Respiratory function, autonomic dysfunction, and systemic inflammation are closely linked in patients with COPD and tidal flow limitation: An exploratory study.

RATIONALE: The study aimed to investigate the interplay among respiratory function, autonomic dysfunction, and systemic inflammation in COPD patients. METHODS: In 19 COPD patients, functional respiratory parameters, heart rate variability (HRV), and plasma high-sensitivity-C-reactive-protein (hs-CRP) were assessed. Forced oscillation technique (FOT) was used to detect the absence (NFL) or presence (FL) of resting tidal expiratory flow limitation. Subsequently, patients underwent an incremental shuttle walking test (ISWT). Twenty healthy subjects were also shown as controls. RESULTS: FEV1, DLCO, and lung volumes displayed significant correlations with LH/FH ratio (0.56 < r2<0.27,p < 0.01). A significant relationship was found between LH/FH ratio with IC/TLC ratio% (r2 = 0.29,p < 0.05) and hs-CRP (r2 = 0.26,p < 0.05). Patients with FL had greater hs-CRP plasma levels (p < 0.05), lower IC/TLC% (p < 0.05), and higher LH/FH ratio (p<0.001). CONCLUSIONS: Worse airflow obstruction was associated with a higher LH/HF ratio, directly related, to hs-CRP and indices of dynamic hyperinflation. The presence of resting tidal FL with dynamic pulmonary hyperinflation is a strong driver of systemic inflammation and autonomic dysfunction.

New insights in the use of pleural ultrasonography for diagnosis and treatment of pleural disease.

The use of transthoracic ultrasound (US) has acquired a wide consensus among respiratory physicians during the last few years. The development of portable devices promotes patient's bedside evaluation providing rapid, real-time and low-cost diagnostic information. The different acoustic impedance between different tissues and organs produces artifacts known as A lines, B lines, sliding sign, lung point, etc. The identification of such artifacts is essential to discriminate normal pleural appearance from the presence of pleural effusion, pneumothorax, thickenings and tumors. Ultrasounds are also a valuable tool during interventional procedures, such as thoracentesis, chest tube insertion and transcutaneous biopsy. Its use is recommended before medical thoracoscopy in order to assess the best site of trocar insertion according to presence, quantity and characteristics of pleural effusion. The aim of this review is to provide practical tips on chest ultrasound in clinical and interventional respiratory practice.

An exploratory association of polymorphisms in angiogenesis-related genes with susceptibility, clinical response and toxicity in gastrointestinal stromal tumors receiving sunitinib after imatinib failure.

The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P < 0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P = 0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P = 0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P = 0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade ≥3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.

Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.

DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.

The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05-0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014-0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77-26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population.

Laboratory test variability and model for end-stage liver disease score calculation: effect on liver allocation and proposal for adjustment.

BACKGROUND: The use of the Model for End-Stage Liver Disease (MELD) score to prioritize patients on liver waiting lists must take the bias of different laboratories into account. METHODS: We evaluated the outcome of 418 patients listed during 1 year whose MELD score was computed by two laboratories (lab 1 and lab 2). The two labs had different normality ranges for bilirubin (maximal normal value [Vmax]: 1.1 for lab 1 and 1.2 for lab 2) and creatinine (Vmax: 1.2 for lab 1 and 1.4 for lab 2). The outcome during the waiting time was evaluated by considering the liver transplantations and the dropouts, which included deaths on the list, tumor progression, and patients who were too sick. RESULTS: Although the clinical features of patients were similar between the two laboratories, 36 (13.1%) out of 275 were dropped from the list in lab 1, compared to 5 (3.5%) out of 143 in lab 2 (P<0.01). The differences were mainly due to the deaths on the list (8% lab 1 vs. 2.1% lab 2, P<0.05). The competing risk analysis confirmed the different risk of dropout between the two labs independently of the MELD score, blood group, and preoperative diagnosis. The bias on MELD calculation was considered and bilirubin and creatinine values were "normalized" to Vmax of lab 1 (corrected value=measured value x Vmax lab 1/Vmax lab 2). By comparing receiver operating characteristic curves, the ability of MELD to predict the 6-month dropouts significantly increased from an area under the curve of 0.703 to 0.716 after "normalization" (P<0.05). CONCLUSIONS: Normalization of MELD is a correct and good compromise to avoid systematic bias due to different laboratory methods.

A histopathologic screening method for rational use of organs from prostate-specific antigen-positive multiorgan donors: the Italian Emilia-Romagna Region experience.

Reduction of waiting-list length requires extension of the organ-donor pool to elderly males bearing an higher risk of prostate cancer incidence. Prostate-cancer screening in organ donors is currently based on prostate-specific antigen (PSA) assays (total PSA and free/total PSA). However, the specificity of these assays is restricted, limiting risk-benefit analysis. Since 2001, 33 multiorgan donor candidates presenting within Emilia-Romagna (Italy) with suspect ultrasonography or abnormal PSA values were submitted to a histopathologic screening method of the entire prostate based on extemporary frozen-section analysis (maximum 1 hour) of over 50% of the organ at 0.1 mm cutting levels. Extemporary diagnosis of adenocarcinoma was made in 12 (36%) cases, corresponding to 4.5% of the male candidates aged more than 50 years in the donor pool. In all cases, the final diagnosis confirmed the extemporary analysis. As well as maximizing safety, this novel approach should permit more refined risk-benefit analysis.

