The impact of the 'hub and spoke' model of care for lung cancer and equitable access to surgery.

OBJECTIVES: To determine the influence of where a patient is first seen (either surgical or non-surgical centre) and patient features on having surgery for non-small cell lung cancer (NSCLC). DESIGN: Cross-sectional study from individual patients, between 1January 2008 and 31March 2012. SETTING: Linked National Lung Cancer Audit and Hospital Episode Statistics datasets. PARTICIPANTS: 95,818 English patients with a diagnosis of NSCLC, of whom 12,759 (13%) underwent surgical resection. MAIN OUTCOME MEASURE: Odds of having surgery based on the empirical catchment population of the 30 thoracic surgical centres in England and whether the patient is first seen in a surgical centre or a non-surgical centre. RESULTS: Patients were more likely to be operated on if they were first seen at a surgical centre (OR 1.37; 95% CI 1.29 to 1.45). This was most marked for surgical centres with the largest catchment populations. In these surgical centres with large catchment populations, the resection rate for local patients was 18% and for patients first seen in a non-surgical centre within catchment was 12%. CONCLUSIONS: Surgical centres that serve the largest catchment populations have high resection rates for patients first seen in their own centre but, in contrast, low resection rates for patients first seen at the surrounding centres they serve. Our findings demonstrate the importance of going further than relating resection rates to hospital volume or surgeon number, and show that there is a pressing need to design lung cancer services which enable all patients, including those first seen at non-surgical centres, to have equal access to lung cancer surgery.

Utility of an immune cell function assay to differentiate rejection from infectious enteritis in pediatric intestinal transplant recipients.

The Cylex Immune Cell Function Assay measures cell-mediated immunity based on ATP production by stimulated CD4 + cells. We hypothesized that this test would discriminate acute cellular rejection (ACR) from infectious enteritis (IE) in pediatric intestinal transplant (ITx) recipients with allograft dysfunction. We retrospectively analyzed 224 Cylex assays drawn in 47 children who received 53 ITx. Samples were classified as stable, ACR, or IE based on clinical status. ATP values were analyzed using Kruskal-Wallis and t-tests. Overall, there was a statistically significant difference in ATP values based on clinical status (p = 0.03); however, overlap was observed between groups. The median ATP value during ACR was significantly greater than during stable periods (p = 0.02). No difference was seen in IE vs. stability (p = 0.8). The difference in median ATP value in ACR vs. IE approached significance (p = 0.1). Relative to previous levels, ACR episodes were associated with a median ATP increase of 101 ng/mL and IE episodes with a decrease of 3 ng/mL (p = 0.3). These data indicate that the Cylex assay has limited utility in differentiating ACR from IE, largely due to interpatient variability. Following longitudinal intrapatient trends may be an adjunctive tool in discriminating IE from ACR and guiding immunosuppression adjustments in select patients.

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

Long-term patient outcome and quality of life after liver transplantation: analysis of 20-year survivors.

OBJECTIVE: To evaluate patient survival and allograft function and health-related quality of life (HRQOL) 20 years after orthotopic liver transplantation (LT). SUMMARY OF BACKGROUND DATA: Although LT is the established treatment of choice for acute and chronic liver failure, allograft function and recipient HRQOL 20 years after LT remain undefined. METHODS: We performed a prospective, cross-sectional study of LT recipients surviving 20 years or more. Clinical data were reviewed to identify factors associated with 20-year survival. Survivors were directly contacted and offered a survey to assess HRQOL (SF-36; Liver Disease Quality of Life), social support, and cognition (Neuropsychological Impairment Scale). Logistic regression analysis was performed to identify clinical factors influencing HRQOL 20 years after LT. RESULTS: Between February 1, 1984 and December 31, 1988, a total of 293 patients (179 adults, 114 children) received 348 LTs. Of the 293 patients, 168 (56%) survived for 20 years or more. Actuarial 20-year survival was 52% (patient) and 42% (graft). Factors associated with 20-year survival included recipient age <18 (P = 0.01), nonurgent LT (P = 0.01), no retransplantation (0.02), female gender (0.03), absence of biliary complications (P = 0.04), and short total ischemia time (P = 0.05). Rejection episodes were seen in a greater proportion of 20-year survivors than in nonsurvivors (35% vs. 27%; P = 0.3). Of the 168 survivors, 87 were contacted, and 68 (78%) completed the HRQOL surveys. Compared with the general population, survivors had lower physical scores (P < 0.01) but comparable mental scores on the SF-36. Overall HRQOL was significantly better in 20-year survivors than in patients with chronic liver disease, congestive heart failure, or diabetes. Clinical factors associated with improved post-LT HRQOL were younger age at LT, allograft longevity, and strong social support. More than 90% of pediatric survivors completed high school. After LT, 34% of pediatric recipients married, and 79% remained married at 20 years' follow-up. CONCLUSIONS: More than 50% of LT recipients survive 20 years, achieve important socioeconomic milestones, and report quality of life superior to patients with liver disease or other chronic conditions. LT is a durable surgery that restores both long-term physiologic and psychologic well-being in patients with end-stage liver disease.

