Independent Determinant Of Survival Research Articles

255 Tricuspid regurgitation in the community by routine echocardiography

Abstract Aims Tricuspid Regurgitation (TR) is quite frequent in the community and often overlooked in routine clinical practice. This study aims to convey the TR rate of diagnosis and impact on survival in a geographically defined population of an Italian referral centre, considering five different clinical contexts. Methods The study included consecutive outpatients with comprehensive echocardiography and complete clinical evaluation over 7 years of practice. Outpatients with TR greater than moderate were included, and the different clinical contexts evaluated: patients with concomitant significant mitral regurgitation (MR-TR), heart failure (HF-TR), previous open-heart surgery (postop-TR), pulmonary hypertension (PHTN-TR) and isolated TR (isolated-TR). Results Among all consecutive echocardiograms performed in routine practice (N=6797) in a geographically defined community, moderate or severe TR was found in 4.8% (N = 327; mean age 76±10, 56% female). Median follow-up was 6.1 [2.2–8.9] years. TR severity was an independent determinant of survival: risk ratio for mortality of severe TR vs. moderate was 1.72 [95% CI 1.06–2.77; P = 0.03] univariate and 1.76 [95% CI 1.02–3.01; P = 0.04] after adjusted for age, sex, MR, PHTN and EF. Only 2.8% of patients underwent tricuspid valve surgery during follow-up. Outpatients with MR-TR or HF-TR held the worst prognosis (Figure). As compared to isolated-TR, the mortality risk was 2.67 [95% CI 1.05–6.78; P = 0.04] for HF-TR and 2.04 [95% CI 1.00–4.14; P = 0.05] for MR-TR. Risk ratios for mortality vs. postop-TR were 3.66 [95% CI 1.19–11.26; P= 0.02] for HF-TR and 2.79 [95% CI 1.08–7.21; P = 0.03] for MR-TR. There was no interaction between the TR clinical context and the survival impact of TR (P=0.09). Conclusions Significant TR is frequent in our community, comparable to key epidemiological studies. TR severity independently impacts survival in all clinical settings, and it is associated with an absolute high event-rate when present with concomitant MR or HF. These results give importance to early diagnosis with grading to be performed through accurate echocardiography and renew the interest in new and safe, less invasive percutaneous intervention to improve patients' survival.

Determinants and prognostic implication of improved left ventricular ejection fraction in chronic heart failure patients with reduced ejection fraction

Abstract Background Previous studies have demonstrated that left ventricular ejection fraction (LVEF) is not associated with overall survival in patients with chronic heart failure (CHF). This study aimed to examine if improved EF is associated with better survival in these patients. Methods Study subjects were selected from the database in the REDEAL trial, which included all patients with CHF and a LVEF of <50% referred to our hospital between 2009 and 2017. Of these, 902 patients completed at least twice echocardiography examinations (BL and FUP) at a minimal interval of 12 [median 17 (14–25)] months. Results At baseline, there were 522 patients with BL_EF >35% (aged 68±12 years, male 74.5%, median EF 44%) and 381 patients with BL_EF ≤35% (aged 65±13 years, male 74.5%, median EF 29%). Survival was similar between groups (76.6% vs. 73.8%, P=0.322). Over a median echocardiography follow-up of 17 months, FUP_ EF increased by 1.3% (−4.0–8.0%) in the subgroup of BL-EF>35% and increased by 11.0% (2.0–20.0%) in the subgroup of BL_EF≤35%. Survival analysis showed that absolute change in EF was significantly associated with survival in the subgroup of BL_EF≤35% but not in the subgroup of BL_EF>35%. Therefore, further analysis was conducted among patients in the subgroup of BL_EF≤35%. In this subset of BL_EF≤35%, improved EF was defined as a FUP_EF of >40%. 171 (44.9%) patients presented with improved EF, EF remained unchanged or reduced in the rest 210 patients (55.1%, FUP_EF≤40%). Patients with improved EF was associated with better survival over a median clinical follow-up of 19 (11–32) months (80.7% vs. 68.1%, P=0.001). Multivariable Cox regression analysis showed that improved EF remained an independent determinant of overall survival after adjusted for potential clinical covariates including age, sex, diabetes, hyperuricemia, renal dysfunction, coronary artery bypass grafting, sleep-disordered breathing, and prior ICD or CRT_D implantation (HR 0.59, 95% CI 0.38–0.91, P=0.018). In this subgroup of BL_EF≤35%, age and sex-independent determinants of improved EF included without prior myocardial infarction (OR 0.40, 95% CI 0.24–0.67, P<0.001), without ICD or CRT-D implantation (OR 0.32, 95% CI 0.17–0.61, P=0.001), and smaller LV end-diastolic diameter (OR=0.94, 95% CI 0.90–0.99, P=0.012). Conclusions Longitudinal improvement in LVEF is significantly associated with survival benefit in the subgroup of baseline EF≤35% but not in the subgroup of baseline EF>35%. In the subgroup of baseline EF≤35%, improved LVEF remains an independent determinant of survival benefit Determinants of improved LVEF in HF patients with baseline EF≤35% include without myocardial infarction, without ICD implantation, and smaller LV chamber at baseline. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by the German Federal Ministry of Education and Research

