Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

Size of metastatic deposits affects prognosis in patients undergoing pulmonary metastectomy for colorectal cancer.

INTRODUCTION: Pulmonary metastectomy for colorectal cancer (CRC) is a well accepted procedure although data regarding indications and prognostic outcomes are inconsistent. This study aimed to analyse our experience with resection of pulmonary CRC metastases to evaluate clinically relevant prognostic factors affecting survival. METHODS: A retrospective analysis was undertaken of the records of all patients with pulmonary metastases from CRC who underwent a thoracotomy between 2004 and 2010 at a single surgical centre. RESULTS: Sixty-six patients with pulmonary metastases from the colon (n=34) and the rectum (n=32) were identified. The 30-day hospital mortality rate was 0%, with 63 patients undergoing a R0 resection and 3 having a R1 resection. The median survival was 45 months and the cumulative 3-year survival rate was 61%. Size of pulmonary metastasis and ASA (American Society of Anesthesiologists) grade were statistically significant prognostic factors (p=0.047 and p=0.009 respectively) with lesions over 20mm associated with a worse prognosis. Sex, age, site, disease free interval (cut-off 36 months), primary tumour stage, hepatic metastases, number of metastases (solitary vs multiple), type of operation (wedge vs lobe resection), hilar lymph node involvement and administration of adjuvant chemotherapy were not found to be statistically significant prognostic factors. CONCLUSIONS: Pulmonary metastectomy has a potential survival benefit for patients with metastatic CRC. Improved survival even in the presence of hepatic metastases or multiple pulmonary lesions justifies aggressive surgical management in carefully selected patients. In our cohort, size of metastatic deposit was a statistically significant poor prognostic factor.

Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer.

BACKGROUND: This analysis compared the efficacy and safety outcomes by histology of nab-paclitaxel (nab-P) plus carboplatin (C) versus solvent-based paclitaxel (sb-P) plus C in patients with advanced non-small-cell lung cancer (NSCLC) based on preplanned stratification factors specified in the phase III trial protocol. PATIENTS AND METHODS: Patients with untreated stage III/IV NSCLC received 100 mg/m(2) nab-P weekly and C (area under the curve, AUC = 6) every 3 weeks (q3w) or 200 mg/m(2) sb-P plus C (AUC = 6) q3w. Primary end point was objective overall response rate (ORR). RESULTS: nab-P/C versus sb-P/C produced a significantly higher ORR (41% versus 24%; response rate ratio [RRR] 1.680; P < 0.001) in patients with squamous cell (SCC) NSCLC. For nab-P/C versus sb-P/C, ORRs were 26% versus 27% (RRR 0.966; P = 0.814) in patients with adenocarcinoma, 33% versus 15% (RRR 2.167; P = 0.323) in patients with large cell carcinoma (LC), and 24% versus 15% (RRR 1.593; P = 0.372) in patients with not otherwise specified histology. Median overall survival for nab-P/C versus sb-P/C in patients with SCC was 10.7 versus 9.5 months (HR 0.890; P = 0.310), and 12.4 versus 10.6 months (HR 1.208; P = 0.721) for patients with LC. nab-P/C produced significantly (P < 0.05) less grade 3/4 neuropathy and arthralgia, whereas sb-P/C produced less thrombocytopenia and anemia. CONCLUSION(S): First-line nab-P/C demonstrated a favorable risk-benefit profile in patients with NSCLC regardless of histology.

Safety and efficacy of weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer.

