SIRS Group Research Articles

The 'analysis of gene expression and biomarkers for point-of-care decision support in Sepsis' study; temporal clinical parameter analysis and validation of early diagnostic biomarker signatures for severe inflammation andsepsis-SIRS discrimination.

Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.

Circulating mtDNA and Impaired Intestinal Barrier after Gastrointestinal Surgery Are Correlated with Postoperative SIRS.

This prospective study aimed to explore the correlation between circulating mitochondrial DNA (mtDNA), intestinal barrier function impairment, and postoperative SIRS in patients undergoing gastrointestinal surgery. Patients were recruited into this study after signing an informed consent form. Circulating mitochondrial DNA and serum DAO concentrations were measured preoperatively and on day 1 and day 7 postoperatively. Postoperative vitals, routine tests, and biochemical indicators were recorded in detail. Forty patients undergoing gastrointestinal surgery were recruited for and completed this study. Patients were divided into non-fever, fever, and SIRS groups according to their postoperative temperature and other corresponding indexes. The mtDNA was expressed as the number of PCR cycles using three specific sequences. Circulating mtDNA tended to increase in patients after gastrointestinal surgery, but the difference was not significant. Nevertheless, mtDNA in the SIRS group was significantly higher than in patients in the fever and non-fever groups (p < 0.05). Serum DAO showed a trend of increase on the first day after surgery compared with that before surgery, but the difference was not significant (p > 0.05). However, patients in the SIRS group showed a significant increase (p < 0.05) compared with the others. Both circulating mtDNA and DAO showed a downward trend on the seventh day after surgery. Circulating mtDNA presented a trend of increase after gastrointestinal surgery, and the degree of the increased fold was related to the extent of the inflammation response. In general, the intestinal barrier damage indicator DAO was the same as mtDNA and tended to increase after gastrointestinal surgery and then gradually decrease, which may play a synergistic role in inducing postoperative fever and SIRS.

The Incidence of Systemic Inflammatory Response Syndrome and Urosepsis following Retrograde Intrarenal Surgery (RIRS) in a Tertiary Care Hospital of Kathmandu, Nepal

In recent years, the use of retrograde intra renal surgery (RIRS) for the management of nephrolithiasis is on the rise worldwide. It is commonly considered a safe procedure with lesser complications. The current study aimed to study the incidence of systemic inflammatory response syndrome and urosepsis following retrograde intra renal surgery (RIRS). This is the retrospective observational study among 356 patients who underwent RIRS and 52 were readmitted as 36 developed SIRS and 16 developed urosepsis as a complication in last 5 years (July 1st 2016 –June 30th 2021) in department of Urology of B&amp;B hospital, Kathmandu. It is found that only post-operative urine culture had significant association with SIRS with p- value (&lt; 0.00). There was no normality in the data so Mann Whitney U test was applied to test the significant difference in the median values of some quantitative variables between the SIRS and No SIRS group. There was significant difference between the median values of stone volume and duration of fragmentation with p values 0.001 and 0.002 respectively. There was no variables that was found to be associated with urosepsis.

The evaluation of SIRS status with hemato-biochemical indices in bitches affected from pyometra and the Usefulness of these indices as a potential diagnostic tool