The Impact of Age and Gender on Outcomes of Patients With Advanced Renal Cell Carcinoma Treated With Targeted Therapy.

A growing body of evidence suggests that age and gender play a role in cancer outcomes. The objective of this study was to investigate the effect of age and gender on survival of patients with metastatic renal cell carcinoma (RCC). We conducted a pooled analysis of patients with metastatic RCC treated on phase II and III clinical trials. Patients were stratified by age (young [<50 years], intermediate [50-70 years], versus elderly [>70 years]) and gender. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. We identified 4736 patients with metastatic RCC. Overall, there was no difference in overall survival (OS) when stratified by age (21.0 vs. 17.3 months for elderly vs. intermediate age groups, P= .382; 20.0 vs. 17.3 months for young vs. intermediate age groups, P= .155) or gender (19.8 vs. 19.0 for male vs. female, P= .510). Progression-free survival (PFS) was shorter in younger individuals compared with the intermediate age patients (6.0 vs. 7.1 months, P< .001), but similar across gender groups. Although all grade adverse events were more common in elderly patients (fatigue, diarrhea, decreased appetite, and weight), serious adverse events were similar between groups. Although OS was similar between age groups, younger individuals had a shorter PFS. Gender was not an independent determinant of survival. Elderly patients experienced more adverse events than their younger counterparts. These findings are important to guide clinicians when counseling patients about expectations and toxicity associated with therapy.

The Impact of Donor and Recipient Age: Older Lung Transplant Recipients Do Not Require Younger Lungs

Lung transplantation for patients with end-stage lung disease continues to grow worldwide. Increasing demand for this therapy generates significant waitlist mortality, indicating that alternative sources of donor lungs, such as older donors, are needed. The effect of the donor-recipient age relationship on outcomes remains unclear. A retrospective review of the United Network for Organ Sharing Standard Transplant Analysis and Research database was performed for adult lung recipients from 2005 to 2015. Variables examined included donor age, recipient age, listing diagnosis, episodes of acute cellular rejection in the first year, and survival. Both donors and recipients were stratified according to age ranges. Survival was compared with thelog-rank test. Propensity score matching was donestratifying donors younger than 60 years versus older than 60 years for the recipient population of 60 to69 years. From May 2005 to February 2015, 15,844 patients underwent lung transplantation. Unadjusted comparisons of donor-to-recipient age showed that older donor age appeared to be more relevant for recipients 60 to 69 years old (p= 0.002). Nevertheless, when propensity matching was done based on relevant covariates for recipients in this age range by donors younger or older than 60 years, there were no differences in survival. Our results suggest that even though donor and recipient age may be important in lung transplantation, the interplay between donor and recipient age alone is not an independent determinant of survival. Careful selection of lungs from donors older than 60 years old should be exercised, taking into consideration the totality of donor demographics and risk factors rather than dismissing lungs based on advanced age alone.

Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail.