BACKGROUND: This analysis evaluates safety and efficacy in elderly (≥ 70 years old) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer (NSCLC) trial. PATIENTS AND METHODS: Untreated stage IIIB/IV patients with PS 0/1 were randomly assigned (1:1) to carboplatin AUC6, day 1 every 3 weeks, and either nab-paclitaxel (Abraxane) 100 mg/m(2) weekly (nab-P/C) or solvent-based paclitaxel (Taxol) 200 mg/m(2) day 1 every 3 weeks (sb-P/C). The primary end-point was overall response rate (ORR). RESULTS: Fifteen percent of 1052 enrolled patients were elderly: nab-P/C, n = 74; sb-P/C, n = 82. In both age cohorts, the ORR was higher with nab-P/C versus sb-P/C (age ≥ 70: 34% versus 24%, P = 0.196; age <70: 32% versus 25%, P = 0.013). In elderly patients, progression-free survival (PFS) trended in favor of nab-P/C (median 8.0 versus 6.8 months, hazard ratio (HR) 0.687, P = 0.134), and overall survival (OS) was significantly improved (median 19.9 versus 10.4 months, HR 0.583, P = 0.009). In younger patients, PFS (median 6.0 versus 5.8 months, HR 0.903, P = 0.256) and OS (median 11.4 versus 11.3 months, HR 0.999, P = 0.988) were similar in both arms. Adverse events were similar in both age groups, with less neutropenia (P = 0.015), neuropathy (P = 0.001), and arthralgia (P = 0.029), and increased anemia (P = 0.007) with nab-P/C versus sb-P/C. CONCLUSIONS: In elderly NSCLC patients, nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS, with substantially longer OS versus sb-PC.

The LLP risk model: an individual risk prediction model for lung cancer.

Using a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period. Data from 579 lung cancer cases and 1157 age- and sex-matched population-based controls were available for this analysis. Significant risk factors were fitted into multivariate conditional logistic regression models. The final multivariate model was combined with age-standardised lung cancer incidence data to calculate absolute risk estimates. Combinations of lifestyle risk factors were modelled to create risk profiles. For example, a 77-year-old male non-smoker, with a family history of lung cancer (early onset) and occupational exposure to asbestos has an absolute risk of 3.17% (95% CI, 1.67-5.95). Choosing a 2.5% cutoff to trigger increased surveillance, gave a sensitivity of 0.62 and specificity of 0.70, while a 6.0% cutoff gave a sensitivity of 0.34 and specificity of 0.90. A 10-fold cross validation produced an AUC statistic of 0.70, indicating good discrimination.If independent validation studies confirm these results, the LLP risk models' application as the first stage in an early detection strategy is a logical evolution in patient care.

Randomized clinical trial to determine the effect of nasogastric drainage on tracheal acid aspiration following oesophagectomy.

BACKGROUND: The aim of this study was to investigate tracheal acid aspiration after oesophagectomy and to determine whether it is influenced by nasogastric (NG) drainage. METHODS: Thirty-four patients undergoing oesophagectomy were randomized to one of three methods of NG drainage: a single-lumen tube with free drainage and 4-hourly aspiration, a sump-type tube on continuous suction drainage, or no NG tube. A tracheal pH probe was used to collect information on acid aspiration for 48 h after surgery. A pH < 5.5 was considered abnormal (normal pH 6.8-7.2). Total time with tracheal pH < 5.5, number of reflux episodes and longest reflux time were compared between groups. RESULTS: There was significant and persistent tracheal acid aspiration in all patients. Patients with a sump-type tube had a significantly shorter total time with tracheal pH < 5.5 than those in the other groups (sump-type tube versus single-lumen tube, P = 0.0069; sump-type tube versus no tube, P = 0.0071). Patients randomized to no NG tube experienced more respiratory complications after surgery than those who had either single-lumen or sump-type tubes (seven of 12 versus four of 22 patients; P = 0.023). Insertion of a NG tube was necessary in the first week after surgery in seven of 12 patients in this group. CONCLUSION: Routine NG drainage after oesophagectomy is necessary. A sump-type NG tube is better at preventing tracheal acid aspiration and may reduce the incidence of respiratory complications.

Effect of training on patient outcomes following lobectomy.

