Optimal Therapeutic Management Research Articles

Are leukotriene inhibitors useful for bronchiolitis?

Bronchiolitis is a prevalent disease in children under two years of age, which carries significant morbidity and mortality. However, there is controversy regarding the optimal therapeutic management. Leukotriene inhibitors have been proposed as an alternative, although its efficacy is not clear yet. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified two systematic reviews comprising six trials addressing the question of this article. We extracted data, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded leukotriene inhibitors might not decrease mortality levels on bronchiolitis patients and it is not clear whether they decrease length of hospital stay. They might reduce recurrent wheezing, but the certainty of the evidence is low, and they increase adverse effects.

Indolent Phenotype of RAS-Associated Autoimmune Leukoproliferative Disorder (RALD) Is Characterized By Single Somatic Mutations in RAS Genes with Absence of Cooperating Mutations

RAS-Associated Autoimmune Leukoproliferative Disorder (RALD) is a chronic indolent condition that typically presents in childhood with monocytosis, lymphocytosis, autoimmune phenomena, splenomegaly, and variable lymphadenopathy. RALD is characterized by somatic mutations in KRAS or NRAS in hematopoietic cells (myeloid and lymphoid), resulting in missense mutations involving the 12th or 13thcodon. Despite the indolent course of RALD, it shares some overlapping clinical features and similar genetic defects with Juvenile Myelomonocytic Leukemia (JMML), which is characterized by canonical and non-canonical RAS-pathway mutations. All RALD patients have normal bone marrow karyotypes. While patients with JMML often harbor monosomy 7 or other karyotypic abnormalities, normal karyotypes are also not uncommon in JMML. Optimal therapeutic management of RALD and JMML differs significantly, necessitating accurate diagnostic discrimination of RALD and normal karyotype JMML.Recent JMML studies have characterized the genomic landscape of JMML, which involves additional recurrent mutations that are thought to cooperate with RAS-pathway mutations driving the malignant phenotype of JMML. We sought to evaluate the genomic landscape of RALD for the presence of non-RAS cooperating mutations reported in JMML.Using targeted sequencing for 54 genes associated with myeloid malignancies, amplicon libraries were constructed from peripheral blood mononuclear cells (PBMCs) collected from 11 patients diagnosed with RALD (6 with previously identified KRAS and 5 with previously identified NRAS mutations) and sequenced with an average read depth of ~3000x. Variants were identified using the Illumina miSeq reporter software and analyzed using Illumina Variant Studio. Variants were filtered based SIFT, PolyPhen, and CADD predictions, ClinVar annotations, and mutations previously identified in JMML. Over 90% of the mutated genes reported in JMML sequencing reports, were evaluated (including KRAS, NRAS, CBL, PTPN11, SH2B3, SETBP1, GATA2, RUNX1, ASXL1, EZH2, DNMT3A, and ZRSR2). Of note, only the KRAS or NRAS mutations, initially identified from Sanger sequencing, were identified as disease-contributing and no other known pathogenic mutations were detected in the RALD cohort. Variant allele frequencies (VAFs) of KRAS and NRAS mutations in RALD ranged from 32.3%-50.8% with a median VAF of 46.6%. In order to further investigate genes not included in the targeted sequencing panel that may be contributing to disease, whole exome sequencing (WES) was performed on PBMCs from 7 RALD patients (4 KRAS patients, 3 NRAS patients). Despite the expanded genomic sequencing in WES (mean coverage of 225x), only the single pathogenic KRAS or NRAS mutation, known to be disease-related, was identified. No other mutations that were previously identified in JMML were detected in the WES data set. Based on presence of autoimmune phenomena in RALD, a multiplex inflammatory cytokine immunoassay investigating GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12p70 was used to quantify cytokine levels in the plasma of 9 RALD patients and 17 healthy volunteers. The levels of IL-2, IL-6, and IL-10 were found significantly increased in RALD patients. IL-2 was 4.6 fold higher in RALD than controls (median 0.696 pg/mL vs. 0.149 pg/mL; p=0.049). Similarly, IL-6 was 10 fold higher in RALD than controls (median 6.42 pg/mL vs. 0.63 pg/mL; p=0.035), and IL-10 was 18 fold higher in RALD than controls (median 26.9 pg/mL vs. 1.49 pg/mL; p=0.018).Overall, these findings provide evidence that RALD, in our patient cohort with an indolent clinical course, is characterized by single somatic KRAS or NRAS mutations with the absence of cytogenetic abnormalities and cooperating mutations that are associated with malignancy. This suggests that in the spectrum of so-called RASopathies, RALD represents a non-malignant proliferative hematopoietic disease that is clinically distinct from JMML. The altered plasma cytokine profile in RALD may play a role in the autoimmune features of the disease and be related to sustained activation of the RAS pathway in hematopoietic cells. Further investigation is imperative to distinguish these two overlapping entities characterized by RAS pathway mutations, and to better understand the spectrum of disease from indolence to aggressive malignancy. DisclosuresNo relevant conflicts of interest to declare.

