Anaesthetic and perioperative considerations for extrapleural pneumonectomy and extended pleurectomy/decortication: a scoping review protocol.

INTRODUCTION: Extrapleural pneumonectomy (EPP) and extended pleurectomy/decortication (ePD) are surgical cytoreductive techniques aimed at achieving macroscopic resection in malignant pleural tumours such as pleural mesothelioma, non-mesothelioma pleural malignancies such as thymoma and sarcoma, and rarely for pleural tuberculosis, in a more limited fashion. Despite extensive studies on both surgical techniques and consequences, a significant knowledge gap remains regarding how best to approach the perioperative anaesthesia challenges for EPP and ePD.It is unknown if the risk stratification processes for such surgeries are standardised or what types of functional and dynamic cardiac and pulmonary tests are employed preoperatively to assist in the perioperative risk stratification. Further, it is unknown whether the types of anaesthesia and analgesia techniques employed, and the types of haemodynamic monitoring tools used, impact on outcomes. It is also unknown whether individualised haemodynamic protocols are used to guide the rational use of fluids, vasoactive drugs and inotropes.Finally, there is a dearth of evidence regarding how best to monitor these patients postoperatively or what the most effective enhanced recovery protocols are to best mitigate postoperative complications and accelerate hospital discharge. To increase our knowledge of the perioperative and anaesthetic treatment for patients undergoing EPP/ePD, this scoping review attempts to synthesise the literature and identify these knowledge gaps. METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Review Protocols methodology. Electronic databases, OVID Medline, EMBASE and the Cochrane Library, will be systematically searched for relevant literature corresponding to EPP or ePD and perioperative or anaesthetic management. Data will be analysed and summarised descriptively and organised according to the three perioperative stages: preoperative, intraoperative and postoperative factors in clinical care. ETHICS AND DISSEMINATION: Ethics approval was not required. The findings will be disseminated through professional networks, conference presentations and publications in scientific journals.

Strategies for the Management of Solitary Pulmonary Nodules: A Survey of Patient Preferences.

BACKGROUND: Guideline-based strategies for evaluation of solitary pulmonary nodules are tailored to the likelihood of malignancy. Surveillance, biopsy, and resection are all reasonable approaches in fit individuals when the likelihood of malignancy is intermediate. Given the paucity of data demonstrating superior outcomes and important trade-offs among strategies, guidelines emphasize the importance of eliciting patient preferences and engaging in shared decision making; however, there is little literature on what patient preferences actually are. METHODS: This study conducted a cross-sectional, interview-administered questionnaire survey in 100 adults recruited from a metropolitan teaching hospital (The Royal Melbourne Hospital, Parkville, Victoria, Australia). The questionnaire used a hypothetical scenario designed to elicit patient preferences for different management strategies of solitary pulmonary nodules with a probability of malignancy between 10% and 70%. RESULTS: The mean age of participants was 62 years (range, 45 to 80 years), 56% were male, and 94% were current smokers or ex-smokers. Ninety-four percent completed all questions. At 10% probability of malignancy, 36.3% preferred surveillance, 42.4% preferred needle biopsy, and 21.2% preferred surgical resection. Preference for surgical resection increased to 53.5% and 86.2% when the probability of malignancy was 30% and 70%, respectively. Changes in the diagnostic yield of computed tomography biopsy significantly altered preferences when the probability of malignancy was 10% or 30%. CONCLUSIONS: The majority of participants surveyed expressed a preference for some type of biopsy over observation at all levels of solitary pulmonary nodule probability of malignancy evaluated. In an era of increasing solitary pulmonary nodule detection and patient-centered care, if confirmed in broader studies, these findings have considerable implications for processes of care and resource allocation.

Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer.

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.

Correlation between molecular analysis, diagnosis according to the 2015 WHO classification of unresected lung tumours and TTF1 expression in small biopsies and cytology specimens from 344 non-small cell lung carcinoma patients.

We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC.

Gallium-68 perfusion positron emission tomography/computed tomography to assess pulmonary function in lung cancer patients undergoing surgery.

