 64 % of the available cases. Significant clinical benefit as well as RFS was better in cases with secondary mutations localized in exon 13 or 14 with regard to those in exon 17 or 18 .Acquisition of secondary KIT mutationsKIT gene amplificationActivation of alternative signaling pathwaysKIT or PDGFRA activation in absence of secondary mutations.Functional resistance due to Resistance to imatinib is a major therapeutic problem as, among patients who fail to respond to initial imatinib  or stop responding (secondary resistance), barely 5 % respond to conventional treatments. Primary resistance can be defined as that occurring in the first months of imatinib therapy. Progression is typically multifocal, and mutations are frequently found in exons 9 and WT. The mechanisms for secondary resistance to imatinib are heterogeneous and can be grouped into various groups , 52:AcquKIT or PDGFRA [The most common mechanism is the appearance of a new mutation. Secondary mutations in exons 13, 14, 17 or 18 account for 62 % of GIST with primary in KIT exon 11 mutations but only in 16 % have a primary mutation of exon 9. Moreover, no secondary mutations appear in GIST which do not have a primary mutation in r PDGFRA . There ir PDGFRA , 53.The clinical application of secondary mutation findings is not so clear-cut at the present time and should be subject to further research studies.Lastly, given the interest in translational studies regarding this neoplasm, it is advised to take fresh tissue for the application of new technologies of molecular pathology, which will ultimately have a positive impact on the patient.It is highly advised that diagnostic and therapeutic processes could be referred to expert teams for GIST care .Complete surgical resection is the standard treatment for localized GIST. Radiological criteria for unresectability include infiltration of the celiac trunk, the superior mesenteric artery or mesenteric artery-to-portal vein. Lymphadenectomy is unnecessary given the low frequency of lymph node metástasis or metastasis. Some exceptions could be SDH-deficient GIST especially in pediatric population.The aim was to achieve a R0-type surgery , complete removal leaving an intact capsule. It is therefore necessary, in some cases, to remove neighboring organs and perform a surgical “block excision.” Segmental resection of intestine and stomach is accepted, and thus, aggressive and a more extensive surgery to remove unaffected tissue is unnecessary .Regarding R1 resection , reexcision could be offered and shared with the patient, if this does not imply major functional squeals. If the context of R1 surgery is a very low- to low-risk tumor, the physician should communicate the wait-and-see approach to the patient as opposed to aggressive surgery with permanent damage since there is no clear evidence that R1 margins entail a worse prognostic in such cases.Peritoneal and hepatic surfaces should be carefully examined during a laparotomy to rule out tumor spread. Tumor resection must be carefully performed to avoid tumor rupture. In this regard, a laparoscopic approach is strongly discouraged in patients with voluminous tumors.Relapse-risk assessment for primary GIST is paramount not only providing prognostic information when trying to determine risk factors but also estimating the potential benefit of adjuvant imatinib. In 2002, an index was proposed (NIH Consensus NIH or Fletcher)  based onSubsequently, Miettinen et al., analyzed data of 1.765 patients with gastric GIST and observed that patients only developed metastasis in 2–3 % tumors with <10 cm and <5 mitosis/50 HPF, compared with 68 % of those who presented >10 cm and >5 mitosis/50 HPF [Based on this data, these same authors put forward a new risk index (AFIP/Miettinen) that includes anatomic site . This clThe main differences between both classification systems lies in patients with gastric GIST, larger than 10 cm but with <5 mitosis per HPF. Using Fletcher’s classification, the latter would be in the high-risk group with a recurrence-free survival (RFS) of 50 % at 5 years. Nevertheless, they would fall within the intermediate-risk category with a RFS of 80 % according to the Miettinen group classification.2 in 50 fields HPF characterized by the use of different optical components, while in practice 50 HPF typically corresponds to a total area of 10 mm2. Therefore, if we use Miettinen’s risk classification, we should also make the correction of dividing the number of mitosis by half including the current optical elements by 50 HPF.On the other end of the spectrum we find GIST tumors with extragastric location of <5 cm and more than 5 mitosis per HPF. According to Fletcher’s classification, they would fall within the intermediate group with a RFS probability of 85 % versus being in the high-risk group with 45 % RFS in the Miettinen group classification. It is important to note that Miettinen