Benefits of a concentrated teaching rotation: Perspectives of pharmacy residents and faculty

The postgraduate pharmacy residency experience requires residents to develop the proper skillset to not only provide optimal therapeutic management to patients, but to effectively deliver their knowledge to trainees and other health care providers. Without specific recommendations for how to achieve these skills, residents may hone their communication, organizational, and teaching skills through a number of different venues currently offered by residency programs nationwide. Residency programs commonly offer a longitudinal experience in order for residents to obtain didactic teaching skills; less often do programs offer a concentrated rotation dedicated to academia. Residents can acquire a number of skills from a focused academic rotation including curriculum development, career growth, and preceptorship by following a schedule that more closely mimics that of a clinical faculty member. These skills are typically more difficult to develop with a longitudinal experience due to time constraints and other resident and faculty member commitments. Prior to implementing this experience, the impact on both the resident and faculty member should be taken into consideration.

Performance of multiplicom's BRCA MASTR Dx kit on the detection of BRCA1 and BRCA2 mutations in fresh frozen ovarian and breast tumor samples.

Next-generation sequencing (NGS) has enabled new approaches for detection of mutations in the BRCA1 and BRCA2 genes responsible for hereditary breast and ovarian cancer (HBOC). The search for germline mutations in the BRCA1 and BRCA2 genes is of importance with respect to oncogenetic and surgical (bilateral mastectomy, ovariectomy) counselling. Testing tumor material for BRCA mutations is of increasing importance for therapeutic decision making as the poly ADP ribose polymerase (PARP) inhibitor, olaparib, is now available to treat patients with specific forms of ovarian cancer and BRCA mutations. Molecular genetics laboratories should develop reliable and sensitive techniques for the complete analysis of the BRCA1 and BRCA2 genes. This is a challenge due to the size of the coding sequence of the BRCA1/2 genes, the absence of hot spot mutations, and particularly by the lower DNA quality obtained from Formalin-Fixed Paraffin-Embedded (FFPE) tissue. As a result, a number of analyses are uninterpretable and do not always provide a result to the clinician, limiting the optimal therapeutic management of patients. The availability of Fresh Frozen Tissue (FFT) for some laboratories and the excellent quality of the DNA extracted from it offers an alternative. For this reason, we evaluated Multiplicom's BRCA MASTR Dx assay on a set of 97 FFT derived DNA samples, in combination with the MID for Illumina MiSeq for BRCA1 and BRCA2 mutation detection. We obtained interpretable NGS results for all tested samples and showed > 99,7% sensitivity, specificity and accuracy.