The definition of resection margin (R) status in pancreatic cancer is under debate. Although a margin of at least 1 mm is an independent predictor of survival after resection for pancreatic head cancer, its relevance to pancreatic body and tail cancers remains unclear. This study aimed to validate R status based on a 1-mm tumour-free margin as a prognostic factor for resected adenocarcinoma involving the pancreatic body and tail. Patients who underwent distal or total pancreatectomy for adenocarcinomas of the pancreatic body and tail between January 2006 and December 2014 were identified from a prospective database. Resection margins were evaluated using a predefined cut-off of 1 mm. Rates of R0, R1 with invasion within 1 mm of the margin (R1 less than 1 mm), and R1 with direct invasion of the resection margin (R1 direct) were determined, and overall survival in each group assessed by Kaplan-Meier analysis. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival. R0 resection was achieved in 107 (23·5 per cent) and R1 in 348 (76·5 per cent) of 455 patients. Among R1 resections, invasion within 1 mm of the margin was found in 104 (22·9 per cent) and direct invasion in 244 (53·6 per cent). The R0 rate was 28·9 per cent after distal and 18·6 per cent after total pancreatectomy. In the total cohort, median survival times for patients with R0, R1 (less than 1 mm) and R1 (direct) status were 62·4, 24·6 and 17·2 months respectively, with 5-year survival rates of 52·6, 16·8 and 13·0 per cent (P < 0·001). In patients who received adjuvant chemotherapy, respective median survival times were 68·6, 32·8 and 21·4 months, with 5-year survival rates of 56, 22 and 16·0 per cent (P < 0·001). In multivariable analysis, R status was independently associated with survival. A cut-off of at least 1 mm for evaluation of resection margins is an independent determinant of survival after resection of adenocarcinomas of the pancreatic body and tail.

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

BackgroundMany factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.MethodsWe performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.ResultsBoth major histopathologic response (tumour regression grade TRG1–2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033).In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).ConclusionsThe histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

Liver transplant offers a survival benefit over margin negative resection in patients with small unifocal hepatocellular carcinoma and preserved liver function

BackgroundStudies comparing orthotopic liver transplantation to margin negative resection for patients with small unifocal hepatocellular carcinoma have not controlled for degree of cirrhosis. MethodsThe National Cancer Database was used to identify patients with preserved liver function (Model for End-stage Liver Disease score ≤12) who underwent orthotopic liver transplantation or margin negative resection for American Joint Committee on Cancer stage I hepatocellular carcinoma lesions <3 cm between 2010 and 2013. Multivariable and Cox regression adjusting for age, demographics, comorbid disease burden, Model for End-stage Liver Disease score, tumor size, and operation were used to compare overall survival between cohorts. ResultsIn the study, 241 (53%) patients underwent orthotopic liver transplantation. In addition, 219 (47%) underwent margin negative resection. On multivariable regression, patients having a Charlson comorbidity score ≥2 were more likely to undergo orthotopic liver transplantation, (odds ratio 1.94, P = .03). African American patients (odds ratio 0.44, P = .02), and patients of advanced age (odds ratio 0.92, P < .001) were more likely to undergo margin negative resection. Patients undergoing orthotopic liver transplantation had longer overall survival than those undergoing margin negative resection (median OS not reached versus 67.6 months, P < .001). Multivariable Cox regression identified surgical procedure as the only independent determinant of survival with margin negative resection conferring a nearly 3-fold increased risk of death (hazard ratio 2.86, P < .001). ConclusionOrthotopic liver transplantation offers a survival advantage relative to margin negative resection for patients with small unifocal hepatocellular carcinoma and preserved liver function.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Prognostic factors in malignant pleural mesothelioma: role of talc pleurodesis

To examine baseline characteristics associated with survival in patients with malignant pleural mesothelioma. 122 patients with histologically proven malignant pleural mesothelioma during the period 2000-2010 were studied. Survival was evaluated by the Kaplan-Meier method with the logrank test. Cox regression analysis was used to estimate the hazard ratios for possible prognostic factors. 105 (86%) patients had complete survival follow-up; 91 died and 14 (13.3%) were alive at the end of the observation period starting from the day of diagnosis. The median survival was 286 days (95% confidence interval: 212-359). Talc pleurodesis was performed in 59 patients, and 17 had surgical interventions (2 chest wall resections, 2 extrapleural pneumonectomies, and 13 decortications). Chemotherapy was used in 41 patients, port-site radiation in 68, and combined therapy in 26. Cox regression analysis identified talc pleurodesis (p=0.04), chemotherapy (p<0.001), port-site radiation (p<0.001), and combined chemotherapy and port-site radiation (p<0.006) as favorable prognostic factors after adjusting for age, sex, histologic subtype, smoking, and performance status. Surgical intervention including decortications and extrapleural pneumonectomy had no effect on survival in this series. Chemotherapy and radiation to port sites independently and in combination were associated with improved overall survival in malignant pleural mesothelioma patients. Talc pleurodesis was an independent determinant of survival, but further studies are warranted.