Survival in Asian Americans after treatments for hepatocellular carcinoma: a seven-year experience at UCLA.

BACKGROUND/RATIONALE: Hepatocellular carcinoma (HCC) is a common malignancy in Asians and is related to the high incidence of chronic viral hepatitis in this ethnic population. The aims of this study were to examine the tumor characteristics and liver disease status in HCC patients of Asian ancestry and determine their survival after treatments for HCC. RESULTS: Between September 2000 and December 2007, 278 patients, mean age 61.5 years, presented with HCC to the University of California Los Angeles (UCLA) Liver Cancer Center. Hepatitis B (HBV) infection was detected in up to 68% of Chinese, Korean, and Vietnamese patients, whereas 60% of Japanese patients had Hepatitis C (HCV) infection. Compared with HCC patients who presented with symptoms, those detected by surveillance had more tumors within the Milan and University of California, San Francisco (UCSF) criteria and more patients in Child-Turcotte-Pugh class A. On the basis of a predefined UCLA treatment algorithm, 83% of patients received surgical and/or loco-regional therapies. Compared with other treatments, orthotopic liver transplantation (OLT), and radiofrequency ablation had the highest overall patient survival (P<0.0001) and OLT has the highest disease free survival rates (P<0.0001). Independent baseline predictors for: (1) patient survival were HBV [hazard ratio (HR) 0.62, P=0.005], UCSF criteria (HR 0.46, P<0.0001), Child Turcotte Pugh class A (HR 0.57, P=0.005), alphafetoprotein per log10 increase (HR 1.26, P=0.0012), and alkaline phosphatase per log10 increase (HR 2.32, P=0.02); and for (2) disease free survival were UCSF criteria (HR 0.66 P=0.007), aspartate aminotransferase per log10 increase (HR 1.50, P=0.04), and age per year increase (HR=1.02, P=0.04). The 4 Asian subgroups had similar survival rates. CONCLUSIONS: HBV and Hepatitis C were associated with over 90% of HCC cases in Asian Americans. HCC detected by surveillance identified more patients eligible for surgical and loco-regional therapies, which improved the overall and disease free survival.

A novel chemotype of kinase inhibitors: Discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors.

Pictet-Spengler condensation of aldehydes or alpha-keto-esters with 4-(2-anilinophenyl)-7-azaindole (11) or deazapurine (12) gave high yields of the 3,4-fused cyclic compounds. SAR studies, by varying the substituted benzaldehyde components, lead to the discovery of a series of potent JAK2 kinase inhibitors.

Ileostomy After Intestinal Transplantation: The First in Depth Report on Techniques, Complications, and Outcomes.

BACKGROUND: Temporary ileostomy during intestinal transplantation (ITx) is the standard technique for allograft monitoring. A detailed analysis of the ITx ileostomy has never been reported. METHODS: A retrospective review of a single-center ITx database was performed. The analysis was divided into ileostomy formation and takedown episodes. RESULTS: One hundred thirty-five grafts underwent ileostomy formation, and 79 underwent ileostomy takedown. Median age at ITx was 7.7 years and weight was 23 kg. Allograft types were intestine (22%), liver/intestine (55%), multivisceral (16%), and modified multivisceral (7%). Sixty-four percent had 1-stage ITx, whereas 36% required 2-staged ITx. Final ileostomy types were end (20%), loop (10%), distal blowhole (59%), and proximal blowhole (11%). Ileostomy formation: Thirty-one grafts had complications (23%), including prolapse (26%), ischemia (16%), and parastomal hernia (19%). Twelve required surgical revision. There were no significant differences in graft type, ileostomy type, survival, and ileostomy takedown rate between grafts with and without complications. Colon inclusive grafts had higher complication rates (P = 0.002). Ileostomy takedown: Ileostomy takedown occurred at a median of 422 days post-ITx. Twenty-five complications occurred after 22 takedowns (28%), including small bowel obstruction (27%) and abscess (18%). Fifteen grafts required surgical correction. Recipients with complications had longer hospital stay (17 versus 9 d; P = 0.001) than those without complications. Graft type, ileostomy type, and survival were not different. CONCLUSIONS: The first of its kind analysis of the surgical ileostomy after ITx reveals that most recipients can undergo successful ileostomy formation/takedown, complication rates are significant but within an acceptable range, and complications do not affect survival. This study demonstrates that the routine use of transplant ostomies remains an acceptable practice after ITx. However, true analysis of risk and benefit will require a randomized control trial.