Inquilinus limosus in pulmonary disease: case report and review of the literature

Inquilinus limosus is a slow growing, gram-negative, oxidase-positive, non-fermentative bacillus that is rarely isolated from clinical samples. When clinically identified, I. limosus is almost exclusively isolated from the respiratory tracts of patients with cystic fibrosis (CF). We report the first case of I. limosus isolation from a pulmonary specimen in an individual without a diagnosis of CF. A review of the English-language literature has been made and shows 33 cases (excluding the present report) in which I. limosus was isolated from the respiratory tracts of patients. Our patient, at 60years of age, is more than two decades older than the any previously reported patient. Similar to previous reports, the I. limosus isolated from her lungs demonstrated intrinsic multidrug resistance. The pathogenicity, clinical relevance, and optimal therapeutic management of I. limosus remains largely unknown due to its infrequent recovery from clinical samples.

Surgery versus non-surgical management for unilateral ureteric-pelvic junction obstruction in newborns and infants less than two years of age.

Unilateral ureteric-pelvic junction obstruction (UPJO) is the most common cause of obstructive uropathy and may lead to renal impairment and loss of renal function. The current diagnostic approach with renal imaging cannot reliably determine which newborns and infants less than two years of age have a significant obstruction and are at risk for permanent kidney damage. There is therefore no consensus on optimal therapeutic management of unilateral UPJO. To assess the effects of surgical versus non-surgical treatment options for newborns and infants less than two years of age with unilateral UPJO. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2016), MEDLINE/Ovid, and EMBASE/Ovid databases from their inception to 13 June 2016. We searched the reference lists of potentially relevant studies without using any language restriction. We also searched the following trial registers for relevant registered studies: www.clinicaltrials.gov/; ISRCTN registry (controlled-trials.com/); www.trialscentral.org/; apps.who.int/trialsearch/; www.drks.de/; and www.anzctr.org.au/trialSearch.aspx. We selected randomised and quasi-randomised controlled trials comparing surgical with non-surgical interventions for the treatment of unilateral UPJO. Two review authors independently assessed study eligibility and risk of bias of included studies and extracted data. In case of disagreements we consulted a third review author. The data reported in the two included studies did not allow us to perform a meta-analysis. We found only two studies at high risk of bias that were eligible for inclusion in this review. The total sample size, including both trials, was small (n = 107 participants less than six months of age from the UK and USA), and not all prespecified outcome measures were assessed. Reported measures only accounted for the short-term follow-ups. The mean split renal function was not statistically different between the surgical and non-surgical group at the six-month or one-year time point (very low-quality evidence). The surgical group showed a significantly less obstructed drainage pattern and a lower urinary tract dilatation than the non-surgical group (very low-quality evidence). Transfer from the non-surgical group to the surgical group was reported for about one out of five participants. Split renal function after secondary surgical intervention was reported with variable results, but most of the participants reverted to pre-deteriorated values. The studies either provided no or insufficient data on the following outcome measures: postoperative complications, UPJO-associated clinical symptoms, costs of interventions, radiation exposure, quality of life, and adverse effects. We found limited evidence assessing the benefits and harms of surgical compared to non-surgical treatment options for newborns and infants less than two years of age with unilateral UPJO. The majority of participants in the non-surgical treatment group did not experience any significant deterioration of split renal function, and only about 20% of them underwent secondary surgical intervention, with minor risk of permanent deteriorated split renal function. The study follow-up period was too short to assess the long-term effects on split renal function in both treatment groups. We need further randomised controlled trials with sufficient statistical power and an adequate follow-up period to determine the optimal therapy for newborns and infants less than two years of age with unilateral UPJO.

A cohort study on breakthrough invasive fungal infections in high-risk patients receiving antifungal prophylaxis.