The effect of season of operation on the survival of patients with resected non-small cell lung cancer

Stage has been defined as the major prognostic factor in resected non-small cell lung cancer (NSCLC). However, there is some evidence that indicates season of operation could play a role in the survival of patients. Between January 1995 and June 2008, 698 (621 men and 77 women) patients who had undergone pulmonary resection for NSCLC were evaluated. Patients were analysed according to surgical-pathological stages and month of the year in which they were operated. Vitamin D receptor (VDR) polymorphism was also analysed in 62 patients. The median survival time in all patients was 60 ± 6 months (95% confidence interval (CI): 44-81 months). The survival of patients who underwent resection in winter was statistically significantly shorter than those operated in summer (P = 0.03). When patients were analysed according to T, N and season, resection time of the year was calculated to be an independent determinant of survival (P = 0.04). A VDR genotype was also associated with better prognosis (P = 0.04). Season of the operation, VDR polymorphism and N status seemed to have independent effects on survival of operated NSCLC patients.

Anaemia and heart failure

Abstract Anaemia is one of the most frequent co-morbidities in patients with heart failure. Its prevalence increases from 4% to7% in subjects with asymptomatic left ventricular dysfunction to &gt;30% in patients with severe heart failure. Renal insufficiency, activation of inflammatory mediators and treatment with renin-angiotensin antagonists seem to be its main determinants. The results of many studies agree in providing evidence that anaemia is a powerful independent determinant of survival in patients with heart failure. However, the mechanisms of this relation are still not fully understood. Moreover a favourable effect of the correction of anaemia on prognosis has not yet been shown. Also In addition to this, controlled studies assessing its effects on exercise tolerance have yielded controversial results. Further research is needed to assess the effect of correcting anaemia in chronic heart failure (CHF) patients; ongoing reduction of events with RED-HF (Darbepoetin alpha in heart failure) trial will help define the role.

Are Uterine Risk Factors More Important Than Nodal Status in Predicting Survival in Endometrial Cancer?

To evaluate factors associated with survival after lymphadenectomy for endometrial cancer and to address their effect relating to systemic therapy. This was a retrospective, population-based cohort study of 316 women with endometrial cancer who underwent surgery including lymphadenectomy in Ontario, Canada, from 1996-2000. Data obtained from administrative databases included comorbidities, socioeconomic status, grade, myometrial invasion, cervical involvement, lymphovascular-space invasion, nodal status, and adjuvant pelvic radiotherapy. Primary outcome was 5-year overall survival. Factors associated with survival were identified in a multivariable Cox proportional hazards model. Mean age was 62.2 years (+/-11.6 years). Thirty-eight women (12%) had positive pelvic nodes. Seventy-five (23.7%) received adjuvant pelvic radiotherapy. Age older than 60, grade 3 tumor, deep myometrial invasion (greater than 50%), and cervical stromal involvement were associated with a higher risk of death compared with reference categories. There were no survival differences according to comorbidities, socioeconomic status, or lymphovascular-space invasion. Five-year overall survival was 53.1% for node-negative patients with two or three uterine risk factors and 75.0% for node-positive patients with none or only one uterine risk factor. Pelvic-node status was not an independent determinant of survival (positive nodes: hazard ratio 1.39, 95% confidence interval 0.89-2.18). High-risk uterine factors including grade 3 tumor, deep myometrial invasion, and cervical stromal involvement are more significant determinants of survival in endometrial cancer than pelvic-node status. Uterine risk factors should be considered, regardless of nodal status, when offering systemic therapy to maximize survival outcomes. II.

Neighborhood socioeconomic status influences the survival of elderly patients with myelodysplastic syndromes in the United States

