Human papillomavirus infection and lung adenocarcinoma: special benefit is observed in patients treated with immune checkpoint inhibitors.

BACKGROUND: Human papilloma virus (HPV) has been associated with the development and modulation of response in a series of neoplasms. In the case of lung adenocarcinoma, its role in etiology and pathogenesis is still controversial. Considering that this infection brings foreign epitopes, it could be of prognostic significance in patients with lung adenocarcinoma treated with immunotherapy. METHODS: In a retrospective cohort study we evaluated the presence of HPV genomic material in lung adenocarcinoma primary lesions with the INNO-LiPA platform. Viral replication was also evaluated by detecting the presence of oncoprotein E6/E7 messenger RNA (mRNA) by quantitative RT-PCR. To confirm possible hypotheses regarding viral oncogenesis, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF1) were evaluated with stromal fibrosis and immunoscore. RESULTS: A total of 133 patients were included in the analysis, of whom 34 tested positive for HPV, reaching an estimated prevalence of 25.6% [95% confidence interval (CI) 18.2% to 32.9%]. E6/7 mRNA was identified in 28 out of the 34 previously positive cases (82.3%). In immune checkpoint inhibitor (ICI)-treated patients, the median overall survival reached 22.3 months [95% CI 19.4 months- not reached (NR)] for HPV-negative and was not reached in HPV-positive (HPV+) ones (95% CI 27.7-NR; P = 0.008). With regard to progression-free survival, HPV- patients reached a median of 9.2 months (95% CI 7.9-11.2 months) compared to 14.3 months (95% CI 13.8-16.4 months) when HPV was positive (P = 0.001). The overall response rate for HPV+ patients yielded 82.4% compared to 47.1% in negative ones. No differences regarding programmed death-ligand 1, VEGF, HIF1, stromal fibrosis, or immunoscore were identified. CONCLUSIONS: In patients with HPV+ lung adenocarcinoma, a significant benefit in overall response and survival outcomes is observed.

Texture analysis of cone beam computed tomography images reveals dental implant stability.

The aim of this study was to characterize the alveolar bone of edentulous maxillary sites using texture analysis (TA) of cone beam computed tomography (CBCT) images and to correlate the results to the insertion torque, thus verifying whether TA is a predictive tool of final implant treatment. This study was conducted on patients who had received single implants in the maxilla (46 implants) 1year earlier and whose torque values were properly recorded. Three cross-sections of the sites were selected on CBCT scans. Two regions of interest (ROIs) corresponding to the implant bone site and peri-implant bone were also outlined, according to virtual planning. The CBCT scans were exported to MaZda software, where the two ROIs were delimited following the previously demarcated contours. Values for the co-occurrence matrix were calculated for TA. With regard to the insertion torque value, there was a direct correlation with the contrast of the peri-implant bone (P<0.001) and an inverse correlation with the entropy of the implant bone site (P=0.006). A greater contrast indicates a greater torque value for insertion of the implants, and there is a possible association with a lower entropy value of the implant-bone interface.

Avaliação da eficácia do sistema rigeneracon no tratamento de lesões de calvária em ratos / [Evaluation of the efficacy of the rigeneracon system in the treatment of calvary injuries in rats]

Defeitos ósseos constituem um problema de saúde global. O sistema Rigenera permite a extração de microenxertos ricos em células-tronco mesenquimais (CTMs). Objetivou-se avaliar o processo de regeneração óssea por enxertos obtidos pelo sistema Rigenera em defeitos críticos na calvária de ratos. Foram utilizados 18 ratos Wistar, machos, pesando 285±29g, distribuídos em três grupos (n=6), sendo cada animal controle de si mesmo, denominados G15-Controle e G15-Tratado (15 dias); G30-Controle e G30-Tratado (30 dias) e G60-Controle e G60-Tratado (60 dias). Foram realizadas duas lesões de 5mm de diâmetro em cada antímero da calvária. Nos grupos tratados, foram utilizados microenxertos autólogos de cartilagem xifoide, obtidos pelo sistema Rigenera. O defeito contralateral serviu como controle em todos os animais. Os animais foram eutanasiados aos 15, 30 e 60 dias após a cirurgia, e as amostras foram processadas para a histoquímica. Nos grupos controle, não foram observados sinais de regeneração óssea, enquanto nos grupos tratamento foram verificadas áreas de formação óssea e tecido mesenquimal ativado. O sistema Rigenera foi eficiente na obtenção de microenxertos autólogos, para terapia celular em defeito crítico de calvária de ratos. Com o aprimoramento do protocolo, o sistema Rigenera poderá ser amplamente utilizado no tratamento de lesões ósseas.(AU)