Antifungal prophylaxis is recommended for haematological patients at high risk of invasive fungal infections (IFIs). Incidence, optimal therapeutic management and outcome of breakthrough IFIs (bIFIs) are largely unknown. To assess bIFI incidence, treatment and outcomes, data on patients undergoing AML remission-induction and consolidation chemotherapy and from allogeneic HSCT recipients on antifungal prophylaxis with itraconazole, micafungin or posaconazole were extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut). bIFIs were classified according to revised EORTC/MSG criteria. From January 2004 to April 2013, 250 AML patients with 329 hospitalizations and 409 HSCT patients with 496 hospitalizations were identified. In AML patients, there were 16 (6.4%) proven or probable bIFIs and 44 (17.6%) possible bIFIs. In HSCT patients, there were 14 (3.4%) proven or probable bIFIs and 37 (9.0%) possible bIFIs. Proven cases included five candidaemias, two mucormycoses, three aspergilloses and one fusariosis. The most frequent choice for bIFI treatment was liposomal amphotericin B in AML patients (21/60; 35.0%) and continuation of posaconazole prophylaxis in HSCT patients (16/51; 31.4%). In HSCT recipients, survival on day 365 was significantly lower in bIFI patients (AML, 63.3% versus 70.0%; P = 0.297; HSCT, 49.0% versus 66.8%; P = 0.012). Comparison of continuation of prophylaxis versus switch of antifungal class as first-line treatment showed no significant difference regarding response to treatment and survival. Rates of bIFIs observed in our population were comparable to previous data. There was no clear shift towards rare species, as previously reported. A high variety of treatment approaches was observed.

Cancer in pregnancy: disentangling treatment modalities

Pregnancy-associated cancer constitutes an uncommon and difficult to manage clinical situation. It is defined as the cancer diagnosed from the first day of childbearing to 1 year post partum. Coexistence of cancer with pregnancy adds complexity to treatment recommendations, as both the mother and the fetus may be affected. The optimal therapeutic management of pregnant women with cancer diagnosis should take into account, apart from medical factors, a host of other parameters (ethical, psychological, religious, legal, etc). Unfortunately, this situation becomes more complex as more women delay childbearing, and consequently the incidence of cancer during pregnancy is constantly increasing. This manuscript summarises the general principles in managing pregnant patients with cancer and gives detailed instructions in the management of pregnant patients with breast cancer, ovarian cancer, melanoma, lymphoma, lung cancer, soft-tissue sarcoma and cervical cancer. Of note, management of pregnant women with cancer diagnosis should be performed in specialised centres with experience and all cases should be discussed in multidisciplinary meetings composed of multiple specialists (medical oncologists, obstetricians, surgeons, radiologists and paediatricians).

Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders.

BackgroundLess than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered.MethodsWe have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015.ResultsFive missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x109/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation.ConclusionsPlatelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.

Molecular Diagnosis in Resource-Limited Settings

The advantages of molecular testing for accurate diagnosis and optimal therapeutic management of patients infected with microorganisms is well established, yet many test methods are not feasible in underdeveloped or resource-limited settings. The disparity in testing methods is controversial from ethical, financial, and scientific perspectives. Over the years, philanthropic funding for early and accurate diagnosis has helped curtail the spread of disease and improved overall survival, yet infections caused by microorganisms are still the leading cause of death in the resource-limited parts of the world. Fortunately, there are promising new tests that are inexpensive, portable, easy-to-use, and practical at even small, rural, and remote health centers. This review describes the potential problems encountered in the routine implementation and performance of molecular assays in resource-poor settings and discusses the adaptations and alternative methodologies that are routinely used in most microbiology laboratories in such settings.