considered a total area 5 mmOther succeeding risk classifications such as the American Joint Committee on Cancer (TNM)  or the nJoensuu H. recently introduced a capsule rupture classification known as modified NIH that simplifies the site classification (gastric/non-gastric) but at the same time renders heat maps to be more complex as categorization of continuous variables is not used .The NCCN  and ESMOA further problem posed, at least theoretically, is regarding adjuvant imatinib clinical trials designed using Fletcher’s risk classification. If we were to adopt a more liberalized stance on drugs, we would recommend adjuvant imatinib treatment for patients with gastric GIST for tumors of 10 cm or larger with <5 mitosis/HPF (considered as high risk according to Fletcher), when the risk of recurrence is 65 %. Therefore, the most rational approach should bear in mind the most current prognostic information in which the high risk of recurrence category is more accurate.Although GIST tumors are a model for the so-called molecular target therapies, molecular prognostic factors have not been incorporated in the risk of recurrence classifications. There is available evidence indicating that the type and location of the mutation has an effect on the risk of recurrence. Deletions affecting exon 11, codon 557/558 of the c-KIT gene, have a higher recurrence risk and it will occur within the first 3–4 years after surgery , 60. TheWe recommend the use of the risk group classification proposed by Miettinen as it is the best at identifying low, intermediate and high-risk populations. Spontaneous or intraoperative capsule rupture should be considered as a very poor prognostic factor.Deletion type of mutations affecting codons 557 and 558 confers a risk for recurrence regardless of its previous classification, according to our experience. The risk is greatest within the first 30 months after surgery and then drops drastically. Nevertheless, results from other prospective studies are needed in order to assess the value of this variable.Despite the fact that complete resection is feasible in most localized GIST cases, there is still a recurrence rate of up to 50 % according to some series. The role of imatinib as adjuvant treatment to prevent recurrence has therefore been assessed in several clinical trials. Evidence derived from the large Phase III randomized trials ACOSOG Z9001  and SSGXAlthough the initial end point was OS, it was changed to time to imatinib failure (TIF) in 2009 due to the small number of relapses in the control group. No significant statistical differences were found in either arms (OS and TFI) after a 4.7-year follow-up. Nevertheless, there was an objective tendency to an improved TFI in high-risk patients (in both NIH 2002 as well as modified NIH classifications). A benefit was also observed in RFS as previous reported studies in favor of adjuvant treatment with imatinib in high-risk patients.In view of these results, both NCCN and ESMO guidelines as well as consensus of the scientific community, recommend 3 years of adjuvant treatment with imatinib in high-risk patients. Adjuvant treatment for low-risk patients is not indicated. However, currently there is not enough scientific evidence to support adjuvant treatment with imatinib in intermediate-risk patients. Based on these considerations, for uncertain cases, it is important to carry out an assessment of risk of recurrence and properly classify them by using modified classification tools (modified Miettinen classification of Joensuu H).There are still many unclear areas concerning duration of adjuvant treatment and whether more than 3 years of treatment would increase benefit in patients at higher risk. Studies like PERSIST-5 may shed some light on this issue. Moreover, another aspect that needs to be clarified is whether relapse is actually avoided or just delayed, given the relapses observed in SSGX-VIII/AIO following adjuvant treatment interruption at 6–12 months in both arms .Capsule break: These are generally accepted as disseminated patients given that 100 % will relapse, at least on a peritoneal level. Therefore, imatinib administration is recommended as advanced disease setting.Specific genotypes: Adjuvant imatinib is not recommended in patients with D842 V PDGFRα mutation given its known resistance to it. There is no consensus regarding the benefit of a daily dose of 400 mg of imatinib for carriers of an exon 9 mutation in the KIT gene. The efficacy of a daily dose of 800 mg of imatinib was extrapolated from the evidence of disseminated disease. Nonetheless, this scenario has not been proven in clinical trials and therefore has not been approved for adjuvant treatment. Survival in patients with wild type does not seem to increase with the use of adjuvant imatinib, and thus, there is still controversy over imatinib administration and each case must be considered