Near-Infrared Fluorescence Tumor-Targeted Imaging in Lung Cancer: A Systematic Review.

Lung cancer is the most common cancer type worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype. Non-disseminated NSCLC is mainly treated with surgical resection. The intraoperative detection of lung cancer can be challenging, since small and deeply located pulmonary nodules can be invisible under white light. Due to the increasing use of minimally invasive surgical techniques, tactile information is often reduced. Therefore, several intraoperative imaging techniques have been tested to localize pulmonary nodules, of which near-infrared (NIR) fluorescence is an emerging modality. In this systematic review, the available literature on fluorescence imaging of lung cancers is presented, which shows that NIR fluorescence-guided lung surgery has the potential to identify the tumor during surgery, detect additional lesions and prevent tumor-positive resection margins.

Variation in incidence, prevention and treatment of persistent air leak after lung cancer surgery.

OBJECTIVES: Persistent air leak (PAL; >5 days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity. Literature is contradictory about the prevention and treatment of PAL. Variation is therefore hypothesized. The aim of this study is to understand the variation in the incidence, preventive management and treatment of PAL. METHODS: Data from the Dutch Lung Cancer Audit for Surgery were combined with results of an online survey among Dutch thoracic surgeons. The national incidence of PAL and case-mix corrected between-hospital variation were calculated in patients who underwent an oncological (bi)lobectomy or segmentectomy between January 2012 and December 2018. By multivariable logistic regression, factors associated with PAL were assessed. A survey was designed to assess variation in (preventive) management and analysed using descriptive statistics. Hospital-level associations between management strategies and PAL were assessed by univariable linear regression. RESULTS: Of 12 382 included patients, 9.0% had PAL, with a between-hospital range of 2.6-19.3%. Factors associated with PAL were male sex, poor lung function, low body mass index, high American Society of Anesthesiologists (ASA) score, pulmonary comorbidity, upper lobe resection, (bi)lobectomy (vs segmentectomy), right-sided tumour and robotic-assisted thoracic surgery. Perioperative (preventive) management of PAL differed widely between hospitals. When using water seal compared to suction drainage, the average incidence of PAL decreased 2.9%. CONCLUSIONS: In the Netherlands, incidence and perioperative (preventive) management of PAL vary widely. Using water seal instead of suction drainage and increasing awareness are potential measures to reduce this variation.

A Prediction Model for Severe Complications after Elective Colorectal Cancer Surgery in Patients of 70 Years and Older.

Introduction Older patients have an increased risk of morbidity and mortality after colorectal cancer (CRC) surgery. Existing CRC surgical prediction models have not incorporated geriatric predictors, limiting applicability for preoperative decision-making. The objective was to develop and internally validate a predictive model based on preoperative predictors, including geriatric characteristics, for severe postoperative complications after elective surgery for stage I-III CRC in patients ≥70 years. PATIENTS AND METHODS: A prospectively collected database contained 1088 consecutive patients from five Dutch hospitals (2014-2017) with 171 severe complications (16%). The least absolute shrinkage and selection operator (LASSO) method was used for predictor selection and prediction model building. Internal validation was done using bootstrapping. RESULTS: A geriatric model that included gender, previous DVT or pulmonary embolism, COPD/asthma/emphysema, rectal cancer, the use of a mobility aid, ADL assistance, previous delirium and polypharmacy showed satisfactory discrimination with an AUC of 0.69 (95% CI 0.73-0.64); the AUC for the optimism corrected model was 0.65. Based on these predictors, the eight-item colorectal geriatric model (GerCRC) was developed. CONCLUSION: The GerCRC is the first prediction model specifically developed for older patients expected to undergo CRC surgery. Combining tumour- and patient-specific predictors, including geriatric predictors, improves outcome prediction in the heterogeneous older population.

Physical performance has a strong association with poor surgical outcome in older patients with colorectal cancer.