Survival outcomes and incidence of brain recurrence in high-grade neuroendocrine carcinomas of the lung: Implications for clinical practice

BackgroundAmong patients with advanced high-grade neuroendocrine carcinoma (HGNEC) of the lung, the optimal therapeutic management is much less established for large cell neuroendocrine carcinomas (LCNECs) than for small cell lung cancers (SCLCs). We evaluated the survival outcomes and incidence of brain recurrence of advanced LCNECs, and compared them with those of a population of SCLCs matched by stage. Materials and methodsForty-eight unresected stage III HGNECs (16 LCNECs and 32 SCLCs) and 113 stage IV HGNECs (37 LCNECs and 76 SCLCs) were eligible for the analysis. The efficacy of platinum-etoposide chemotherapy with or without thoracic radiotherapy (TRT) and/or prophylactic cranial irradiation (PCI) was investigated. ResultsOverall response was significantly lower for LCNECs compared with SCLCs for both stage III (43.8% vs 90.6% respectively, P=0.004) and stage IV (43.3% vs 64.5%, respectively, P=0.04). Similarly, an inferior outcome was observed in terms of progression-free survival (PFS), and overall survival (OS) for LCNECs compared with SCLCs, which, however, reached significance only for stage III disease (median: 5.6 vs 8.9 months, P=0.06 and 10.4 vs 17.6 months, P=0.03 for PFS and OS, respectively). In the lack of PCI, LCNECs showed a high cumulative incidence of brain metastases, as 58% and 48% of still living stage III and IV patients, respectively, developed brain metastases at 18 months. ConclusionPatients with advanced LCNECs are at high risk for brain recurrence. Unresected stage III LCNECs treated with platinum-etoposide with or without TRT bear a dismal prognosis, when compared indirectly with SCLC counterparts. Randomized trials should evaluate whether PCI could improve survival of advanced LCNECs.

Endoscopic Hip Surgery in the Treatment of External Snapping Hip for A 22 Years Old Women

The snapping hip is a painful and disabling condition, related to a conflict between the greater trochanter and the soft tissue surrounding it. It is characterized by an audible click and sometimes visible on the thigh lateral region during the movements. The classical treatment is with opened surgery, but only few cases are reported. We present the case of a young 22 years old Caucasian female with external snapping hip and associated with tendinitis of the medium and maximus gluteus. The diagnosis was done clinically and radiologically with a nuclear magnetic resonance. The treatment was performed by a hip endoscopy after failure of medical treatment and physiotherapy. The bursectomy and the adhesions’s release gave very good results for our patient. Peritrochanteric endoscopy seems to have a place in the treatment of external snapping hip, allowing good visualization of lesions and optimal therapeutic management by first mini invasive routes. It might be a way for a better recover.

Pancreatic small cell cancer

Small cell carcinoma (SCC) is most commonly associated with lung cancer. Extra-pulmonary SCC can originate in virtually any organ system, with the gastrointestinal tract being the most common site of involvement. We review the clinical presentation, pathogenesis, histology, imaging modalities and optimal therapeutic management of PSCC in light of available evidence.

Tumeurs de l'apex pulmonaire

Superior sulcus tumors are a rare subset of lung carcinomas which occur with an incidence of less than 5 % of all lung cancers. In thoracic oncology, management of superior sulcus tumors remains challenging because of their anatomical location. The optimal therapeutic management is still controversial. Combined approach including surgery and radiotherapy allows for a good rate of complete resection. So, in selected patients without contraindications, induction chemoradiation followed by surgical resection has become the established standard treatment approach.

Possibilities of telemedicine in work to improve survival in multiple trauma victims

World experience providing medical assistance to victims of trauma indicates high efficiency of telemedicine methods in organization of medical care to trauma victims and an effective and adequate implementation of therapeutic and diagnostic measures. A condition of Ukraine’s health care system does not allow providing full medical and diagnostic care in all medical institutions of Ukraine. Therefore, there is request to continuing consulting practitioners with in damage control speciality, dynamics of treatment, as well as providing opportunities to discuss and select the optimal therapeutic and diagnostic management.