individually.Patients with R1 surgery: There is no evidence confirming the benefit of adjuvant imatinib in low-risk patients with affected microscopic margins. Surgical reexcision could be considered for these cases .High-risk patients: 3 years of adjuvant treatment with imatinib is recommended.Low-risk patients: adjuvant treatment is not indicated.Intermediate-risk patients: currently, there is not enough scientific evidence to support adjuvant treatment with imatinib. For uncertain cases, it is important to carry out an assessment of risk of recurrence and properly classify them by using modified classification tools (modified Miettinen classification of Joensuu H).Gastrointestinal stromal tumors have been a paradigmatic example of chemo-resistant tumors with <5 % of responses and 14 months as the median of survival reported in the literature. Imatinib mesylate  is a selective tyrosine kinase inhibitor (TKI), whose targets include ABL, BCR-ABL, KIT and PDGFR and constitutes as a very effective agent for the treatment of clinically advanced, metastatic or surgically unresectable GIST , 66.2 per day was established from two different randomized phase III trials in metastatic GIST with positive immunostaining for kit (EORTC-ISG-AGITG y NASG-S0033). In both trials, daily doses of 400 versus 800 mg were compared without any survival difference and with a more favorable toxicity profile for lower doses. The clinical benefit rates  for 400 and 800 mg were 90 and 88 %, respectively, in NASG-S0033 study. These rates were 91 and 87 %, respectively, in EORTC-ISG-AGITG study. Furthermore, there was statistically significant difference, in terms of progression-free survival (PFS), favoring 800 mg dose in an European trial: progression-free rate at 2 years 52 versus 44 % (HR 0.78) [The standard dose of imatinib of 400 mg/mHR 0.78) , 68. In HR 0.78) . NeverthInterestingly, one of the notable features of the clinical studies of imatinib for GIST treatment is the consistent observation that defined subsets of GIST according to their mutational status have different outcomes during treatment and therefore should be considered in devising treatment strategies.Responses to imatinib depend on the functional domain affected . Table 4p = 0.0017) in the 800-mg/day arm compared with the 400-mg/day dose of imatinib. In the same direction, the risk of death was also reduced in a 31 % in this subgroup of patients.On the other hand, the meta-analysis also confirmed the observations previously reported in the European/Australasian trial, and therefore, it was concluded that KIT exon 9 mutations constituted a dose-dependent predictive factor for imatinib treatment identifying patients with a better response to high doses of imatinib (400 mg twice daily). Consequently, the estimated risk of progression for patients with KIT exon 9 mutations was drastically reduced . Evidence IV, B.Thus, taking together the previous information, there is a consensus in the following recommendations:How long should the therapy last? The BFR14 trial, which randomized patients with nonprogressive GIST to continuation versus interruption of imatinib after 1, 3, or 5 years of treatment, showed that treatment interruption was associated with a high risk of progression even in patients with a complete response . InteresCompliance. Although imatinib is usually a well-tolerated drug with as few as 2 % of grade III–IV adverse events, the long duration of therapy and persistent grade I–II side effects could impact in treatment compliance and consequently in disease outcome. Therefore, a good education of patients regarding the importance of compliance and potential interactions with other drugs or foods as well a proper and prompt management of side effects is crucial.Imatinib plasma levels. Although it remains to be demonstrated in a prospective setting, retrospective data suggest that low plasma levels at steady state are associated with a worse outcome. So, the median time to progression was 11.3 months for patients with imatinib plasma levels <1, 11 ng/mL compared to more than 30 months for patients with plasma levels above that threshold . Plasma Rechallenge of imatinib after adjuvant treatment. For patients recurring during adjuvant treatment, second-line treatments including imatinib 800 mg/day should be discussed. For those patients relapsing with metastatic or unresectable disease after imatinib interruption, although no direct prospective evidence is available, based on the data from the previously mentioned BRF14 trial, the general recommendation is that imatinib should be reintroduced at the same dose as recommended for first line. Evidence II, B.The first step to undertake when dealing with advanced GIST patients, who have progressed despite imatinib treatment, is to ensure treatment adherence and check for drug interactions that might decrease efficacy. Consideration may also be given to