Bone defects are a global health problem. The Rigenera system allows the extraction of micro grafts rich in mesenchymal stem cells (MSCs). The objective of this study was to evaluate the bone regeneration process by grafts obtained by the Rigenera system in defects in the rats calvarian. Eighteen male Wistar rats were used, weighing 285 ± 29g, distributed in three groups (n = 6), where each animal was treatment and control, called G15-Control and G15-Treated (15 days); G30-Control and G30-Treated (30 days) and G60-Control and G60-Treated (60 days). Two 5mm diameter lesions were performed on each calvaria side. In the treated groups, autologous micrograft from xiphoid cartilage, obtained by the Rigenera system, were used. The other defect served as a control in all animals. The animals were euthanized at 15, 30 and 60 days after the surgery and the samples were processed for histochemistry. In the control groups, no signs of bone regeneration were observed, while in the treatment groups, areas of bone formation and activated mesenchymal tissue were verified. The Rigenera system was efficient in obtaining autologous micrograft for cell therapy in a critical calvaria defect in rats. Rigenera system can be widely used in the treatment of bone injuries.(AU)

Systemic therapy treatment patterns in patients with advanced non-small cell lung cancer (NSCLC): PIvOTAL study.

The aim of this multinational retrospective cohort study, conducted at academic and community oncology centres, was to describe real-world treatment patterns for patients with a confirmed diagnosis of advanced/metastatic (stage IIIB/IV) non-small cell lung cancer (NSCLC) who initiated first-line systemic therapy from January 2011 through June 2014. The study included 1265 patients in Italy, Spain, Germany, Australia, Korea, Taiwan and Brazil. The proportion of patients with squamous versus non-squamous NSCLC was approximately 20% versus 75%, and associated patient demographic characteristics were similar in all countries, excepting race. Patients with squamous NSCLC were predominantly male and current/ex-smokers. Biomarker tests were performed for the majority of patients with non-squamous NSCLC, ranging from 54% (Brazil) to 91% in Taiwan, where, of those tested, 68% with non-squamous NSCLC had positive epidermal growth factor receptor (EGFR)-mutation status; in other countries the EGFR-positive percentages ranged from 17% (Spain/Brazil) to 40% (Korea). Platinum-based regimens were the most common first-line therapy in all countries except Taiwan, where gefitinib was the most common first-line agent. Median overall survival ranged from 9.3 months (Brazil) to 25.5 months (Taiwan). The diagnostic and treatment patterns recorded in this study were heterogeneous but largely in line with NSCLC guidelines during the study period.

Factors associated with topographic changes of the optic nerve head induced by acute intraocular pressure reduction in glaucoma patients.

PURPOSE: To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG). METHODS: Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient's systemic and ocular characteristics. RESULTS: A total of 42 patients were included (mean age, 66.7 ± 11.8 years). After a mean IOP reduction of 47.3 ± 11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P < 0.01), but not in mean cup depth (P = 0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r(2) = 0.17, P < 0.01) and diabetes diagnosis (r(2) ≥ 0.21, P < 0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r(2) = 0.30, P < 0.01). Age, race, disc area, and CCT were not significant (P ≥ 0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P < 0.01). CONCLUSIONS: Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.

Effect of oral sirolimus therapy on inflammatory biomarkers following coronary stenting.

We studied the effect of oral sirolimus, administered to prevent and treat in-stent restenosis (ISR), on the variation of serum levels of inflammatory markers following coronary stenting with bare metal stents. The mean age of the patients was 56 +/- 13 years, 65% were males and all had clinically manifested ischemia. Serum levels of high sensitivity C-reactive protein (hs-CRP) concentration were determined by chemiluminescence and serum levels of all other biomarkers by ELISA. One group of patients at high risk for ISR received a loading oral dose of 15 mg sirolimus and 5 mg daily thereafter for 28 days after stenting (SIR-G). A control group (CONT-G) was submitted to stenting without sirolimus therapy. The increase in hs-CRP concentration was highest at 24 h after stenting in both groups. A significant difference between SIR-G and CONT-G was observed at 4 weeks (-1.50 +/- 5.0 vs -0.19 +/- 0.4, P = 0.008) and lost significance 1 month after sirolimus discontinuation (-1.73 +/- 4.3 vs -0.01 +/- 0.7, P = 0.0975). A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks (-352.9 +/- 455 vs +395.2 +/- 377, P = 0.0004), while a positive variation was noted 4 weeks after sirolimus discontinuation (227 +/- 708 vs 406.2 +/- 472.1, P = 0.0958). SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 (46.1 +/- 67.9 vs 5.8 +/- 23.7, P = 0.0025). These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression.