Mutations in the BCR-ABL1 Kinase Domain and Elsewhere in Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) has been the first human malignancy to be associated, more than 50 years ago, with a consistent chromosomal abnormality--the t(9;22)(q34;q11) chromosomal translocation. The resulting BCR-ABL1 fusion gene, encoding a tyrosine kinase with deregulated activity, has a central role in the pathogenesis of CML. Ancestral or additional genetic events necessary for CML to develop have long been hypothesized but never really demonstrated. CML can successfully be treated with tyrosine kinase inhibitors (TKIs). Mutations in the BCR-ABL1 kinase domain might arise, however, that confer resistance to 1 or more of the currently available TKIs. Hence, the critical role of BCR-ABL1 mutation screening for optimal therapeutic management, with the current gold standard technique, conventional sequencing, likely to be replaced soon by ultra-deep sequencing. Mutations in genes other than BCR-ABL1 include ASXL1, TET2, RUNX1, DNMT3A, EZH2, and TP53 in chronic phase patients and RUNX1, ASXL1, IKZF1, WT1, TET2, NPM1, IDH1, IDH2, NRAS, KRAS, CBL, TP53, CDKN2A, RB1, and GATA-2 mutations in advanced phase patients. The latter also display additional cytogenetic abnormalities, including submicroscopic regions of gain or loss that only single nucleotide polymorphism arrays or array comparative genomic hybridization can detect. Whether whole genome/exome sequencing studies will uncover novel mutations relevant for pathogenesis, progression, and risk-adapted therapy is still unclear.

Input of molecular analysis in medical management of primary brain tumor patients

Primary brain tumors comprise a large group of malignant and non-malignant tumors including heterogeneous entities with various biological and clinical behaviors. Up till recently, diagnosis of brain cancers, that drives treatment decision-making, was based on integration of clinical, radiological and pathological features of patients and tumors. Over the last years, practical neuro-oncology has entered an era of molecular-based personalized medicine. Indeed, molecular features of tumors provide critical information to physicians for daily clinical management of patients and for design of relevant clinical research. Sporadic gliomas or glial tumors are the most common primary brain tumors in adults. Recently, their medical management has been revolutionized by molecular data. Indeed, optimal therapeutic management of grade III glioma patients now requires assessment of chromosome arms 1p/19q copy number and IDH mutational statuses as predictive and prognostic biomarkers. Indeed, two large phase III clinical trials have demonstrated that early chemotherapy plus radiotherapy, versus radiotherapy alone, doubles median overall survival of patients suffering from 1p/19q co-deleted and/or IDH mutated anaplastic oligodendroglial tumor. Interestingly, both biomarkers have been identified in a large proportion of WHO grade II gliomas. Their clinical value, in this population, is under investigation through multiple phase III clinical trials. In sporadic WHO grade I gliomas, and specifically in pilocytic astrocytomas, MAPK signaling pathway activation is a frequent event, mainly due to genetic alterations involving BRAF gene. This characteristic opens new therapeutic perspectives using MAPK signaling pathway inhibitors. Finally, in the most aggressive gliomas, WHO grade IV gliomas, two critical biomarkers have been identified: (i) MGMT promoter methylation associated with longer survival and better response to chemotherapy and (ii) IDH mutations predicting better prognosis. Although, further studies are needed, MGMT promoter methylation will undoubtedly be transferred soon to clinical practice. Molecular characteristics are beginning to be valuable and indispensable in neuro-oncology for better management of brain tumors patients. The near future will be marked by identification of novel molecular biomarkers and their validation for clinical practice.

0447 : Optimal therapeutic management improves long-term survival in ST-elevation myocardial infarction patients with altered glomerular filtration rate. A propensity score comparison