BACKGROUND: Low lumbar skeletal muscle mass and density have been associated with adverse outcomes in different populations with colorectal cancer (CRC). We aimed to determine whether skeletal muscle mass, density, and physical performance are associated with postoperative complications and overall survival (OS) in older CRC patients. METHODS: We analysed consecutive patients (≥70 years) undergoing elective surgery for non-metastatic CRC (stage I-III). Lumbar skeletal muscle mass and muscle density were measured using abdominal CT-images obtained prior to surgery. Low skeletal muscle mass and low muscle density were defined using commonly used thresholds and by gender-specific quartiles (Q). The preoperative use of a mobility aid served as a marker for physical performance. Cox regression proportional hazard models were used to investigate the association between the independent variables and OS. RESULTS: 174 Patients were included (mean age 78.0), with median follow-up 2.6 years. 36 Patients (21%) used a mobility aid preoperatively. Low muscle density (Q1 vs Q4) and not muscle mass was associated with worse postoperative outcomes, including severe complications (p < 0.05). Use of a mobility aid was associated with more complications, including severe complications (39% vs 17%, p = 0.004) and OS (HR 2.65, CI 1.29-5.44, p = 0.01). However, patients with mobility aid use and low skeletal muscle mass had worse OS (HR 5.68, p = 0.003). CONCLUSION: Low skeletal muscle density and not muscle mass was associated with more complications after colorectal surgery in older patients. Physical performance has the strongest association for poor surgical outcomes and should be investigated when measuring skeletal muscle mass and density.

Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or faecal peritonitis (LADIES): a multicentre, parallel-group, randomised, open-label, superiority trial.

BACKGROUND: Previous studies have suggested that sigmoidectomy with primary anastomosis is superior to Hartmann's procedure. The likelihood of stoma reversal after primary anastomosis has been reported to be higher and reversal seems to be associated with lower morbidity and mortality. Although promising, results from these previous studies remain uncertain because of potential selection bias. Therefore, this study aimed to assess outcomes after Hartmann's procedure versus sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy, for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or IV disease) in a randomised trial. METHODS: A multicentre, randomised, open-label, superiority trial was done in eight academic hospitals and 34 teaching hospitals in Belgium, Italy, and the Netherlands. Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free air or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to Hartmann's procedure or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Patients were enrolled by the surgeon or surgical resident involved, and secure online randomisation software was used in the operating room or by the trial coordinator on the phone. Random and concealed block sizes of two, four, or six were used, and randomisation was stratified by age (<60 and ≥60 years). The primary endpoint was 12-month stoma-free survival. Patients were analysed according to a modified intention-to-treat principle. The trial is registered with the Netherlands Trial Register, number NTR2037, and ClinicalTrials.gov, number NCT01317485. FINDINGS: Between July 1, 2010, and Feb 22, 2013, and June 9, 2013, and trial termination on June 3, 2016, 133 patients (93 with Hinchey III disease and 40 with Hinchey IV disease) were randomly assigned to Hartmann's procedure (68 patients) or primary anastomosis (65 patients). Two patients in the Hartmann's group were excluded, as was one in the primary anastomosis group; the modified intention-to-treat population therefore consisted of 66 patients in the Hartmann's procedure group (46 with Hinchey III disease, 20 with Hinchey IV disease) and 64 in the primary anastomosis group (46 with Hinchey III disease, 18 with Hinchey IV disease). In 17 (27%) of 64 patients assigned to primary anastomosis, no stoma was constructed. 12-month stoma-free survival was significantly better for patients undergoing primary anastomosis compared with Hartmann's procedure (94·6% [95% CI 88·7-100] vs 71·7% [95% CI 60·1-83·3], hazard ratio 2·79 [95% CI 1·86-4·18]; log-rank p<0·0001). There were no significant differences in short-term morbidity and mortality after the index procedure for Hartmann's procedure compared with primary anastomosis (morbidity: 29 [44%] of 66 patients vs 25 [39%] of 64, p=0·60; mortality: two [3%] vs four [6%], p=0·44). INTERPRETATION: In haemodynamically stable, immunocompetent patients younger than 85 years, primary anastomosis is preferable to Hartmann's procedure as a treatment for perforated diverticulitis (Hinchey III or Hinchey IV disease). FUNDING: Netherlands Organisation for Health Research and Development.

Lessons learned from the Dutch Institute for Clinical Auditing: the Dutch model for quality assurance in lung cancer treatment.