The potential role of socioeconomic status (SES) in the survival of patients with myelodysplastic syndromes (MDS) has not been evaluated. We conducted the first study to assess the prognostic role of neighborhood SES among a cohort of 2,118 patients (age >/= 66 years) who were diagnosed with incident MDS in the United States during 2001-2002. Principal component analysis was used to develop a summary SES score by combining multiple measures of neighborhood SES. The score was then used to classify the census tract each patient resided in into a category of high, medium, or low SES. Hazard ratios (HRs) were estimated using multivariate Cox proportional hazard models. After adjusting for age, gender, comorbidities, and histological subtypes, compared with MDS patients lived in high-SES census tracts, those resided in medium (HR = 1.14, 95% CI: 1.01-1.30) and low (HR = 1.17, 95% CI: 1.02-1.34) SES census tracts had significantly increased the risks of death. The impact of SES on survival was more apparent for patients with refractory anemia with ringed sideroblasts-patients residing in medium (HR = 1.85, 95% CI: 1.17-2.91) and low (HR = 2.06, 95% CI: 1.27-3.37) census tracts had a nearly two-fold increased the risk of mortality, compared with those living in high-SES census tracts. In conclusion, this population-based study suggests that neighborhood SES status is a significant and independent determinant of survival among elderly patients with MDS in the United States.

Diaphragm adaptations in patients with COPD

Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD.

The Side of Pneumonectomy Influences Long-Term Survival in Stage I and II Non-Small Cell Lung Cancer

The impact of pneumonectomy as an independent factor on long-term survival after lung resection for centrally or locally advanced non-small cell lung cancer (NSCLC) remains controversial. The aim of this paper is to study the impact of pneumonectomy, and the influence of side of surgery, on long-term survival in patients with pathologic stage I and II NSCLC. A retrospective review of a prospective multi-institutional database of patients operated on for lung cancer was undertaken. In all, 1,475 patients with pathologic stage I or II NSCLC were studied (421 underwent pneumonectomy; 1,054 had a lobectomy/bilobectomy). Survival and impact of side of surgery for pneumonectomy and lesser resection groups were analyzed and compared using the Kaplan-Meier method and the Cox proportional hazards model. Median survival was worse after pneumonectomy than after less extensive resections for patients overall (33 versus 57 months) and for those with stage I NSCLC (38 versus 70 months); however, median survival was better after pneumonectomy for stage II left tumors (55 versus 19 months). Pneumonectomy was an independent adverse determinant of survival for both stage I right tumors (p < 0.001) and stage I left tumors (p < 0.001), but was associated with improved survival for stage II left tumors (p = 0.009). Pneumonectomy was found to be an independent determinant of survival in patients with stage I and II NSCLC, but results differed for right- and left-sided tumors. Further studies of survival comparing pneumonectomy with lesser resections should differentiate between right and left procedures.

Diaphragm Muscle Fiber Dysfunction in Chronic Obstructive Pulmonary Disease

Inspiratory muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is of major clinical relevance; maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered of pathologic nature. Although the fiber-type shift toward oxidative type I fibers in COPD diaphragm is regarded as beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single-fiber level is associated with loss of myosin content. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. The current Pulmonary Perspective postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force-generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients do not appear to be limited in their daily-life activities. Therefore, investigating in vivo diaphragm function in mild to moderate COPD should be the focus of future research. Treatment of diaphragm dysfunction in COPD is complex because its etiology is unclear, but recent findings show promise for the use of proteasome inhibitors in syndromes associated with muscle wasting, such as the diaphragm in COPD.

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ET(A)R expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ET(A)R represents a new target in NPC treatment, we tested the therapeutic role of ET(A)R in NPC. Cell proliferation was inhibited by the ET(A)R-selective antagonist ABT-627 in two ET(A)R-positive NPC cells in a dose-dependent manner. Proliferation of ET(A)R-negative NPC cells was not decreased. ET(A)R blockade also resulted in sensitization to cisplatin and 5-fluorouracil-induced apoptosis. In nude mice, ABT-627 inhibited the growth of NPC cell xenografts. Combined treatment of ABT-627 with the cytotoxic drug cisplatin or 5-fluorouracil produced additive antitumor effects. The antitumor activity of ABT-627 was demonstrated finally on an experimental lung metastasis by a reduction in the number of tumors. These results support the rationale of combining ABT-627 with current standard chemotherapy to further improve the therapeutic ratio in the treatment of NPC.