Effect of oral sirolimus therapy on inflammatory biomarkers following coronary stenting

We studied the effect of oral sirolimus, administered to prevent and treat in-stent restenosis (ISR), on the variation of serum levels of inflammatory markers following coronary stenting with bare metal stents. The mean age of the patients was 56 ± 13 years, 65 percent were males and all had clinically manifested ischemia. Serum levels of high sensitivity C-reactive protein (hs-CRP) concentration were determined by chemiluminescence and serum levels of all other biomarkers by ELISA. One group of patients at high risk for ISR received a loading oral dose of 15 mg sirolimus and 5 mg daily thereafter for 28 days after stenting (SIR-G). A control group (CONT-G) was submitted to stenting without sirolimus therapy. The increase in hs-CRP concentration was highest at 24 h after stenting in both groups. A significant difference between SIR-G and CONT-G was observed at 4 weeks (-1.50 ± 5.0 vs -0.19 ± 0.4, P = 0.008) and lost significance 1 month after sirolimus discontinuation (-1.73 ± 4.3 vs -0.01 ± 0.7, P = 0.0975). A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks (-352.9 ± 455 vs +395.2 ± 377, P = 0.0004), while a positive variation was noted 4 weeks after sirolimus discontinuation (227 ± 708 vs 406.2 ± 472.1, P = 0.0958). SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 (46.1 ± 67.9 vs 5.8 ± 23.7, P = 0.0025). These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression.

A comparison between microperimetry and standard achromatic perimetry of the central visual field in eyes with glaucomatous paracentral visual-field defects.

BACKGROUND AND AIMS: The aim was to correlate retinal sensitivity as determined by scanning laser ophthalmoscope microperimetry (SLO-MP) in glaucomatous eyes with paracentral visual field (VF) defects detected by standard automated perimetry (SAP). METHODS: Twenty eyes with glaucomatous optic neuropathy and an SAP VF defect involving the central 16 test points (at least one point with p<1% in the 24-2 VF) were enrolled. Eyes with diseases other than glaucoma were excluded. All patients underwent SLO-MP and SAP of the central 10 degrees . Results from each eye were divided into four quadrants for analysis. Normal and abnormal quadrants by SAP were compared with the corresponding normal and abnormal quadrants by SLO-MP. Regression analysis was used to correlate the mean threshold values (dB) of SLO-MP and SAP in each quadrant. Macular optical coherence tomography (OCT) was performed when there was a disagreement between functional tests. RESULTS: The mean age and VF mean deviation were 60.8 (13.4) years and -7.3 (6.1) dB, respectively. There was a significant correlation between SLO-MP and SAP results in all quadrants (r(2)> or =0.68, p<0.001). All abnormal SAP quadrants had a corresponding abnormal SLO-MP quadrant. However, 21% of the normal SAP quadrants had an abnormal corresponding microperimetry result; a corresponding significant reduction in total macular thickness measured by OCT was present in 75% of these quadrants. CONCLUSIONS: Macular sensitivity evaluated by SLO-MP correlates significantly with SAP paracentral VF defects. SLO-MP detected retinal sensitivity reduction in areas of OCT structural damage with normal SAP and suggests that subtle paracentral functional deficits may be present in many more eyes with established glaucoma than generally assumed.

Retinal vascular occlusions occur more frequently in the more affected eye in exfoliation syndrome.

PURPOSE: To evaluate the relationship between retinal vascular occlusions (RVOs) and exfoliation syndrome (XFS) in a cohort of patients with the two conditions. METHODS: We reviewed the records of patients with XFS with or without glaucoma and any type of RVO between 1983 and 2007. Patients with prior incisional surgery or a history of uveitis were excluded. Data collected included demographics, systemic comorbidities, type of RVO, and intraocular pressure (IOP) before the RVO. Slit-lamp biomicroscopy regarding the presence of exfoliation material on the lens capsule and pupillary margin before the vascular event was used to evaluate the laterality and degree of XFS. RESULTS: We identified 36 patients (mean age 78.4+/-8.3 years, 19 women). Most patients were of European descent (34/36) and 20 (56%) had no prior glaucoma diagnosis. The most common retinal vascular events were central retinal vein occlusion (18/36) and BRVO (10/36). Mean IOP between eyes with (19.5+/-6.5 mm Hg) and without (17.9+/-4.8 mm Hg) RVO was similar (P=0.12). RVOs occurred more commonly in the eye with more pronounced XFS in 92% (33/36) of the cases. A similar agreement was found when considering patients with and without glaucoma separately (94% (15/16) vs90% (18/20); P=0.83). In addition, no difference in the agreement percentage was observed when comparing patients with unilateral XFS (87% (13/15)) with all study patients (P=0.87). CONCLUSIONS: Retinal vascular occlusion in patients with XFS occurs most often in the affected or more severely affected eye. As vascular occlusions happened in patients with and without glaucoma in similar proportions, the presence of XFS seems to play an important role in these findings.