determine plasma imatinib concentrations, to better analyze these issues . If therImatinib dose escalation. The first recommended therapeutic maneuver consists of increasing the dose of imatinib to 800 mg/daily. The decision is based on results of crossover to 800 mg after disease progression on 400 mg in EORTC phase III trial studies [ studies  and Amer studies . In both studies . These d studies .Sunitinib is a multitargeted or selective TKI active inhibitor that is active against alpha-type and beta-type PDGFR and VEGFR receptors. Results of a randomized phase III trial versus placebo revealed a prolongation of the time to progression from 1.5 to 6.3 months in patients with GIST who progressed despite imatinib treatment [reatment . Accordireatment . The mosreatment . LikewisRegorafenib is a second generation TK inhibitor targeting KIT, RET, BRAF, VEGFR, PDGFR and FGFR. A median PFS of 4.8 months with imatinib, sunitinib and regorafenib versus 0.9 months with placebo was observed in a randomized trial for patients with refractory GIST. The most frequent side effects were high-blood pressure, hand-foot syndrome and diarrhea [diarrhea . The onlThe available treatment options following imatinib, sunitinib and regorafenib administration  are still in the experimental phase. The first recommendation is to offer these patients the opportunity to participate in clinical trials conducted under an investigational new drug. If this is not possible, an individual treatment can be scheduled for selected patients with other drugs such as:Nilotinib is a second generation TK inhibitor active in chronic myeloid leukemia and with the inhibitory effect of KIT and PDGF. Preliminary results of a phase III trial comparing nilotinib with imatinib, sunitinib or supportive care in resistant GIST patients whose disease had progressed to imatinib and sunitinib did not show differences in PFS and OS treatment groups. On the other hand, significant differences in overall survival were noted when the analyses were limited to those who received nilotinib as strictly third-line treatment  [therapy) .Sorafenib is a VEGFR, KIT, PDGR and BRAF inhibitor. Preliminary results of a phase II trial showed activity in imatinib-resistant and sunitinib-resistant patients with acceptable tolerance. This could be an alternative until regorafenib becomes available [vailable .Imatinib and doxorubicin combination: Promising activity was been observed in a GEIS group study with doxorubicin dose of 20 mg/m2/once a week, which could be particularly suitable for patients with wild-type GIST [ype GIST .An abdominal and pelvic CT with contrast and image acquisitions of the arterial and portal phases allows identification of hypervascular hepatic lesions that would otherwise go unnoticed and become evident when they become hypodense with treatment. Choi criteria  combine Other techniques such as MRI are strictly limited to hepatic studies, complex locations such as the rectum  and alleBoth RECIST 1.1 and Choi  criteriaAn abdomen and pelvic CT with contrast and image acquisitions of the arterial and portal phases is the method of choice for initial diagnosis and follow-up for GIST. Due to low metastatic frequency of pulmonary metastases (2 %) , thoraciOther techniques such as MRI are strictly limited to hepatic studies, complex locations such as the rectum and allergic reactions to iodine contrast given that evaluation of Hounsfield units is not feasible. PET is reserved for inconclusive cases by other techniques such as CT or MRI or the early assessment of response to imatinib .Follow-up after resection according to risk group:Very low risk: Routine follow-up is not indicated due to the low-risk of relapse- even if it is not null.Low risk: Follow-up can be carried out every 6 months at diagnosis up to the fifth year.Intermediate high risk: Patients receiving adjuvant imatinib treatment require regular monitoring with clinical analysis every 3 months to control drug tolerance. A follow-up CT scan should be done every 3–6 months during adjuvant treatment. The highest risk of recurrence takes place in the first 2 years. After this period, a CT scan should be performed every 3–6 months up to the fifth year and annually up to 10 years.Follow-up should be conducted every 3 months since the beginning and can be prolonged up to every 6 months if response is obtained, especially if response remains beyond a 5-year period. Both RECIST 1.1 and Choi  criteriaSystemic induction therapy has the aim of facilitating surgery through tumor shrinkage, whereas systemic neoadjuvant therapy targets survival advantage .In locally advanced and unresectable GIST, there are few cases that would eventually become resectable after induction treatment with imatinib . HoweverEarly assessment of response is needed to minimize risks since a delay could further hamper surgery after an unsuccessful imatinib treatment. Mutational