BACKGROUND: Pre-operative evaluation of lung cancer patients relies on calculation of predicted post-operative (PPO) lung function based on split lung function testing. Pulmonary perfusion (Q) PET/CT can now be performed by substituting Technetium-99 m labeling of macroaggregated albumin (MAA) with Gallium-68. This study compares Q PET/CT with current recommended methods of pre-operative lung function assessment. METHODS: Twenty-two patients planned for curative surgical resection (mean FEV1 77 %, SD 21 %; mean DLCO 66 %, SD 17 % predicted) underwent pre-operative Q PET/CT. Sixteen patients also underwent conventional lung scintigraphy. Lobar and lung split PPO lung function were calculated using Q PET/CT and current recommended methods, i.e. calculation based on anatomical segments for lobar function, and conventional perfusion scan for pneumonectomy. Bland-Altman statistics were used to calculate agreement between methods for PPO FEV1 and PPO DLCO. RESULTS: While mean split lobar functions were comparable, there was variation on an individual level between Q PET/CT and the anatomical method, with absolute difference over 5 % and 10 % in 37 % and 11 % of patients, respectively. For lobectomy the mean difference in PPO FEV1 was-1.2, but limits of agreement were-10 to 8.1 %. For DLCO, values were-1.1 % and-9.7 to 7.5 %, respectively. For pneumonectomy, PPO FEV1 values were-0.4 and-5.9 to 5.1 %. For DLCO, values were 0.3 % and-5.1 to 4.6 %. CONCLUSIONS: While anatomic estimation provides "fixed" results, split lobar functions computed with Q PET/CT vary widely, reflecting the intra and inter-individual variability of regional lung function. Further studies to assess the role of Q PET/CT in predicting peri-operative risk in lung cancer patients planned for lobectomy are warranted.

Utility of Routine PET Imaging to Predict Response and Survival After Induction Therapy for Non-Small Cell Lung Cancer.

BACKGROUND: Data from clinical trials suggest that changes in the glucose avidity of the primary site of lung cancer during induction therapy, measured by changes in (18)F-fluorodeoxyglucose positron emission tomography, correlate with tumor response. Little information about the utility of changes in positron emission tomography imaging of involved lymph nodes during induction chemotherapy is available. The utility of positron emission tomography imaging of either the primary site or nodal metastases, obtained during routine clinical care outside of a clinical trial setting, to predict response has also not been examined. METHODS: A retrospective review of all surgical patients with non-small cell lung cancer at a single institution imaged between 2000 and 2006 with (18)F-fluorodeoxyglucose positron emission tomography before or after induction therapy was performed. RESULTS: An increase in standardized uptake value in the primary site of disease during induction therapy was associated with reduced overall survival after resection. Neither pretreatment standardized uptake value nor percentage change in the primary site was associated with overall survival after resection. A decrease in standardized uptake value of greater than 60% in the involved N2 mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary site of disease. CONCLUSIONS: An increase in glucose avidity of non-small cell lung cancers during induction therapy was associated with a worse prognosis compared with stable or any decrease in standardized uptake value. Changes in the glucose avidity of mediastinal nodal metastases may be a stronger predictor of survival than changes in the primary site of disease.

Respiratory-gated (4D) FDG-PET detects tumour and normal lung response after stereotactic radiotherapy for pulmonary metastases.

BACKGROUND: Response assessment after stereotactic ablative body radiotherapy (SABR) in lung can be confounded by radiation-induced inflammation, fibrosis and subsequent alteration of tumour motion. The purpose of this prospective pilot study was to evaluate the utility of four-dimensional (4D) FDG-PET/CT for post-SABR tumour and normal lung response assessment in pulmonary oligometastases. MATERIAL AND METHODS: Patients enrolled from February 2010 to December 2011 in this prospective ethics approved study had 1-2 pulmonary metastases on staging FDG-PET. Serial contemporaneous 3D and 4D FDG-PET/CT scans were performed at baseline, 14 days and 70 days after a single fraction of 26 Gy SABR. Tumour response was evaluated in 3D and 4D using SUVmax, RECIST and PERCIST criteria. Normal lung radiotoxicity was evaluated using SUVmean within 0-2 Gy, 2-5 Gy, 5-10 Gy, 10-20 Gy and 20 + Gy isodose volumes. RESULTS: In total, 17 patients were enrolled of which seven were ineligible due to interval progression from staging PET to baseline 4D-PET. The mean time between scans was 62 days. At a median follow-up of 16 months, 10 patients with 13 metastases received SABR, with no patient having local progression. The vector of tumour motion was larger in patients with discordant 3D and 4D PET PERCIST response (p < 0.01), with a mean (± SEM) motion of 10.5 mm (± 0.96 mm) versus 6.14 mm (± 0.81 mm) in those patients with concordant 3D and 4D response. Surrounding normal lung FDG uptake at 70 days was strongly correlated to delivered radiation dose (r(2) = 0.99, p < 0.01), with significant elevations across all dose levels (p ≤ 0.05), except the < 2 Gy volume (p = 0.30). CONCLUSIONS: We demonstrate high rates of interval progression between staging PET scans in patients with oligometastases. We found that tumour response on conventional 3D PET is not concordant with 4D PET for tumours with large motion. Normal lung metabolic uptake is strongly dose dependent after SABR, a novel finding that should be further validated.

The role of Cancer-Testis antigens as predictive and prognostic markers in non-small cell lung cancer.

BACKGROUND: Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. METHODS: We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. RESULTS: NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. CONCLUSIONS: NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

Correlation of mutation status and survival with predominant histologic subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification in stage III (N2) patients.