BACKGROUND: Little is known about the effect of surgical training on outcomes in thoracic surgery. The impact of surgeon training on outcomes following lung resection was examined, focusing on lobectomy as a marker operation. METHODS: 328 consecutive patients who underwent lobectomy at our institution between 1 October 2001 and 30 June 2003 were studied. Data were collected prospectively during the patient's admission as part of routine clinical practice and validated by a designated audit officer. Patient characteristics and postoperative outcomes were compared between trainee led and consultant led operations. RESULTS: In 115 cases (35.1%) the operation was performed by a trainee thoracic surgeon as the first operator. There were no significant differences in patient characteristics between the two groups. In-hospital mortality was similar for operations led by trainees and consultants (3.5% and 2.8%, respectively; p > 0.99). Outcomes in the two groups did not differ significantly with respect to respiratory, cardiovascular, renal, neurological, chest infection, bleeding, and gastrointestinal complications. Survival rates at 1 year were 82.6% for procedures led by trainees compared with 81.7% for procedures led by consultants (p = 0.83). CONCLUSIONS: With appropriate supervision, trainee thoracic surgeons can perform lobectomies safely without compromising short or intermediate term patient outcome.

Preventing of chylothorax after oesophagectomy by routine pre-operative administration of oral cream.

The anatomy of the thoracic duct varies considerably. This can make it difficult to locate during oesophageal surgery, especially in the fasted patient. We describe the technique of administering cream orally before primary oesophageal surgery, to aid in the identification of the thoracic duct. The duct along with other lymphatic channels can then be ligated as appropriate, helping to reduce the incidence of post-operative chylothorax.

Primary hepatic lymphoma: favorable outcome after combination chemotherapy.

BACKGROUND: Primary hepatic non-Hodgkin lymphoma (PHL) is a rare and difficult to diagnose lymphoproliferative disorder of unknown etiology. It is believed that the prognosis in affected patients is dismal, consisting of early recurrence and short survival. METHODS: A retrospective cohort review of patients with PHL diagnosed between 1974 and 1995 at a university cancer center was performed. RESULTS: Twenty-four patients with PHL were identified. Typically, the disease occurred in middle-aged men (median age, 50 years). The primary presenting complaint was right upper quadrant abdominal pain, with hepatomegaly found at physical examination. Serum liver enzymes, lactate dehydrogenase, and beta-2-microglobulin levels all were elevated, but alpha-fetoprotein and carcinoembryonic antigen levels were within normal range. Hypercalcemia was found in 6 of 15 patients who were tested. Six of 10 patients who were tested were positive for the hepatitis C virus (HCV). Liver scans demonstrated either a solitary lesion or multiple lesions. Pathologic examination revealed diffuse large cell lymphoma in 23 patients (96%). Combination chemotherapy was the mainstay of treatment; surgery consisted of diagnostic biopsy. The complete remission rate was 83.3%, and the 5-year cause specific and failure free survival rates were 87.1% and 70.1%, respectively. HCV infection did not appear to influence the outcome of therapy. CONCLUSIONS: The outcome of patients with PHL who are treated with combination chemotherapy may be more favorable than that reported elsewhere. The frequent association of PHL with HCV infection observed in this series warrants further investigation.

Scapular osteochondroma with reactive bursitis presenting as a chest wall tumour.

A 32-year-old male presented with a painful, rapidly enlarging chest wall mass. A malignant chest wall neoplasm was suspected. A CT scan was performed which showed a mass extending from under the scapular and an exostosis arising from the anterior surface of the scapular. The mass and exostosis were resected resulting in complete resolution of symptoms. Histological examination showed the mass to be a reactive bursa, with no evidence of neoplasia.

From gene to organismal phylogeny: reconciled trees and the gene tree/species tree problem.

The processes of gene duplication, loss, and lineage sorting can result in incongruence between the phylogenies of genes and those of species. This incongruence complicates the task of inferring the latter from the former. We describe the use of reconciled trees to reconstruct the history of a gene tree with respect to a species tree. Reconciled trees allow the history of the gene tree to be visualized and also quantify the relationship between the two trees. The cost of a reconciled tree is the total number of duplications and gene losses required to reconcile a gene tree with its species tree. We describe the use of heuristic searches to find the species tree which yields the reconciled tree with the lowest cost. This method can be used to infer species trees from one or more gene trees.

Stapler design and strictures at the esophagogastric anastomosis.

