Management of stage I and II nonsmall cell lung cancer.

The incidence of stage I and II nonsmall cell lung cancer is likely to increase with the ageing population and introduction of screening for high-risk individuals. Optimal management requires multidisciplinary collaboration. Local treatments include surgery and radiotherapy and these are currently combined with (neo)adjuvant chemotherapy in specific cases to improve long-term outcome. Targeted therapies and immunotherapy may also become important therapeutic modalities in this patient group. For resectable disease in patients with low cardiopulmonary risk, complete surgical resection with lobectomy remains the gold standard. Minimally invasive techniques, conservative and sublobar resections are suitable for a subset of patients. Data are emerging that radiotherapy, especially stereotactic body radiation therapy, is a valid alternative in compromised patients who are high-risk candidates for surgery. Whether this is also true for good surgical candidates remains to be evaluated in randomised trials. In specific subgroups adjuvant chemotherapy has been shown to prolong survival; however, patient selection remains important. Neoadjuvant chemotherapy may yield similar results as adjuvant chemotherapy. The role of targeted therapies and immunotherapy in early stage nonsmall cell lung cancer has not yet been determined and results of randomised trials are awaited.

Limited resections in high-risk patients.

PURPOSE OF REVIEW: The role of limited, sublobar resection in patients with early-stage nonsmall cell lung cancer (NSCLC) remains controversial. Alternative treatments for surgical resection include stereotactic radiotherapy and radiofrequency ablation. In this review, the role of limited resection is discussed in patients presenting a s high-risk for s surgical intervention. RECENT FINDINGS: Clear definitions of high-risk patients are currently lacking, as well as, randomized prospective studies indicating which treatment to offer in this population. Awaiting results of two major ongoing trials, at this moment the decision-making process is heavily dependent on retrospective analyses. For selected patients sublobar resection may be a valid oncological option for clinical stage IA NSCLC. SUMMARY: Surgery remains the gold standard for NSCLC. In case of high-risk patients, a multidisciplinary consultation should advise the patient which treatment option to choose. In early-stage NSCLC, sublobar anatomical resection is preferred over nonsurgical procedures to determine nodal status and prognosis. In case of patients unfit for surgery, stereotactic radiotherapy is a good alternative. A randomized prospective study is necessary to determine survival in high-risk patients allocated to surgery (lobectomy or sublobar resection) or radiation-based treatment.

Surgical treatment of early-stage non-small-cell lung cancer.

Surgical resection remains the standard of care for functionally operable early-stage non-small-cell lung cancer (NSCLC) and resectable stage IIIA disease. The role of invasive staging and restaging techniques is currently being debated, but they provide the largest biopsy samples which allow for precise mediastinal staging. Different types of operative procedures are currently available to the thoracic surgeon, and some of these interventions can be performed by video-assisted thoracic surgery (VATS) with the same oncological results as those by open thoracotomy. The principal aim of surgical treatment for NSCLC is to obtain a complete resection which has been precisely defined by a working group of the International Association for the Study of Lung Cancer (IASLC). Intraoperative staging of lung cancer is of utmost importance to decide on the extent of resection according to the intraoperative tumour (T) and nodal (N) status. Systematic nodal dissection is generally advocated to evaluate the hilar and mediastinal lymph nodes which are subdivided into seven zones according to the most recent 7th tumour-node-metastasis (TNM) classification. Lymph-node involvement not only determines prognosis but also the administration of adjuvant therapy. In 2011, a new multidisciplinary adenocarcinoma classification was published introducing the concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma. This classification has profound surgical implications. The role of limited or sublobar resection, comprising anatomical segmentectomy and wide wedge resection, is reconsidered for early-stage lesions which are more frequently encountered with the recently introduced large screening programmes. Numerous retrospective non-randomised studies suggest that sublobar resection may be an acceptable surgical treatment for early lung cancers, also when performed by VATS. More tailored, personalised therapy has recently been introduced. Quality-of-life parameters and surgical quality indicators become increasingly important to determine the short-term and long-term impact of a surgical procedure. International databases currently collect extensive surgical data, allowing more precise calculation of mortality and morbidity according to predefined risk factors. Centralisation of care has been shown to improve results. Evidence-based guidelines should be further developed to provide optimal staging and therapeutic algorithms.

Two unusual variants of pulmonary intra-lobar sequestration.

A pulmonary sequestration is a congenital malformation characterized by non-functional lung tissue with abnormal arterial systemic supply and abnormal connection to the bronchial tree. This may lead to recurrent infections rendering a surgical intervention more demanding. Because of multiple anatomic variations, it is important to obtain high-quality preoperative radiological clarification to determine the most suitable surgical approach. Although a non-surgical technique, consisting of embolization of the aberrant artery has been described, a surgical technique remains the treatment of choice in operable patients. Preoperative embolization of the aberrant artery may reduce the risk of haemorrhage but could cause technical challenges in a hybrid approach and therefore unforeseen peroperative stress to the surgical team. We report 2 adult patients with unusual intra-lobar sequestration with aberrant vascular rare anatomy. Both were treated by surgery. In the latter patient, we performed a hybrid approach. This was complicated by peroperative coils exposure making it a technical challenge to proceed.

A rare case of invasive pulmonary aspergillosis presenting as organizing pneumonia due to Aspergillus niger in an immunocompetent host.

Invasive pulmonary aspergillosis associated with organizing pneumonia is increasingly described and mainly affects the immunocompromised individual. Most of Aspergillus invasive infections in both immunocompetent and immunocompromised patients are attributed to Aspergillus fumigatus. Herein we describe a clinical case of pulmonary Aspergillus niger infection presenting as an organizing pneumonia in an immunocompetent patient. A wedge resection and two successive cures of azoles (voriconazole 6 weeks then itraconazole 6 weeks) were necessary for the patient to be totally recovered. The association of OP and IPA is rare. The involvement of A. niger makes it even rarer, this is the reason why we decided to report on this case.