The aims of this study were to establish a cut-off point by evaluating the usability of the hemato-biochemical indices to determine the severity of inflammation caused by pyometra, and to determine the practical usage of the indices as a diagnostic biomarker in cases of pyometra. Animals that were admitted to Ankara University Veterinary Faculty Obstetrics and Gynecology Clinic were included in the present study. Dogs suffering from pyometra were allocated to two groups according to their SIRS status (SIRS, n = 12; Non-SIRS (NSIRS, n = 16)). Healthy dogs presented for routine ovariohysterectomy were used as the control (n = 13). Blood samples were collected into two tubes containing EDTA for hematological analysis and without anticoagulant for biochemical tests before the beginning of treatment. Hemato-biochemical indices, which are Neutrophil-Lymphocyte Ratio (NLR), Monocyte-Lymphocyte Ratio (MLR), Neutrophil Percentage-Albumin Ratio (NPAR), Platelet-Lymphocyte Ratio and Systemic Immune-Inflammation Index, were calculated. All data were analyzed using the MIXED procedure of the SPSS. Receiver operating characteristics curves were used to determine the dog level threshold for evaluating the SIRS status and used to determine a predicted threshold with hemato-biochemical indices for differentiation between dogs with pyometra (regardless of SIRS status) and the control. Pairwise comparisons were carried out of the area under the curve (AUC) for thresholds of SII, NLR, PLR, MLR, NPAR. White blood cells, lymphocytes, monocyte, neutrophil, ALP, NLR, MLR, and NPAR levels were greater in dogs that suffer from SIRS (P < 0.05). Red blood cells and hematocrit levels were significantly higher in the control group (P < 0.05). Albumin levels were higher in the control group (P < 0.05). Moreover, NLR, MLR and NPAR levels were found to be significantly higher in the SIRS group (P < 0.05). Besides, NLR and MLR were the best predictors for diagnosis of the SIRS with the AUC values of 0.936, and 0.966 respectively. Furthermore, NLR, MLR and SII could be a useful diagnostic tool for pyometra with the AUC values of 0.955, 0.931, 0.716. The blood indices could be used as fast, easily accessible, and inexpensive markers for the evaluation of the SIRS status in dogs with pyometra together with diagnosis.

Predictors of postoperative systemic inflammatory response syndrome after scoliosis surgery in adolescents with cerebral palsy: A retrospective analysis

BackgroundSystemic inflammatory response syndrome (SIRS) is known to complicate postsurgical intensive care patients. We noticed that roughly half children with cerebral palsy who undergo posterior spinal fusion (PSF) for neuromuscular scoliosis developed SIRS in the intensive care unit. There is a paucity of literature detailing the impact of intraoperative causes of postoperative SIRS and downstream consequences in these patients. Study purpose was to understand the factors associated with SIRS in children who undergo PSF for neuromuscular scoliosis. MethodsThis retrospective, case control study included children who underwent PSF for neuromuscular scoliosis. Patients with idiopathic scoliosis, osteogenesis imperfecta, and tracheotomy were excluded. Subjects were divided into two study groups based on the diagnosis of SIRS in the intensive care unit. Descriptive statistical analysis was used to identify factors associated with SIRS; a regression analysis was used to further evaluate the independent and significant influence of these factors. ResultsThere was no significant difference in the demographic and other preoperative variables. However, total blood products (ml/kg) administered was significantly higher among the SIRS group compared with the non-SIRS group (54.4±41.0 vs 34.1±21.5 P <0.034). Percent of patients remaining intubated was greater in the SIRS group compared with the non-SIRS group (44.1% vs 7.0%, P < 0.001). The regression model revealed that the odds to develop SIRS in patients who were not extubated were 7.467-fold higher (CI: 1.534-36.347) compared with those who were extubated (p=0.013). ConclusionsThe incidence of SIRS is significantly higher among the patients who were not extubated at the end of PSF surgery. Further prospective studies are needed to look at the factors that impede the ability to extubate these patients at the end of surgery.

Diagnosis of sepsis with inflammatory biomarkers, cytokines, endothelial functional markers from SIRS patients.

BackgroundSepsis is a life-threatening illness with a challenging diagnosis. Rapid detection is the key to successful treatment of sepsis. To investigate diagnostic value, the plasma protein profiles of inflammatory biomarkers, cytokines, and endothelial functional markers were compared between healthy controls, SIRS, and septic patients.MethodsThe plasma protein profiles were performed by Luminex Assay in a cohort of 50 SIRS patients, 82 septic patients and 25 healthy controls. Fourteen plasma proteins were analyzed in the same cohort: IL-1β, IL-6, IL-8, IL-10, CCL-2, VEGF, VEGF-C, VEGFR2, CD62E, CD62P, MFG-E8, ICAM-1, TFPI, Urokinase.ResultIL-2R, IL-6, IL-8, IL-10, CCL-2, ICAM-1, and Urokinase were significantly higher in sepsis patients than SIRS patients. VEGF, IL-1β, CD62E, CD62P, MFG-E8, and TFPI have no statistical difference. VEGF-C, VEGFR2 were significantly different in SIRS patients than sepsis patients. Urokinase, ICAM-1, and VEGFR2 were significantly different between sepsis group and SIRS group. The AUCs of Urokinase, ICAM-1, and VEGFR2 and the combination for the diagnosis of sepsis were 0.650, 0.688, 0.643, and 0.741, respectively.ConclusionsMost patients have the higher level of several cytokines and developed endothelial cell injury in the initial phase of sepsis, Urokinase, ICAM-1, and VEGFR2 may be useful to evaluate severity and prognosis of sepsis patients.