Safety and efficacy of sirolimus in kidney transplant patients and in patients with coronary artery disease undergoing angioplasty.

UNLABELLED: We show the key results of our 4-year experience with sirolimus in kidney transplant patients and in nontransplanted patients undergoing coronary angioplasty. METHODS: Recipients of one-haplotype living-related kidney allografts were randomized to receive sirolimus (2 mg/d, n = 35) or azathioprine (2 mg/kg per day, n = 35). Recipients of fully mismatched living kidney allografts (n = 55) received sirolimus (2 mg/day). High-risk recipients of black ethnicity (n = 68) were randomized to target whole-blood trough sirolimus concentrations between 8 and 12 ng/mL or 15 to 20 ng/mL. All kidney transplant patients received cyclosporine and prednisone. Sirolimus/cyclosporine pharmacokinetic studies were performed in 40 patients receiving 2 mg (n = 20) or 5 mg (n = 20) of sirolimus 7 days after transplantation. In the coronary intervention study, 12 patients at high risk for in-stent restenosis received sirolimus for 28 days after angioplasty. RESULTS: The incidence of biopsy-confirmed acute rejection was 11.4% in recipients of one-haplotype living-related kidney allografts, 16.4% in recipients of fully mismatched living kidney allografts, and 15% (8 to 12 ng/mL) and 4% (15 to 20 ng/mL) in high-risk recipients of black ethnicity. Cyclosporine exposure was higher after morning administration compared to evening administration. There were poor correlations between sirolimus and cyclosporine exposures. The 4-month follow-up angiography revealed no restenosis (stenosis diameter > 50%), a late loss of 0.56 +/- 0.40 mm, and a loss index of 0.33 +/- 0.30. The follow-up 3D-intravascular ultrasound restudy showed an in-stent relative volumetric obstruction of 9.9 +/- 5.5%. Sirolimus in highly effective in preventing kidney allograft acute rejection and in-stent coronary restenosis.

Influence of autonomic neuropathy upon left ventricular dysfunction in insulin-dependent diabetic patients.

BACKGROUND: Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic, vascular, and hypertensive disease. HYPOTHESIS: The study was undertaken to test the relationship among autonomic neuropathy (AN), 24-h blood pressure (BP) profile, and left ventricular function. METHODS: Nineteen type-1 diabetic patients underwent autonomic tests and echocardiographic examination. Patients were divided according to the presence (AN+) or absence (AN-) of AN. RESULTS: In the AN+ group (n = 8), the E/A ratio at echo was lower than in the AN- group (n = 11) (1.1 +/- 0.3 vs. 1.6 +/- 0.3; p < 0.005). Systolic and diastolic BP reductions during sleep were smaller in the AN+ than in the AN- group (6.6 +/- 6.6 vs. 13.0 +/- 4.3%; p < 0.03 for systolic and 12.8 +/- 6.8 vs. 20.0 +/- 4.0% for diastolic BP reduction; p < 0.03, respectively). Considering all patients, the E/A ratio correlated inversely with awake diastolic BP (r - 0.63; p = 0.005); sleep systolic BP (r - 0.48; p = 0.04), and sleep diastolic BP (r - 0.67; p = 0.002). The AN correlated with diastolic interventricular septum thickness (r 0.57; p = 0.01), sleep systolic BP (r 0.45; p = 0.05), sleep diastolic BP (r 0.54; p = 0.02), and correlated inversely with systolic and diastolic sleep BP reduction (r - 0.49; p = 0.03 and r - 0.67; p = 0.002, respectively). Finally, E/A ratio and AN score correlated between themselves (r - 0.6; p = 0.005). CONCLUSION: Our results suggest that left ventricular diastolic dysfunction may be detected very early in type-1 diabetic patients with AN. Parasympathetic lesion and nocturnal elevations in BP could be the link between AN and diastolic ventricular dysfunction.

Non-invasive determination of the systolic peak-to-peak gradient in children with aortic stenosis: validation of a mathematical model.