BACKGROUND: Quality registries play an important role in the professional quality system for cancer treatment in The Netherlands. This article provides insight into the Dutch Lung Cancer Audit (DLCA); its core principles, initiation and development, first results and what lessons can be learned from the Dutch experience. METHODS: Cornerstones of the DLCA are discussed in detail, including: audit aims; the leading role for clinicians; web-based registration and feedback; data handling; multidisciplinary evaluation of quality indicators; close collaborations with all stakeholders in healthcare and transparency of results. RESULTS: In 2012 the first Dutch lung cancer specific sub-registry, focusing on surgical treatment was started. Since 2016 all major treating specialisms (lung oncologists, radiation-oncologists, general- and cardiothoracic surgeons-represented in the DLCA-L, -R and -S sub-registries respectively) have joined. Over time, the number of participating hospitals and included patients has increased. In 2016, the numbers of included patients with a non-small cell lung cancer (NSCLC) were 3,502 (DLCA-L), 2,427 (DLCA-R) and 1,979 (DLCA-S). Between sub-registries mean age varied from 66 to 70 years, occurrence of Eastern Cooperative Oncology Group (ECOG) performance score 2+ varied from 3.3% to 20.8% and occurrence of clinical stage I-II from 27.6% to 81.3%. Of all patients receiving chemoradiotherapy 64.2% was delivered concurrently. Of the surgical procedures 71.2% was started with a minimally invasive technique, with a conversion rate of 18.7%. In 2016 there were 17 publicly available quality indicators-consisting of structure, process and outcome indicators- calculated from the DLCA. CONCLUSIONS: the DLCA is a unique registry to evaluate the quality of multidisciplinary lung cancer care. It is accepted and implemented on a nationwide level, enabling participating healthcare providers to get insight in their performance, and providing other stakeholders with a transparent evaluation of this performance, all aiming for continuous healthcare improvement.

National quality registries: how to improve the quality of data?

BACKGROUND: Data of quality registries are increasingly used by healthcare providers, patients, health insurance companies, and governments for monitoring quality of care, hospital benchmarking and outcome research. To provide all stakeholders with reliable information and outcomes, reliable data are of the utmost importance. METHODS: This article describes methods for quality assurance of data-used by the Dutch Institute for Clinical Auditing (DICA)-regarding: the design of a registry, data collection, data analysis, and external data verification. For the Dutch Lung Cancer Audit for Surgery (DLCA-S) results of data analysis and data verification were assessed with descriptive statistics. RESULTS: Of all registered patients in the DLCA-S in 2016 (n=2,391), 98.2% was analysable and completeness of data for calculations of transparent outcomes was 90.7%. Data verification for the year 2014 showed a case ascertainment of 99.4%. Of 15 selected hospitals, 14 were verified. All these hospitals received the conclusion 'sufficient quality' on case ascertainment, mortality (0% under-registration) and complicated course (3.3% wrongly registered complications). One hospital was not able to deliver patients lists, and therefore not verified. CONCLUSIONS: Quality of data can be promoted in many different ways. A completeness indicator and data verification are useful tools to improve data quality. Both methods were used to demonstrate the reliability of registered data in the DLCA-S. Opportunities for further improvement are standardised reporting and adequate data extraction.

MEDIASTinal staging of non-small cell lung cancer by endobronchial and endoscopic ultrasonography with or without additional surgical mediastinoscopy (MEDIASTrial): study protocol of a multicenter randomised controlled trial.

BACKGROUND: In case of suspicious lymph nodes on computed tomography (CT) or fluorodeoxyglucose positron emission tomography (FDG-PET), advanced tumour size or central tumour location in patients with suspected non-small cell lung cancer (NSCLC), Dutch and European guidelines recommend mediastinal staging by endosonography (endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)) with sampling of mediastinal lymph nodes. If biopsy results from endosonography turn out negative, additional surgical staging of the mediastinum by mediastinoscopy is advised to prevent unnecessary lung resection due to false negative endosonography findings. We hypothesize that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection. In addition, omitting mediastinoscopy comprises no extra waiting time until definite surgery, omits one extra general anaesthesia and hospital admission, and may be associated with lower morbidity and comparable survival. Therefore, this strategy may reduce health care costs and increase quality of life. The aim of this study is to compare the cost-effectiveness and cost-utility of mediastinal staging strategies including and excluding mediastinoscopy. METHODS/DESIGN: This study is a multicenter parallel randomized non-inferiority trial comparing two diagnostic strategies (with or without mediastinoscopy) for mediastinal staging in 360 patients with suspected resectable NSCLC. Patients are eligible for inclusion when they underwent systematic endosonography to evaluate mediastinal lymph nodes including tissue sampling with negative endosonography results. Patients will not be eligible for inclusion when PET/CT demonstrates 'bulky N2-N3' disease or the combination of a highly suspicious as well as irresectable mediastinal lymph node. Primary outcome measure for non-inferiority is the proportion of patients with unforeseen N2 disease at surgery. Secondary outcome measures are hospitalization, morbidity, overall 2-year survival, quality of life, cost-effectiveness and cost-utility. Patients will be followed up 2 years after start of treatment. DISCUSSION: Results of the MEDIASTrial will have immediate impact on national and international guidelines, which are accessible to public, possibly reducing mediastinoscopy as a commonly performed invasive procedure for NSCLC staging and diminishing variation in clinical practice. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register on July 6th, 2017 ( NTR 6528 ).