Impact of Systemic Inflammatory Response Syndrome on Clinical, Echocardiographic, and Computed Tomographic Outcomes Among Patients Undergoing Transcatheter Aortic Valve Implantation.

BackgroundSystemic inflammatory response syndrome (SIRS) is a systemic insult that has been described with many interventional cardiac procedures. The outcomes of patients undergoing transcatheter aortic valve implantation (TAVI) are thought to be influenced by this syndrome not only on short-term, but also on long-term.ObjectiveWe assessed the association of SIRS to different clinical, echocardiographic, and computed tomographic (CT) outcomes after TAVI.MethodsTwo hundred and twenty-four consecutive patients undergoing TAVI were enrolled in this study. They were assessed for the occurrence of SIRS within the first 48 h after TAVI. Patients were followed-up for short- and long-term clinical outcomes. Serial echocardiographic follow-ups were conducted at 1-week, 6-months, and 1-year. CT follow-up at 1 year was recorded.ResultsEighty patients (36%) developed SIRS. Among different parameters, only pre-TAVI total leucocytic count (TLC), pre-TAVI heart rate, and post-TAVI systolic blood pressure independently predicted the occurrence of SIRS. The incidence of HALT was not significantly different between both groups, albeit higher among SIRS patients (p = 0.1) at 1-year CT follow-up. Both groups had similar patterns of LV recovery on serial echocardiography. Long-term follow-up showed that all-cause death, cardiac death, and re-admission for heart failure (HF) or acute coronary syndrome (ACS) were significantly more frequent among SIRS patients. Early safety and clinical efficacy outcomes were more frequently encountered in the SIRS group, while device-related events and time-related valve safety were comparable.ConclusionAlthough SIRS implies an early acute inflammatory status post-TAVI, yet its clinical sequelae seem to extend to long-term clinical outcomes.

Bedside determination of microcirculatory oxygen delivery and uptake: a prospective observational clinical study for proof of principle

Assessment of microcirculatory functional capacity is considered to be of prime importance for therapy guidance and outcome prediction in critically ill intensive care patients. Here, we show determination of skin microcirculatory oxygen delivery and consumption rates to be a feasible approach at the patient’s bedside. Real time laser-doppler flowmetry (LDF) and white light spectrophotometry (WLS) were used for assessment of thenar skin microperfusion, regional Hb and postcapillary venous oxygen saturation before and after forearm ischemia. Adapted Fick’s principle equations allowed for calculation of microcirculatory oxygen delivery and uptake. Patient groups with expected different microcirculatory status were compared [control (n = 20), sepsis-1/2 definition criteria identified SIRS (n = 10) and septic shock patients (n = 20), and the latter group further classified according to sepsis-3 definition criteria in sepsis (n = 10) and septic shock (n = 10)], respectively. In otherwise healthy controls, microcirculatory oxygen delivery and uptake approximately doubled after ischemia with maximum values (mDO2max and mVO2max) significantly lower in SIRS or septic patient groups, respectively. Scatter plots of mVO2max and mDO2max values defined a region of unphysiological low values not observed in control but in critically ill patients with the percentage of dots within this region being highest in septic shock patients. LDF and WLS combined with vasoocclusive testing reveals significant differences in microcirculatory oxygen delivery and uptake capacity between control and critically ill patients. As a clinically feasible technique for bedside determination of microcirculatory oxygen delivery and uptake, LDF and WLS combined with vasoocclusive testing holds promise for monitoring of disease progression and/or guidance of therapy at the microcirculatory level to be tested in further clinical trials.ClinicalTrials.gov: NCT01530932.