Decreased glomerular filtration rate (GFR) is associated with an increased risk of cardiovascular events following acute ST elevation myocardial infarction (STEMI). However, patients with chronic kidney disease have more comorbidities and will receive fewer evidence-based therapies In a prospective STEMI patient cohort we assessed the effect of an optimal therapeutic management (OTM) according to GFR categories on long-term all-cause mortality. In a single tertiary referral center, 1,199 patients admitted for acute STEMI were enrolled between 2007 and 2011. We classified patients into 4 categories according to estimated GFR, <45, 45 to 60, 60 to 90, and >90mL/min/1,73m2 with the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation. Optimal therapeutic management was defined as a combination of reperfusion within 12 hours of symptom onset, primary percutaneous coronary intervention (PCI), double anti-platelet regimen, angiotensin converting enzyme inhibitors, statins, beta blockers, and antialdosterone treatment (if left ventricle ejection fraction <40%) upon discharge. The effect of OTM on survival according to GFR categories was analysed in a multivariate survival model including other risk factors and using a propensity score method. Long-term mortality was the principal endpoint. Patients were followed-up for a median of 4.7 years and 148(12.3%) patients died. OTM was applied in 431 (39.1%) patients of our cohort and overall, was associated with a significantly lower mortality (HR of 0.43 [95% CI, 0.26-0.70; P<0.001). There was a significant mortality reduction in the OTM group compared to the non-OTM group that tended to increase with increasing levels of renal dysfunction (HR of 0.28 [95% CI, 0.13-0.61] in the eGFR<60ml/min patient subgroup; P=0.001) (Figure 1). OTM lowers long-term mortality whatever the eGFR category and with a trend towards increased efficiency with increasing levels of renal dysfunction.

Immunostaining of phospho-histone H3 and Ki-67 improves reproducibility of recurrence risk assessment of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial tumors in the digestive tract. Beyond surgery, therapeutic management depends on risk of recurrence. Risk evaluation of GIST takes into account location and size of the tumor, whether or not the tumor was intact or ruptured and mitotic index. The mitotic index lacks in intra- and interobserver reproducibility. In this study, we evaluated on 61 GISTs, the reproducibility of mitotic counting using classical hematoxylin-eosin-saffron (HES) staining, and its correlation with the mitotic count obtained through immunohistochemical staining for phospho-histone H3 (PHH3) and the proliferation index based upon Ki-67 immunostaining. Mitotic counts by HES and PHH3 staining and Ki-67 proliferation index were evaluated twice by three independent observers taking into account interpretation times per tumor for each technique. HES-based and PHH3-based mitotic counts and Ki-67 proliferation index correlated well and presented good intra- and interobserver reproducibility. PHH3 staining resulted in a slight but statistically significant difference of about two more mitotic figures per 5 mm(2) than the HES-based count, which might have put some borderline tumors in a different risk category. Immunohistochemical staining for PHH3 and Ki-67 allowed more rapid interpretation than mitotic counts based upon HES staining, but only PHH3 staining allows counting of mitoses. Immunostaining using anti-PHH3 and anti-Ki-67 antibodies will eventually provide improved recurrence risk stratification of GIST and may become effective ancillary tools in deciding on optimal therapeutic management.

Valoarea prognostică a markerilor tradiţionali şi a biomarkerilor în leucemia limfatică cronică în practica clinică

Chronic lymphocytic leukemia is a disease with long natural evolution, receiving low efficiency therapy and rarely with complete response to treatment. More and more patients are diagnosed in asymptomatic stages and at younger ages. Recent progress in uncovering the molecular mechanisms involved in the pathogenesis of the disease, accompanied by the emergence of new therapeutic agents, generates an ongoing challenge for clinicians in establishing optimal therapeutic management of these patients. In parallel, studies were conducted to highlight the factors that effectively influence therapeutic response and duration of response – prognostic markers – in order to adopt the best therapeutic strategy for the patient. Although clinical staging remains the basis for evaluating prognosis in chronic lymphocytic leukemia, a number of biological markers, in particular serum markers, cytogenetic abnormalities, IgVH mutation status, CD38 and ZAP-70 expression in leukemic cells, provides important and independent prognostic information. Before being incorporated into everyday clinical practice, however, these markers require, standardization and validation in larger prospective studies. Currently they try to combine these prognostic markers in order to obtain an integrated risk stratification system, with broad clinical application.