Risk stratification for surgical outcomes in older colorectal cancer patients using ISAR-HP and G8 screening tools.

BACKGROUND: Older patients are at risk for adverse outcomes after surgical treatment of cancer. Identifying patients at risk could affect treatment decisions and prevent functional decline. Screening tools are available to select patients for Geriatric Assessment. Until now their predictive value for adverse outcomes in older colorectal cancer patients has not been investigated. OBJECTIVE: To study the predictive value of the Geriatric 8 (G8) and Identification of Seniors at Risk for Hospitalized Patients (ISAR-HP) screening tools for adverse outcomes after elective colorectal surgery in patients older than 70years. Primary outcomes were 30-day complication rates, secondary outcomes were the length of hospital stay and six-month mortality. STUDY DESIGN AND METHODS: Multicentre cohort study from two hospitals in the Netherlands. Frail was defined as a G8 ≤14 and/or ISAR-HP ≥2. Odds ratio (OR) is given with 95% CI. RESULTS: Overall, 139 patients (52%) out of 268 patients were included; 32 patients (23%) were ISAR-HP-frail, 68 (50%) were G8-frail, 20 were frail on both screening tools. Median age was 77.7years. ISAR-HP frail patients were at risk for 30-day complications OR 2.4 (CI 1.1-5.4, p=0.03), readmission OR 3.4 (1.1-11.0), cardiopulmonary complications OR 5.9 (1.6-22.6), longer hospital stay (10.3 versus 8.9day) and six-months mortality OR 4.9 (1.1-23.4). When ISAR-HP and G8 were combined OR increased for readmission, 30-day and six-months mortality. G8 alone had no predictive value. CONCLUSIONS: ISAR-HP-frail patients are at risk for adverse outcomes after colorectal surgery. ISAR-HP combined with G8 has the strongest predictive value for complications and mortality. KEY POINTS: Patients screening frail on ISAR-HP are at increased risk for morbidity and mortality. Screening results of G8 alone was not predictive for postoperative outcomes. Predictive value increased when G8 and ISAR-HP were combined.

Differences between colon and rectal cancer in complications, short-term survival and recurrences.

PURPOSE: Many apparent differences exist in aetiology, genetics, anatomy and treatment response between colon cancer (CC) and rectal cancer (RC). This study examines the differences in patient characteristics, prevalence of complications and their effect on short-term survival, long-term survival and the rate of recurrence between RC and CC. METHODS: For all stage II-III CC and RC patients who underwent resection with curative intent (2006-2008) in five hospitals in the Netherlands, occurrence of complications, crude survival, relative survival and recurrence rates were compared. RESULTS: A total of 767 CC and 272 RC patients underwent resection. Significant differences were found for age, gender, emergency surgery, T-stage and grade. CC patients experienced fewer complications compared to RC (p = 0.019), but CC patients had worse short-term mortality rates (1.5 versus 6.7 % for 30-day mortality, p = 0.001 and 5.2 versus 9.5 % for 90-day mortality, p = 0.032). The adjusted HR (overall survival) for CC patients with complications was 1.57 (1.23-2.01; p < 0.001) as compared to patients without complications; for RC, the HR was 1.79 (1.12-2.87; p = 0.015). Relative survival analyses showed high excess mortality in the first months after surgery and a sustained, prolonged negative effect on both CC and RC. Complications were associated with a higher recurrence rate for both CC and RC; adjusted analyses showed a trend towards a significant association. CONCLUSION: Large differences exist in patient characteristics and clinical outcomes between CC and RC. CC patients have a significantly higher short-term mortality compared to RC patients due to a more severe effect of complications.

The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitis and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitis in perforated diverticulitis (NTR2037).

BACKGROUND: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). METHODS/DESIGN: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. DISCUSSION: The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis. TRIAL REGISTRATION: Nederlands Trial Register NTR2037.