Pemenuhan Kewajiban Suami Penyandang Disabilitas Intelektual (Tunagrahita) dalam Membentuk Keluarga Sakinah

In this world not all humans have normal conditions in terms of quality and quantity of their limbs. Such is the case with families with intellectual disabilities (tunagrahita) in Jambon, Ponorogo. In such conditions, people with disabilities need improvisation and variety in managing and managing their household because if seen from their intellectual abilities they are not able to become leaders in the family. The purpose of this study was to determine the role and review of Islamic law in fulfilling the obligations of husbands with intellectual disabilities (tunagrahita) to form a Sakinah family. The type of research carried out is field research using qualitative methods, while data collection techniques used are interviews and observations. The conclusion of this study is that the husband's role in earning the main living is included in the mu'sir group, the parties who are obliged to help are relatives, the state or wealthy Muslims. And for his role as a leader in the family, this husband with intellectual disability (tunagrahita) cannot be burdened with taklif law, especially Ahliyyah Al'ada'. So external factors (family, relatives, and others) are more dominant in them in forming a sakinah family.

Protective role of melatonin and spirulina in aortic occlusion-reperfusion model in rats.

The aim of this experiment was to investigate the role of melatonin and spirulina on multiorgan damage induced by ischemia/reperfusion injury (IR) in a rat model. A total of 32 male rats weighing 200-220 g were allocated into 4 groups (n = 8/group) (Sham, Control-IR [CIR], Melatonin-IR [MIR], and Spirulina-IR [SIR]). Sham group underwent midline laparotomy and dissection of the aorta without injury. In other groups, an IR model was established by clamping (ischemia) and releasing (reperfusion) the abdominal aorta at the supraceliac level for 20 min. All rats were given 3 ml/kg of distilled water by gavage for 14 days before and 7 days after the experiment. The treatment groups received either melatonin (50 mg/kg) or spirulina (50 mg/kg) by the same route. On the 21st day of the experiment, the rats were sacrificed. We found that melatonin and spirulina ameliorated the effects of IR at different levels of significance (ranging from p = .01 to p < .001), increasing total antioxidant capacity (TAC) and superoxide dismutase levels, and decreasing total oxidant status, oxidative stress index (OSI), myeloperoxidase, tumor necrosis factor-alfa and malondialdehyde levels. When compared MIR and SIR groups, only TAC and OSI levels did differ in favor of melatonin between the groups (p < .05). Histopathological and immunohistochemical examinations showed that melatonin and spirulina similarly reduced IR-related tissue damage and apoptosis. We concluded that melatonin and spirulina may have a protective role against oxidative tissue damage and apoptosis in the abdominal aortic IR animal model. PRACTICAL APPLICATIONS: Coarctation of aorta (CoA) and interrupted aortic arch (IAA) are serious cardiac defects with high morbidity and mortality if not diagnosed and treated early in life. Restoration of blood flow in CoA or IAA through prostaglandin E1 infusion, angioplasty or surgery can cause ischemia/reperfusion (IR) injury. This reperfusion period may be complicated IR injury at remote organs. It may be beneficial to increase antioxidant capacity in preventing stress-induced tissue damage. Melatonin and spirulina are agents with strong antioxidant properties. In this animal research, protective role of these products on multiorgan damage induced by IR was investigated for the first time. We found that both melatonin and spirulina ameliorate the effects of IR to varying degrees. This study provides evidence that melatonin and spirulina may have preventive effects on oxidative tissue damage and apoptosis in the abdominal aortic IR animal model.

The Significance of Routine Biochemical Markers in Patients with Sepsis

Background: Sepsis is a highly complex and fatal syndrome, considered to be the main cause of death in the intensive care unit. Early diagnosis is beneficial to reduce the mortality and improve the prognosis of patients. Therefore, we look forward to finding cheap and fast diagnostic criteria to quickly assess the patient’s condition. Methods: Our study enrolled 499 patients in our hospital from January to 2020, and 96 healthy cases in the same period. Used the diagnostic criteria of bacterial infection, SIRS criteria and Sepsis-2 consensus criteria, 499 patients were divided into 4 groups: sepsis group (n=300), SIRS group (n=151), infection group (n=48). We collected the results of routine laboratory tests, inflammation indicators and blood culture results of these patients. Results: The sepsis group compared with the control group, many indicators had significant statistical differences. D-dimer, CRP and PCT had higher diagnostic efficiency. Compared between the infection group and the SIRS group, PLT and IL-6 were statistically different, and have a certain diagnostic value. Sepsis group VS infection group, WBC, IL-6, NE and TBIL showed significant differences. Among them, NE had the highest diagnostic efficiency and the highest specificity (95.8%). Conclusions: This retrospective study shows that NE, WBC and D-dimer are helpful for early diagnosis of sepsis in which of them D-dimer performs best. WBC and NE can be used to distinguish sepsis from common infection. This result can provide a timely and convenient assessment tool for early diagnosis of sepsis.