INTRODUCTION: We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. METHODS: We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom's OncoCarta Panel (v1.0; Sequenom, San Diego, CA). RESULTS: The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) (p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) (p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22-0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR-mutant micropapillary predominant tumors had similar survival to those with EGFR-mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. CONCLUSIONS: The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.

Contemporary results of surgical resection of non-small cell lung cancer after induction therapy: a review of 549 consecutive cases.

OBJECTIVE: We previously reported a high mortality after induction therapy and pneumonectomy for non-small cell lung cancer. Recent reports suggest that operative mortality in these patients is declining. We analyzed our contemporary results to define operative mortality and factors determining surgical risk. METHODS: Eligible patients were identified from our prospective surgical database. Complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Uni- and multivariate logistic regression models assessed the association of preoperative tests and clinical characteristics with outcome. Receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) statistics were calculated in a leave-one-out crossvalidation scheme to evaluate the predictive value of various models. RESULTS: From January 2000 to December 2006, 549 patients underwent surgery after induction therapy. Median patient age was 64 years (range: 30-86), and 54% were women (298/549). All received chemotherapy, and 17% also had radiation. Lobectomy (388/549, 71%) and pneumonectomy (70/549, 13%) were the most common procedures. Complications occurred in 250 patients (46%), with grade 3 or higher in 23% (126/549). Inhospital mortality was 1.8% (10/549), with only one death after right pneumonectomy (1/30, 3%). Multivariate analysis showed that predicted postoperative (PPO) pulmonary function was associated with postoperative morbidity. By receiver operating characteristic curves, PPO product (AUC = 0.75, p < 0.001), PPO diffusion capacity (AUC = 0.70, p < 0.001), and preoperative % predicted PPO diffusion capacity (AUC = 0.66, p < 0.001) predicted mortality. CONCLUSION: Our current experience shows that resection of non-small cell lung cancer after induction therapy, including pneumonectomy, is associated with low mortality. PPO pulmonary function is the strongest predictor of operative risk and should be used to select patients for surgery.

Randomized clinical trials in esophageal carcinoma.

The treatment of esophageal cancer with curative intent remains highly controversial, with advocates of surgery alone, chemoradiotherapy alone, surgery with adjuvant therapy (including neoadjuvant and postoperative), and trimodality therapy each contributing prospective randomized controlled trials (PRCTs) to the body of scientific publications between 2000 and 2008. Any improvements in survival have been small in absolute percentage terms, and as such PRCTs published over the last decade have met the same primary obstacle encountered by the studies from the two prior decades, namely lack of power to detect small differences in outcome. Variations in staging methods, surgical technique, radiotherapy technique, and chemotherapy regime have in turn been the subject of PRCTs over the last nine years. In many cases primary end points have not been survival but rather rates of complication or response. As well as giving an overview of PRCTs, this article collates the level Ia evidence published to date.

Pancreaticoduodenectomy: does preoperative biliary drainage, method of pancreatic reconstruction or age influence perioperative outcome? A retrospective study of 104 consecutive cases.

BACKGROUND: Whether preoperative biliary drainage (PBD) is beneficial in reducing complications after pancreaticoduodenectomy is controversial. There remains a reluctance to consider pancreaticoduodenectomy in older patients. The major source of morbidity and potential mortality after pancreaticoduodenectomy is pancreatic fistula, which is caused by difficulties associated with the pancreatic anastomosis. The purpose of this study was to examine the effect of PBD, patient age and method of pancreatico-enteric reconstruction on postoperative morbidity and mortality. METHODS: A total of 104 consecutive patients undergoing pancreaticoduodenectomy between November 1992 and November 2004 were identified from a prospectively collected database. Multiple preoperative and intraoperative variables were examined and their relationship to postoperative outcome was analysed. RESULTS: Postoperative mortality was <1%. Forty-three patients (43%) suffered a total of 85 complications. Median length of stay was 12.5 days (range, 1-88 days). The group undergoing PBD did not have higher rates of infectious complication (12 vs 19%; P = 0.34) or overall complication (41 vs 42%; P = 0.88) compared with the undrained group. Rate of anastomotic leak (18 vs 4%; P = 0.045) and anaemia requiring transfusion (41 vs 9%; P = 0.001) were significantly higher in the pancreaticojejunostomy group compared with the pancreaticogastrostomy group. Patients over the age of 70 years did not have higher rates of complication (44 vs 41%, P = 0.5) or postoperative length of stay. CONCLUSION: Preoperative biliary drainage was not associated with increased postoperative complications. Pancreaticogastrostomy after pancreaticoduodenectomy is a safe and reliable method of reconstruction. Finally, pancreaticoduodenectomy can be carried out with acceptable rates of postoperative morbidity and mortality in selected patients over 70 years of age.