A multiorgan donor cancer screening protocol: the Italian Emilia-Romagna region experience.

BACKGROUND: We describe the Emilia-Romagna screening protocol for all multiorgan donors within this region of Italy and report on the first 2 years of implementation. SETTING: Setting is a 24-hour multidisciplinary call service covering the 16 intensive care units in Emilia-Romagna (3,969,000 inhabitants) and a centralised pathology center, directed by a transplant coordination center. STUDY POPULATION AND PERIOD: All 271 effective donor candidates presenting in Emilia-Romagna in 2001-2002. PROTOCOL: Anamnesis, external examination, and thorough laboratory and instrumental screening is followed by sampling of internal effusions and evaluation of all internal organs. All suspect findings are then investigated by extemporary pathologic evaluation. To fit national legal requirements, candidates are classified as standard risk (no transmissible risk); nonstandard risk (low-risk of transmission, eligibility restricted to certified clinical emergencies pending informed consent); and unacceptable risk (unconditional exclusion because of high-risk pathologies). RESULTS: The protocol was successfully implemented for all 271 candidates. In addition to 14 independent exclusions, clinical suspicion of cancer was raised for 61 donors presenting with 82 lesions or effusions. Along with one case of lymph-node tuberculosis (unacceptable risk), histocytologic screening revealed eight cases of malignancy (5 prostate, 1 papillary-thyroid, 1 follicular-thyroid, and 1 renal cell, all nonstandard risk); the remainder were benign (standard risk). Protocol implementation led to exclusion of 8 (3.0%) candidates (1 nonstandard risk transplantation was performed). CONCLUSIONS: This stringent protocol-now adopted with some modifications at a national level-provides an initial example of a feasible intervention aimed at maximising donation safety while rationalizing use of marginal donors.

Improving donor identification with the Donor Action programme.

The increasing demand for organs for transplantation entails a consensual need for enhancement of organ procurement activity. As organ donors reside mainly in hospital intensive care units (ICUs), the Donor Action programme is aimed at identifying critical areas in ICUs, in order to improve the first step of organ donation. The purpose of this paper is to analyse the problem of identification of potential donors by means of a chart revision of patients who died in 14 ICUs in the Emilia-Romagna region between 1 July 1998 and 31 December 2000. All deaths and patients with severe brain insult (score on Glasgow Coma Scale (GCS) = 3/15) were assessed by the local transplant coordinators together with a professional at the Transplant Reference Centre. Brain death diagnoses and potential donor referrals were therefore assessed in the study period, which was subdivided into five semesters. Of the 3,056 deaths reported in 30 months, 1,248 were due to severe brain damage (GCS score = 3). Brain death diagnosis (BD) was performed in 509 patients (40.8%). Although we applied the same parameters over the whole length of the study, we observed a significant increase in BDs (from 87 in the first semester to 125 in the last, 30.5% to 53.0% of the patients with GCS 3 ( P=0.003, chi(2) for trend=16.072), in spite of a slight decrease in the total number of deaths and in the total number of patients with GCS score = 3 (from 649 to 587, and from 44% to 41%, respectively). Study population characteristics could have contrasted with rather than facilitated our results: age and gender did not change significantly, whilst cause of death showed a significant reduction in trauma and an increase in cerebrovascular incidents over the whole length of the study. We can conclude that the more careful assessment of patients dying in ICUs, by the Donor Action programme, significantly contributed to the improvement of BDs observed in the study period. Therefore, Donor Action seems to be an efficient quality control programme to improve identification of potential donors, the first stage of organ procurement.

Donor Action program in the Emilia-Romagna region of Italy.

CONTEXT: The high demand for organs for transplantation necessitates enhancement of organ procurement activity worldwide. OBJECTIVE: To detect critical areas in the organ donation process and to assess whether careful monitoring of deaths in each intensive care unit could improve rates of identification of brain death. DESIGN: Records of patients who died in intensive care units in the Emilia-Romagna region between July 1, 1998 and June 30, 2000 were reviewed through the Donor Action program. RESULTS: Of the 2469 patients who died during the period studied, 1010 (40.9%) had severe brain damage, as indicated by a score of 3 on the Glasgow coma scale. A total of 857 patients with severe brain damage who had spent more than 6 hours in the intensive care unit (34.7% of all deaths) were considered as potential donors. Signs of brain death were observed in 383 (44.7%) of the 857 patients who died. Rates of identification of brain death increased from 36% to 55% during the study period. CONCLUSION: Considering that the characteristics of the study population had not changed, we believe that the Donor Action program was an important factor leading to the observed improvement in identification of brain death.