Leukocytes Ratios in Feline Systemic Inflammatory Response Syndrome and Sepsis: A Retrospective Analysis of 209 Cases.

Simple SummaryFeline sepsis is a life-threatening syndrome in which blood diagnostic and prognostic markers are limited. We investigated the differences in neutrophil-to-lymphocyte ratio and other white-blood-cell ratios between healthy and sick cats (systemic inflammation (SIRS) and/or septic cats) and then the use of these ratios as prognostic markers. This study included 76 healthy cats (blood-donors), 54 cats with SIRS and 79 cats with sepsis. A cat with an NLR > 4.53 had a 44-fold chance to have SIRS or sepsis, although only BLR and BNLR were different between SIRS and sepsis groups. The NLR has been shown as a prognostic marker in sick cats. This is a novel investigation about leukocyte ratios in the cat, and the NLR may be used as a prognostic parameter in cats with SIRS or sepsis, and BLR and BNLR demonstrate themselves as promising tools in differentiating SIRS from sepsis.Sepsis is a challenging condition in which hematological prognostic and diagnostic markers in cats are limited. The aims of this study were to test if there are any differences in leukocyte ratios (NLR, BLR and BNLR) between healthy, SIRS and septic cats (sick cats), and if, within sick cats, NLR, BLR and BNLR may be prognostic markers. A retrospective medical database study included 76 healthy cats (blood-donors), 54 SIRS and 79 septic cats. SIRS group was defined if cats fulfilled SIRS criteria. Sepsis was confirmed with an infectious focus on cytology or a positive culture for bacterial infection. Leukocyte ratios were compared among the three study groups and between survivors and non-survivors in sick cats. NLR resulted significantly higher in the sick group compared to healthy cats (p < 0.0001), although NLR was not different between SIRS and sepsis. An NLR > 4.53 had a sensitivity of 76% and a specificity of 93.4% to detect SIRS/sepsis (OR 44.8 95%CI 17–107). Only BLR and BNLR were significantly different between SIRS and sepsis. NLR was associated with mortality in the sick group (p = 0.04). Although NLR resulted higher in sick cats than healthy, BLR and BNLR demonstrated as promising tools in differentiating SIRS from sepsis. NLR was associated with mortality in sick cats.

The Effect of Lutein on Ischemia-reperfusion-induced Vasculitic Neuropathic Pain and Neuropathy in Rats.

Neuropathic pain and neuropathy is commonly seen after ischemia-reperfusion injuries. Our aim was to evaluate the effect of lutein on ischemia-reperfusion (I/R)-induced vasculitic neuropathic pain and neuropathy in rats. An hour before anesthesia, 6 Albino Wistar male rats with I/R were orally administered with 1 mg/kg lutein (LIR group). Two groups of 6 such rats who underwent surgery were provided with 0.5 ml distilled water (as solvent) either via oral administration (SIR group) or by gavage (sham group or SG). One hour following the administration, the later femoral arteries of the LIR and SIR rats were closed using a sterile silk thread and ischemia was induced in the sciatic nerve for 4 h, followed by reperfusion for 24 h. The femoral artery of the SG group was not closed with suture. Next, 1 mg/kg lutein was re-administered only to the LIR group for 1 h, followed by measurement of the paw pain thresholds by the Basile Algesimeter. The levels of malondialdehyde (MDA), total glutathione (tGSH), nuclear factor-kB (NF-κB), and tumor necrosis factor-alpha (TNF-α) in the sciatic nerve tissues were measured, and the tissues were histopathologically examined. We found that the MDA, NF-κB, and TNF-α levels were higher and the tGSH level was lower in the SIR group relative to those in the LIR group, and the differences were statistically significant. Significant histopathological damage was noted in the SIR group, whereas the LIR group demonstrated protection from oxidative damage. Lutein is potentially useful in the treatment of I/R-related neuropathy and neuropathic pain.