analysis should be mandatory due to the robust genotype predictive biomarker (IIb). Hence, exon 9 mutants would require 800 mg/day of imatinib; D842 V mutants no induction treatment would be active and for those KIT/PDGFRA wild type, is doubtful that imatinib could be active enough. A CT scan can be of some usefulness for assessing early response, but the use of PET scan after induction therapy seems more advantageous given its ability to verify the efficacy of the treatment within a very short time .The recommended duration of preoperatory treatment cannot be based on objective criteria. However, it is estimated that surgery could be performed within 6–12 months after starting imatinib, since maximal response and minimal risk of secondary resistance is expected in this time interval.There is a lack of published evidence regarding neoadjuvant treatment in operable GIST and therefore should not be used outside clinical trials.Induction treatment could be recommended in individual basis with the aim of offering a less mutilating/function sparing surgery.Many small GIST, <2 cm, are incidental findings during surgeries carried out for a number of other reasons. A small GIST found accidentally in a surgical specimen does not require any additional therapeutic procedure.In those uncommon cases of small GIST diagnosed before surgery, the excision is not clear enough and a shared decision-making process with the patient should be offered.Anyway, the mitotic index of those tumors should be taken into account, although the incidence of small size and high mitotic index is very low according the literature.There is a well-documented type of secondary resistance to imatinib called nodule within mass. This is a focal disease progression, while most of the tumor burden is still under control. For these cases, maintenance of systemic treatment  as well as applying local measures, can keep the patient free of progression for over a year in one-third of cases (xii). It is the treatment of choice over second-line systemic treatments.The most common local treatments are surgery, radioablation and arterial embolization. In the absence of controlled trials, the choice of treatment should be based disease characteristics as well as on an experienced medical team.Systemic therapy should not be interrupted or replaced when progression is limited to a single or only a few focal points amenable to local treatment.Choice treatment for focal progression is maintenance of systemic therapy together with local control techniques appropriate for each case.


Ambulatory blood pressure (BP) measurements (ABPM) predict health outcomes better than office BP, and are recommended for assessing BP control, particularly in high-risk patients. We assessed the performance of office BP in predicting optimal ambulatory BP control in sub-Saharan Africans with type 2 diabetes (T2DM).Participants were a random sample of 51 T2DM patients (25 men) drug-treated for hypertension, receiving care in a referral diabetes clinic in Yaounde, Cameroon. A quality control group included 46 non-diabetic individuals with hypertension. Targets for BP control were systolic (and diastolic) BP.Mean age of diabetic participants was 60 years (standard deviation: 10) and median duration of diabetes was 6 years (min-max: 0-29). Correlation coefficients between each office-based variable and the 24-h ABPM equivalent (diabetic vs. non-diabetic participants) were 0.571 and 0.601 for systolic (SBP), 0.520 and 0.539 for diastolic (DBP), 0.631 and 0.549 for pulse pressure (PP), and 0.522 and 0.583 for mean arterial pressure (MAP). The c-statistic for the prediction of optimal ambulatory control from office-BP in diabetic participants was 0.717 for SBP, 0.494 for DBP, 0.712 for PP, 0.582 for MAP, and 0.721 for either SBP + DBP or PP + MAP. Equivalents in diabetes-free participants were 0.805, 0.763, 0.695, 0.801 and 0.813.Office DBP was ineffective in discriminating optimal ambulatory BP control in diabetic patients, and did not improve predictions based on office SBP alone. Targeting ABPM to those T2DM patients who are already at optimal office-based SBP would likely be more cost effective in this setting. Blood pressure (BP) is a major determinant of the risk of cardiovascular disease, the main killer in diabetes , 2. TherAccurate BP measurement is a key component of strategies aiming to reduce blood pressure related risk. This involves approximating as much as possible the true current levels of BP, but also directing BP appraisal at those indices and measurements that are better correlated with future risk of BP related health hazards . NumerouThe aim of this study was to assess the diagnostic capability of office BP measurements in predicting optimal ambulatory BP control in sub-Saharan African with type 2 diabetes mellitus. We draw comparisons of the observed effects with those in people without