An apparent reduction in the rate of benign anastomotic stricture after stapled esophagogastrectomy prompted us to review the results obtained with different stapling devices since 1988. We present a retrospective review of 125 consecutive patients undergoing esophageal resection for malignancy with stapled intrathoracic anastomoses. Benign anastomotic stricture was deemed present when a patient required endoscopic dilatation to treat postoperative dysphagia. We found no difference in risk factors not related to stapler size (tumor histologic characteristics, adjuvant therapy) between patients with stricture and patients without stricture. Event-free survival was compared for different stapler diameters as well as for different stapler designs. We found that staplers of smaller diameter were associated with significantly more strictures (p < 0.005). In a comparison of different designs of 25 mm stapler, the newer CDH device (Ethicon Ltd., Edinburgh, United Kingdom) was associated with a similar stricture rate to that associated with other designs (ILP [Ethicon] and EEA [Autosuture Company Division, United States Surgical Corp., Norwalk, Conn.]). For a given stapler diameter, it appears that different stapler designs have no effect on stricture rate.

Evidence that continuous normothermic blood cardioplegia offers better myocardial protection than intermittent hypothermic cardioplegia.

OBJECTIVES: To compare transmyocardial ischaemia and oxidative stress, as well as non-infarction myocardial injury, in patients randomised to intermittent hypothermic cardioplegia or continuous normothermic blood-potassium cardioplegia. DESIGN: Prospective randomised trial. SETTING: Tertiary cardiac referral centre. METHODS: 24 patients undergoing elective coronary artery bypass surgery were randomised to hypothermic (13 patients, mean (SEM) age 59.5 (2.6) years) or normothermic (11 patients, mean (SEM) age 59.7 (3.3) years) cardioplegia. Transmyocardial oxidative stress and ischaemia were assessed by the difference in plasma concentrations of oxidised glutathione and lactate respectively, from samples taken simultaneously from the coronary sinus and aortic root. Blood samples were taken just before cross clamp application and at intervals up to 15 min after cross clamp release. Non-infarction myocardial injury was assessed by measurement of creatine kinase MB isoenzyme activity from peripheral venous blood taken 2 and 18 h after surgery. RESULTS: Intermittent hypothermic cardioplegia resulted in a significant increase in transmyocardial ischaemia (P < 0.001) and oxidative stress (P < 0.001). Evidence of significantly increased myocyte damage was also present (P < 0.01). No significant corresponding changes were present with normothermic cardioplegia. CONCLUSIONS: Normothermic blood cardioplegia seems to avoid significant changes in myocardial ischaemic status and consequent oxidative stress. This study provides direct evidence that normothermic cardioplegia offers enhanced myocardial protection compared with that of hypothermic cardioplegia. Certain subsets of patients may derive more benefit from normothermic cardioplegia, although it is unclear whether this would be the case for all patients.

Continuous warm versus intermittent cold blood cardioplegia for coronary bypass surgery in patients with left ventricular dysfunction.

Between October 1991 and March 1994, 108 consecutive patients with moderate to severe left ventricular dysfunction underwent non-emergency isolated coronary artery surgery under the care of one surgeon (A.R.). They were prospectively randomised to receiving either intermittent cold (Group 1-50 patients) or continuous warm (Group 2-58 patients) blood cardioplegia for myocardial protection. There were no significant differences in clinical outcome between the two groups, as judged by operative mortality, rates of perioperative myocardial infarction, the serum CKMB isoenzyme level at 2 and 18 h after operation, need for circulatory support, postoperative neurological deficit, or duration of hospital stay. Group 2 patients required significantly more potassium (68 vs 29 mmol, P < 0.001) to maintain diastolic arrest and also had higher serum potassium levels after removal of the cross-clamp (P < 0.001). However, sinus rhythm returned spontaneously with greater frequency (91.2% vs 45.8%, P < 0.001) in Group 2 patients. In conclusion this report suggests that retrograde continuous warm blood cardioplegia provides comparable myocardial protection to that achieved with retrograde intermittent cold blood cardioplegia in patients with moderate to severe left ventricular dysfunction undergoing isolated coronary artery surgery.