Rhein Activates Janus Protein Tyrosine Kinase2/Signal Transducer and Transcription Activation Factor3 Reduces Mitochondrial Oxidative Damage Caused by Myocardial Ischemia/Reperfusion Injury

Background: Rhein is a kind of lipophilic anthraquinone widely existing in herbal medicine. Here we aim to investigate whether Rhein can reduce the degree of myocardial ischemia/reperfusion injury and inhibit the development of oxidative stress, and elucidate the molecular mechanism of Rhein in protecting myocardial cells. Methods: The anti-oxidation and anti-apoptosis effects of Rhein were studied by using the primary myocardial cells of ischemia/reperfusion rat as the model of myocardial injury. Cell viability was detected by MTT, The level of LDH and CK-MB released by cardiomyocytes was measured by Colorimetric assay. The ROS was observed under microscope and the level of catalase and glutathione peroxidase were detected by enzymatic methods. The JAK2/STAT3 signaling pathway mediated by Rhein was observed by Western blot. Results: Compared with that of the SIR group, cell viability in the SIR and Rhein co-treatment groups increased significantly (P &lt; 0.001), the release of LDH and CK-MB decreased, the positive rate of ROS in cardiomyocytes decreased, and the concentration of catalase and glutathione peroxidase increased significantly (P &lt; 0.001). Besides, Rhein can activate JAK2/STAT3 signaling pathway. JAK2 siRNA can inhibit the JAK2/STAT3 signaling mediated by Rhein. The addition of Rhein can significantly increase the activity of mitochondrial superoxide dismutase (SOD) and reduce the MDA, which indicates that the oxidative damage of mitochondria induced by Rhein was significantly weakened. The mitochondrial functional changes induced by Rhein can be reversed by JAK2 siRNA. Conclusion: Our study shows that Rhein can reduce ROS in cardiomyocytes by JAK2/STAT3 signaling pathway activation, and effectively inhibit the apoptosis of cardiomyocytes, thus having a direct protective effect on cardiomyocytes under SIR.

Determinants of suboptimal CD4+ T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV‐1 infection

IntroductionUp to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm3 despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI).MethodsParticipants who started ART in Fiebig I to V AHI with ≥48 weeks of continuous documented HIV‐RNA < 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/mm3), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre‐ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks.ResultsOf 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post‐exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre‐ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/mm3 (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the CD8+T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL‐6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices.ConclusionsDespite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre‐ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment.

Cómo es de importante el momento de la ablación con radioyodo en los carcinomas diferenciados de tiroides: la experiencia de un centro de referencia

IntroductionIt's difficult to make a scientific, evidence-based approach about the timing of radioiodine remnant ablation (RRA) in patients with differentiated thyroid carcinomas (DTCs). Primary aim of the study was to reveal whether timing of RRA relates to achievement of non- structurally incomplete response (non-SIR) in low/intermediate and high-risk patients. Another aim was to reveal the correlation of timing with non-SIR status in reproductive-age women. Materials and MethodsRecords of 279 low, intermediate, and high-risk patients were analysed, retrospectively. Number of days between surgery and RRA is referred to as timing. Low/intermediate-risk patients, high-risk patients, and low/intermediate-risk reproductive-age women were divided into non-SIR and SIR groups, according to 2015 American Thyroid Association guidelines for therapy response. The relationship between timing and therapy response was analysed statistically. ResultsWe could not find any significant relationship in patients with low/intermediate risk between timing and non-SIR, including women between 18-49 years of age (p >0.1). For high-risk patients, we found a statistically significant relationship between timing and non-SIR response. According to ROC analysis, RRA ≤58 days was found as a cut-off value. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated as 83.3%, 70.0%, 2.78, and 0.24, respectively. ConclusionRRA must be initiated within 58 days after surgery in patients with high-risk DTCs. Under this approach, risk of SIR and associated mortality risk may be reduced. RRA timing for women in reproductive ages with low/intermediate risk groups may be planned according to their pregnancy/breastfeeding intent. For other low/intermediate risk groups, they can safely proceed according to the capacity of the medical facility and related logistical considerations.