diabetes.This cross-sectional study was conducted at the National Obesity Centre of the Yaounde Central Hospital in the Capital city of Cameroon. The study setting has been described in details previously , 16. ParParticipants were patients with type 2 diabetes and hypertension for whom BP control medications had not changed over the three preceding months. Were excluded from the study patients on night-time shift, patients with arrhythmia which precluded accurate BP measurement through oscillometric method, and patients with arm circumference greater than 32 centimetres and for whom larger cuff size was required. For quality control purpose, a group of 43 diabetes-free hypertensive adults was also recruited. They were all individuals who underwent ABPM at the Doula General Hospital for various purposes indications. Participants underwent clinical and paraclinical examinations with data collected on age, gender, diagnosed duration of diabetes, blood pressure variables and treatments, fasting blood glucose, haemoglobin A1c (HbA1c), lipid profile, serum urea and creatinin.® aneroid sphygmomanometer, following the Riva-Rocci Korotkoff method [® 2430 PC2 device in participants with diabetes, and with a DIASYS INTEGRA II  device in diabetes-free participants. The BP cuff was displayed on the non-dominant arm in participants when the between-arm office-based difference systolic BP was less than 10 mmHg; otherwise the cuff was displayed on the arm with the highest office-based systolic BP. The two first measurements was recorded under the supervision, and subsequent measurements were recorded every 15 minutes between 7 a.m. and 10 p.m., and every 30 minutes between 10 p.m. and 7 a.m. The device was collected after 24 hours of recording and data transferred to a computer with the use of the Profil-Manager 3® software  for participants with diabetes, and with the HolterSoft Ultima version 2.4.4  in diabetes-free participants. Records were considered to be of good quality when they spanned the entire 24 hours, had at least 70% of valid measurements and no gap of more than 2 hours without a single measurement.Office BP measurement was performed by the same investigator with the use of a Spencerf method  in partiThe following definitions were applied: 1) BP controlled based on Office measurements: systolic (and diastolic) BP < = 130 (80) mmHg on at least two consecutive visits over at least the three preceding months , 19; 2) Data were analyzed with SAS/STAT version 9.1 . Data are summarised as mean , median (minimum-maximum) or count (percentages). Group comparisons used Person χ2 test and equivalents for qualitative variables, and Student t-test and Mann-Whitney U test for quantitative variables. The concordance between different BP measurements was assessed with the Pearson correlation coefficient. Logistic regressions were used to assess the association between office BP variables and optimal BP control based on ABPM. The area under the receiver operating characteristic curve (AUC) then assessed and compared the ability of office BP variables to predict optimal control based on ABPM. AUC comparisons used non-parametric methods . A p-valOf the 51 participants with type 2 diabetes included, 26 (51%) were women and 32 (63%) were at target office BP control Ambulatory blood pressure profile is depicted in In people with diabetes, correlation coefficients were low-to-good among concomitant BP variables . Among cLogistic regression curves are shown in In this group of type 2 diabetic patients with hypertension and acceptable-to-good blood pressure control based office measurement, the 24-hour ambulatory blood pressure control was rather poor-to-acceptable. This was primarily driven by less optimal ambulatory pressure control during daytime opposed to night-time. Among concomitant office or ambulatory pressure variables, SBP was always strongly correlated with other variables than DBP, while between office variables and their ambulatory equivalents, the strongest correlation was always observed with pulse pressure and to some extend SBP. Based on AUC comparisons, office SBP outperformed DBP in predicting optimal 24-hour ambulatory control. All patients not at optimal office SPB were also likely not to be at optimal 24-hour control. Comparisons with non-diabetic participants suggested that some of these findings were likely specific to people with diabetes.The agreement between office and ambulatory BP measurements has been examined in few previous studies in people with diabetes –24. CorrThere have been recent attempts in people with diabetes to derive models for estimating ambulatory pressure variables from their office equivalents . The modEvidences from clinical trials have established the safety and efficacy of blood pressure lowering in people with diabetes, regardless of the starting blood pressure levels, in reducing cardiovascular risk . Its rem