Doppler derived systolic pressure gradients have become widely applied as noninvasively obtained estimates of the severity of aortic valvar stenosis. There is little correlation, however, between the Doppler derived peak instantaneous gradient and the peak-to-peak gradient obtained at catheterisation, the latter being the most applied variable to determine severity in children. The purpose of this study was to validate a mathematical model based on data from catheterisation which estimates the peak-to-peak gradient from variables which can be obtained by noninvasive means (Doppler derived mean gradient and pulse pressure), according to the formula: peak-to-peak systolic gradient = 6.02+/-1.49*(mean gradient)-0.44*(pulse pressure). Simultaneous cardiac catheterization and Doppler studies were performed on 10 patients with congenital aortic valvar stenosis. Correlations between the gradients measured at catheter measured, and those derived by Doppler, were performed using linear regression analysis. The mean gradients correlated well (y = 0.67 x +11.11, r = 0.87, SEE = 6 mm Hg, p = 0.001). The gradients predicted by the formula also correlated well with the peak-to-peak gradients measured at catheter (y = 0.66 x +14.44, r = 0.84, SEE = 9 mm Hg, p = 0.002). The data support the application of the model, allowing noninvasive prediction of the peak-to-peak gradient across the aortic valvar stenosis.

Long-term endothelial dysfunction after coronary artery stenting.

OBJECTIVES: We assessed the endothelial-dependent vasomotor function in nonrestenotic coronary arteries more than six months following stent implantation, balloon angioplasty (BA), and directional atherectomy (DCA). BACKGROUND: Catheter-based coronary interventions are associated with extensive arterial injury. Endothelial function has been shown to remain chronically abnormal after vascular injury. The long-term effects of different percutaneous coronary interventions on endothelial function are not known. METHODS: Thirty-nine patients treated at least six months earlier with a coronary intervention for isolated proximal left anterior descending (LAD) stenosis, with no evidence of restenosis, were studied. Twelve patients had been stented, 15 had been treated with BA, and 12 had undergone DCA. Changes in diameter of the intervened LAD, and the unintervened circumflex coronary artery (Cx), in response to intracoronary acetylcholine infusions were assessed by quantitative angiography. RESULTS: The groups had similar angiographic characteristics and risk factors for endothelial dysfunction. The LAD constricted significantly more (p = 0.02) in previously stented patients (-21.8+/-4.3%), as compared to patients previously treated with BA (-9.5+/-2.8%) or with DCA (-9.1+/-3.6%). In contrast, acetylcholine infusion resulted in mild constriction in the Cx, which was similar in the three groups (p = 0.47). By multiple regression analysis, previous implant of a stent was the only significant predictor of LAD constriction (p = 0.008). CONCLUSIONS: More severe endothelial dysfunction was observed long term after stenting as compared to BA or DCA. These findings may have implications with respect to the progression of atherosclerosis in coronary arteries subjected to percutaneous interventions.

Hantavirus pulmonary syndrome. Report of the first three cases in São Paulo, Brazil.

The hantavirus pulmonary syndrome was first recognized in cases that occurred in the U.S. in 1993, which served as an alert not only for American physicians but also for physicians in other countries for the identification of the disease. In the city of São Paulo, Brazil, 3 cases of the syndrome were recorded in 1993. The patients were young brothers residing in the Mata Atlântica (Atlantic Forest) region submitted to recent deforestation. Two of the patients died of acute respiratory insufficiency and the third recovered without sequelae. In the surviving patient the diagnosis was established by a laboratory criterion based on the detection of specific IgM and IgG class antibodies by indirect immunofluorescence. In the two patients who died, the diagnosis was confirmed by laboratory tests using immunoperoxidase technique for hantavirus in tissue, in histological lung and heart sections in one case, and by clinical and epidemiological data in the other.

Cardiac sympathetic activity in response to acute myocardial ischemia.

Although experimental evidence has demonstrated that brief periods of myocardial ischemia are not associated with norepinephrine overflow from the heart, cardiac sympathetic responses to myocardial ischemia in humans remain unclear. Eleven patients undergoing angioplasty of the left anterior descending coronary artery had cardiac norepinephrine spillover measured immediately before inflation, during the final minute of a 5-min balloon inflation, and 1 min after deflation. Angioplasty caused significant S-T segment elevation and a reduction in the transcardiac lactate extraction ratio. Cardiac norepinephrine spillover was reduced from a mean value of 58 +/- 14 pmol/min at control to 41 +/- 15 pmol/min during balloon inflation and 38 +/- 14 pmol/min after deflation (P < 0.05 vs. control for both inflation and deflation values). In contrast, during balloon inflation, there were significant increases in arterial norepinephrine and epinephrine concentrations. Therefore, a brief period of myocardial ischemia caused by angioplasty of the left anterior descending coronary artery does not result in cardiac sympathetic activation, despite evidence of generalized sympathoadrenal activation.