Atrial fibrillation in dogs with and without structural or functional cardiac disease: A retrospective study of 109 cases

Objectives To determine if the heart rate and survival of dogs with atrial fibrillation (AF) varied amongst those: (1) without structural and functional disease (Group NoDz), (2) with structural or functional disease without pulmonary edema or ascites (Group DzNoF), and (3) with structural or functional disease with pulmonary edema or ascites (Group DzF). Animals, materials and methods The records of 109 dogs from the Veterinary Teaching Hospital of the University of Montreal ( n = 30) and the Cornell University Hospital for Animals ( n = 79) were examined. Results Large and giant breed dogs were most commonly affected (95.5%) with the Irish Wolfhound, Mastiff, Newfoundland, and Rottweiler overrepresented ( P < 0.01) in Group NoDz and the Irish Wolfhound, Boxer, English Sheepdog, Great Dane and Doberman Pincher overrepresented ( P < 0.01) in Groups DzNoF and DzF. Males (73.4%) were more commonly affected ( P < 0.001). Heart rate (mean ± SD) on presentation was different amongst the 3 groups of dogs ( P < 0.001) (Group NoDz: 120 ± 8.0 bpm, Group DzNoF: 155 ± 7.6 bpm, and Group DzF: 203 ± 6.2 bpm). Kaplan–Meier survival analysis revealed a longer survival for dogs in Group NoDz ( P = 0.006) and large and giant breeds ( P = 0.02). Initial heart rate could not be separated from diseased group as an independent determinant of survival. Conclusions Results suggest that dogs with AF and no demonstrable cardiac disease have a slower presenting heart rate and greater survival than dogs with structural disease with and without heart failure.

Outcomes Among Valvular Heart Disease Patients Experiencing Ischemic Stroke or Transient Ischemic Attack in Olmsted County, Minnesota

To estimate the rates and predictors of survival and recurrence among residents of Olmsted County, Minnesota, who received an Initial diagnosis based on 2-dimensional color Doppler echocardiography of moderate or severe mitral or aortic stenosis or regurgitation and who experienced a first ischemic stroke, transient ischemic attack (TIA), or amaurosis fugax. At the Mayo Clinic in Rochester, Minn, we used the resources of the Rochester Epidemiology Project to identify Individuals who met the criteria for inclusion in the study and to verify exclusion criteria. The study included all residents of Olmsted County, Minnesota, who experienced a first Ischemic stroke, TIA, or amaurosis fugax within 30 days of or subsequent to receiving a first-time 2-dimensional color Doppler echocardlography-based diagnosis of moderate or severe mitral or aortic stenosis or regurgitation between January 1, 1985, and December 31, 1992. The Kaplan-Meier product-limit method was used to estimate the rates of subsequent stroke and death after the ischemic stroke, TIA, or amaurosis fugax. The Cox proportional hazards model was used to assess the effect of several potential risk factors on subsequent stroke occurrence and death. For the 125 patients in the study, the Kaplan-Meier estimates of the risk of death and the risk of stroke at 2-year follow-up were 38.6% (95% confidence interval [CI], 29.9%-47.5%) and 18.5% (95% CI, 10.0%-27.0%), respectively. Compared with the general population, death rates were significantly Increased (standardized mortality ratio = 1.75; 95% CI, 1.38-2.19; P < .001) but rates of subsequent stroke occurrence were not (standardized morbidity ratio = 1.20; 95% CI, 0.75-1.84; P = .40). After adjustment for age, sex, and cardiac comorbidity, neither the type nor severity of valvular heart disease was an independent determinant of survival or subsequent stroke occurrence. Patients with mitral or aortic valvular heart disease who experience Ischemic stroke, TIA, or amaurosis fugax have Increased rates of death, but not recurrent stroke, compared with expected rates. Other cardiovascular risk factors are more important determinants of survival In these patients than the type or echocardiographic severity of the valvular heart disease.

Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis

All patients with organ dysfunction are currently classified as having severe acute pancreatitis. The aim of this study was to characterize the systemic inflammatory response syndrome (SIRS) and early organ dysfunction in patients with acute pancreatitis and the relationship with overall mortality. Patients with predicted severe acute pancreatitis of less than 48 h duration had daily organ dysfunction scores and SIRS criteria calculated. These features were then correlated with outcome. Of 121 patients, 68 (56 per cent) did not develop organ dysfunction; only two of these patients died (mortality rate 3 per cent). Fifty-three (44 per cent) had early organ dysfunction, of whom 11 died (21 per cent). Organ dysfunction and persistent SIRS were both associated with an increased mortality rate, but on multivariate analysis only deteriorating organ dysfunction was an independent determinant of survival. Early organ dysfunction in acute pancreatitis usually resolves and in itself has no significant influence on mortality. In contrast, worsening organ dysfunction was associated with death in more than half of the patients (11 of 20); it is this group of patients who should be classified as having severe acute pancreatitis.