INNV-41. PROSPECTIVE SELECTION OF RECURRENT GLIOBLASTOMA PATIENTS FOR TAILORED THERAPIES. RESULTS OF AN INSTITUTIONAL EXPERIENCE

Abstract INTRODUCTION Failure of clinical trials with targeted therapies in glioblastoma (GBM) is probably due to the enrollment of molecularly unselected patients. In preliminary studies, we prospectively selected recurrent GBM patients on the basis of molecular pattern and administered targeted therapy accordingly. This tailored approach gave encouraging results in term of low recurrence rate (RR) and high 6-month progression free survival (PFS-6). Here, we present the long-term results of our work. METHODS On recurrent tumor samples of 34 adult patients, we assessed the expression of VEGF and PTEN through immunohistochemistry and of EGFRvIII through RT-PCR. Patients with VEGF overexpression were treated with bevacizumab (10 mg/Kg i.v. every 2 weeks in 6-week cycles). Patients with EGFRvIII expression and normal PTEN expression added erlotinib (150 mg/day orally). Patients with loss of PTEN expression, irrespective of EGFRvIII status, added sirolimus (1–10 mg/day orally). RESULTS Sixteen patients received bevacizumab alone (bev), 14 bevacizumab plus erlotinib (bev+erl) and 4 bevacizumab plus sirolimus (bev+sir). RR was 50% in the whole cohort and 37.5%, 57.1% and 75% in bev, bev+erl and bev+sir groups, respectively. PFS-6 was 55.9% in the whole cohort and 50%, 64.3% and 50% in bev, bev+erl and bev+sir groups, respectively. Our data compare favorably with those from the large EORTC 26101 trial, which showed a RR of 41.5% and a PFS-6 lower than 30%. When considering sustained response (defined as PFS ≥ 12 months), we overall observed a 20.6% rate, with the highest value in bev+erl subgroup (28.6%). Interestingly, in EORTC 26101 trial, less than 10% of patients achieved PFS ≥ 12 months. CONCLUSIONS Our results confirm that the tailored approach in recurrent GBM provides an advantage in terms of RR, PFS and, above all, of long-term responses, compared with trials without molecular selection.

How Important is the Timing of Radioiodine Ablation in Differentiated Thyroidal Carcinomas: A Referral Centre Experience

IntroductionIt's difficult to make a scientific, evidence-based approach about the timing of radioiodine remnant ablation (RRA) in patients with differentiated thyroid carcinomas (DTCs). Primary aim of the study was to reveal whether timing of RRA relates to achievement of non- structurally incomplete response (non-SIR) in low/intermediate and high-risk patients. Another aim was to reveal the correlation of timing with non-SIR status in reproductive-age women. Materials and MethodsRecords of 279 low, intermediate, and high-risk patients were analysed, retrospectively. Number of days between surgery and RRA is referred to as timing. Low/intermediate-risk patients, high-risk patients, and low/intermediate-risk reproductive-age women were divided into non-SIR and SIR groups, according to 2015 American Thyroid Association guidelines for therapy response. The relationship between timing and therapy response was analysed statistically. ResultsWe could not find any significant relationship in patients with low/intermediate risk between timing and non-SIR, including women between 18-49 years of age (p >0.1). For high-risk patients, we found a statistically significant relationship between timing and non-SIR response. According to ROC analysis, RRA ≤58 days was found as a cut-off value. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated as 83.3%, 70.0%, 2.78, and 0.24, respectively. ConclusionRRA must be initiated within 58 days after surgery in patients with high-risk DTCs. Under this approach, risk of SIR and associated mortality risk may be reduced. RRA timing for women in reproductive ages with low/intermediate risk groups may be planned according to their pregnancy/breastfeeding intent. For other low/intermediate risk groups, they can safely proceed according to the capacity of the medical facility and related logistical considerations.