Fulminant hepatic failure in children: superior and durable outcomes with liver transplantation over 25 years at a single center.

OBJECTIVE(S): Death occurs in half of all children with fulminant hepatic failure (FHF). Although liver transplantation (LT) is potentially life-saving, there are only a few published series with limited experience. The aim was to examine predictors of survival after LT for FHF. METHODS: Between 1984 and 2008, all LT for FHF performed in recipients less than or equal to 18 years of age were analyzed from a prospectively maintained database using 35 demographic, laboratory, and operative variables. Unique calculated variables included creatinine clearance (cCrCl) and Pediatric End-Stage Liver Disease score (PELD). Study end-points were patient and death censored graft survival. Median follow-up was 98 months. Statistical analysis involved the log-rank test and Cox proportional hazards model. RESULTS: A total of 122 children underwent 159 LTx. Cryptogenic was the primary etiology (70%) and the median age was 53 months. The significant (P < 0.05) univariate predictors of worse graft survival were: recipient age <24 months, cCrCl <60 mL/min/1.73m, PELD >25 points, and warm ischemia time >60 minutes. The significant (P < 0.05) univariate predictors of worse patient survival were: recipient African-American and Asian race, recipient age <24 months, cCrCl <60 mL/min/1.73m, and time from onset jaundice to encephalopathy <7 days. On multivariate analysis, survival was significantly impacted by 4 variables: cCrCl <60 mL/min/1.73m (GRAFT and PATIENT), PELD >25 points (GRAFT), recipient age <24 months (GRAFT), and time from onset jaundice to encephalopathy <7 days (PATIENT). While overall 5- and 10-year survival was 73% and 72% (GRAFT) and 77% and 73% (PATIENT), these were significantly worse when a combination of multivariate risk-factors were present. CONCLUSIONS: This data from a large, single-center experience demonstrates that LT is the treatment of choice for FHF and results in durable survival. Analysis revealed 4 novel outcome predictors. Young children with rapid onset acute liver failure are a high-risk subpopulation. Unique to this study, cCrCl and PELD accurately predicted the end-points. This analysis identifies patient subpopulations requiring early aggressive intervention with LT.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Residual apical space following surgery for pneumothorax increases the risk of recurrence.

OBJECTIVE: Residual air spaces on chest radiographs after pneumothorax surgery are not uncommon. We aimed to study their incidence and impact on surgical outcomes. METHODS: Four hundred and twenty-seven patients [283 men and 144 women with a median age of 31 (14-96) years] underwent surgery for pneumothorax from 1995 to 2005 in a single unit. Video-assisted thoracoscopy was used in 225 cases (53%). Outcomes were: duration of intercostal drainage and hospital stay, recurrence, re-operation and referral to chronic pain clinic. RESULTS: Median duration of intercostal drainage and hospital stay were 5 and 6 days, respectively. We found a recurrence rate of 6.6% (n=28), re-operation rate of 2.8% (n=12) and need for referral to pain clinic of 7% (n=30). In 129 patients (30%) a small residual apical space (RAS) was reported on chest radiograph prior to discharge. Hospital stay and duration of drainage were longer in these cases (p=0.002 and 0.02, respectively). On multivariate analysis RAS on chest radiograph was associated with increased risk of recurrence [hazard ratio 3.1 (1.4-6.8 95% CI)] (p=0.005); but no need for re-operation or referral to pain clinic. Re-operation was associated with VATS surgery (p=0.001) and when no abnormalities were identified at operation (p=0.04). Referral to pain clinic was more common after open surgery (p=0.01). DISCUSSION: The risk of recurrence after pneumothorax surgery is low. But the presence of a residual apical space on chest radiography after surgery increases it significantly. Recurrence may be due to the failure to achieve early pleural symphysis.