Sirolimus + Tacrolimus Maintenance with No Induction Therapy May Maximize Survival in Lung Transplant Recipients

Purpose Sirolimus has purported advantages in lung transplant maintenance therapy, such as anti-fibrotic, anti-proliferative, and anti-aging effects, which may help improve survival. Methods Among U.S. lung transplant recipients from 2003-2016 in the United Network for Organ Sharing (UNOS) dataset, we compared sirolimus [SIR] (n=219) to mycophenolate mofetil [MMF] (n=5482), within a tacrolimus-based regimen. The SIR group consisted of patients on SIR within 1 year post-transplant, since prophylactic SIR initiation is usually delayed by up to 1 year to avoid the risk of bronchial anastomotic dehiscence and other complications. Due to the delayed initiation of SIR, this study was restricted to patients alive at 1 year in both groups, to prevent immortal time bias. All patients in both groups were free of bronchiolitis obliterans syndrome and malignancy at 1 year, to exclude these common rescue uses of SIR. We also assessed survival for SIR and MMF after subdividing by whether or not patients received induction therapy (with basiliximab, daclizumab, antithymocyte globulin, or alemtuzumab). Survival comparisons were based on Kaplan-Meier estimates and Cox multivariable regression utilizing multiple imputation to handle missing data. Results SIR had better survival than MMF: median (MS) 8.9 vs 7.1 yr.; adjusted Hazard Ratio (HR)=0.71, p=0.003. When subdividing by whether patients received induction, SIR with no induction had the best survival (MS=10.7 yr.; HR=0.48, p=0.002), followed by SIR with induction (MS=7.9 yr.; HR=0.90, p=0.45), MMF with induction (MS=7.4 yr.; reference group), and MMF with no induction (MS=6.8 yr.; HR=1.15, p=0.01). Conclusion Sirolimus, initiated within 1 year after lung transplantation in a tacrolimus-based regimen, may improve survival compared to MMF. National data representing the U.S. lung transplant population suggest that sirolimus + tacrolimus maintenance with no induction therapy is associated with a median survival of approximately 10 years.

The importance in diagnosing patients with conflicting observational data for post surgery radioiodinated ablation of thyroid remnants.

There is a special group of patients, according to 2015 American Thyroid Association guidelines. This group is defined as "the patients with conflicting observational data for post-surgery radioiodine ablation (COD for PSRIA)". For this special group of patients RIA is applied after a thorough reassessment of histopathological, clinical and biochemical features, including thyroglobulin (Tg). However, there is no consensus on what is the suitable cut-off value for the radioiodine ablation (RIA) decision or for therapy prediction. Moreover, is also unclear which Tg parameters should be used for these purposes. If we can determine useful and practical cut-off values for excellent response (ER) and non-structural incomplete response (non-SIR) response categories, this will facilitate our therapy response prediction before RIA and may allow us to categorize the group of "COD for PSRIA" based on a higher risk of recurrence/relapse or disease specific mortality rates according to serum thyroglobulin (Tg). This categorization may also enable us to plan the follow-up frequency of patients more scientifically. Consequently, it may provide the more efficient use of medical facility and healthcare system resources. Two hundred forty-nine patients (out of 577 examined) with "COD for PSRIA" were included in this study. Firstly, patients with indeterminate, biochemical incomplete and structural incomplete responses were considered as the non-ER group and compared to the ER group. Secondly, patients with excellent, indeterminate, and biochemically incomplete responses were considered as the non-SIR group and compared to the SIR group. The data were evaluated by MedCalc Statistical Software version 18.9. The cut-off value for ER patients was calculated as ≤6.57ng/mL. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 67.9%, 75.4%, 55.6% and 83.8%, respectively. The cut-off value for non-SIR patients was calculated as ≤12.7ng/mL. Sensitivity, specificity, PPV and NPV were 78.5%, 91.7%, 35.5% and 98.6%, respectively. If a patient has ≤6.57ng/mL pre-ablative Tg, follow-up intervals of patients with "COD for PSRIA" may be extended due to lower recurrence/relapse rates. However, if a patient has >12.7ng/mL pre-ablative Tg, these patients should be followed-up more frequently in order to determine SIR earlier. This approach may enable more efficient use of medical facility and healthcare system resources and a more scientific planning of their follow-up treatment. This approach seems to have the potential to contribute significantly to cost-effectiveness.