A second mediastinoscopy: how to decide and how to do it?

Specific indications for a second or remediastinoscopy include an inadequate first procedure, metachronous second primary or recurrent lung cancer, lung cancer after unrelated disease, and restaging after induction therapy. Nowadays, restaging is the most frequent indication for remediastinoscopy. Only patients with proven mediastinal downstaging will benefit from a subsequent surgical resection. In contrast to imaging or functional studies, remediastinoscopy provides pathological evidence of response after induction therapy. Although technically more challenging than a first procedure, remediastinoscopy can select patients for subsequent thoracotomy and provides prognostic information. Technically, mediastinal dissection is usually started at the left paratracheal side to avoid the innominate artery. Under the aortic arch, dissection proceeds in the pretracheal plane until the subcarinal nodes are reached. Sensitivity of a second mediastinoscopy is lower than a first procedure but in the most recent series it is higher than 70% with an accuracy around 85%. Survival also depends on the findings of remediastinoscopy, patients with persisting mediastinal involvement having a poor prognosis. An alternative approach consists of the use of minimally invasive staging procedures as endobronchial or endoscopic esophageal ultrasound to obtain an initial proof of mediastinal nodal involvement. Mediastinoscopy is subsequently performed after induction therapy to evaluate response. In this way, a technically more difficult remediastinoscopy can be avoided.

Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients.

OBJECTIVE: Precise restaging of non-small cell lung cancer after induction therapy is of utmost importance. Remediastinoscopy remains a controversial procedure. In a combined, updated series of two thoracic centres, accuracy and survival of remediastinoscopy were determined. METHODS: From November 1994 to August 2005, remediastinoscopy was performed in 104 patients (98 men, 6 women) after induction therapy for locally advanced non-small cell lung cancer. Mean age was 64.3 years (range 38-85). Neoadjuvant chemotherapy was given in 79 patients and chemoradiotherapy in 25. Follow-up data were completed in January 2007. RESULTS: Remediastinoscopy was technically feasible in all patients except for one who died due to perioperative haemorrhage. Remediastinoscopy was positive in 40 patients and negative in 64; the latter group underwent thoracotomy. There were 17 false-negative remediastinoscopies. Sensitivity of remediastinoscopy was 71%, specificity 100% and accuracy 84%. Follow-up was complete for all patients. Sixty-nine died, mostly of distant metastases. Median survival time for the whole group was 18 months (95% confidence interval 11-25). Median survival time in patients with a positive remediastinoscopy was 14 months (95% confidence interval 8-20), with a negative remediastinoscopy 28 months (95% confidence interval 15-41) and with a false-negative remediastinoscopy 24 months (95% confidence interval 3-45). In univariate analysis the difference between positive and negative remediastinoscopies was highly significant (p=0.001). In a multivariate analysis including sex, age, histology, centre, and nodal status at remediastinoscopy, only nodal status was a significant independent prognostic factor (p=0.008). CONCLUSIONS: Remediastinoscopy is a valuable restaging procedure after induction therapy. Persisting mediastinal nodal involvement proven at remediastinoscopy heralds a poor prognosis.

Does the usage of digital chest drainage systems reduce pleural inflammation and volume of pleural effusion following oncologic pulmonary resection?-A prospective randomized trial.

BACKGROUND: Prolonged air leak and high-volume pleural drainage are the most common causes for delays in chest tube removal following lung resection. While digital pleural drainage systems have been successfully used in the management of post-operative air leak, their effect on pleural drainage and inflammation has not been studied before. We hypothesized that digital drainage systems (as compared to traditional analog continuous suction), using intermittent balanced suction, are associated with decreased pleural inflammation and postoperative drainage volumes, thus leading to earlier chest tube removal. METHODS: One hundred and three [103] patients were enrolled and randomized to either analog (n=50) or digital (n=53) drainage systems following oncologic lung resection. Chest tubes were removed according to standardized, pre-defined protocol. Inflammatory mediators [interleukin-1B (IL-1B), 6, 8, tumour necrosis factor-alpha (TNF-α)] in pleural fluid and serum were measured and analysed. The primary outcome of interest was the difference in total volume of postoperative fluid drainage. Secondary outcome measures included duration of chest tube in-situ, prolonged air-leak incidence, length of hospital stay and the correlation between pleural effusion formation, degree of inflammation and type of drainage system used. RESULTS: There was no significant difference in total amount of fluid drained or length of hospital stay between the two groups. A trend for shorter chest tube duration was found with the digital system when compared to the analog (P=0.055). Comparison of inflammatory mediator levels revealed no significant differences between digital and analog drainage systems. The incidence of prolonged post-operative air leak was significantly higher when using the analog system (9 versus 2 patients; P=0.025). Lobectomy was associated with longer chest tube duration (P=0.001) and increased fluid drainage when compared to sub-lobar resection (P<0.001), regardless of drainage system. CONCLUSIONS: Use of post-lung resection digital drainage does not appear to decrease pleural fluid formation, but is associated with decreased prolonged air leaks. Total pleural effusion volumes did not differ with the type of drainage system used. These findings support previously established benefits of the digital system in decreasing prolonged air leaks, but the advantages do not appear to extend to decreased pleural fluid formation.

Nodal status at repeat mediastinoscopy determines survival in non-small cell lung cancer with mediastinal nodal involvement, treated by induction therapy.

OBJECTIVE: Remediastinoscopy is a valuable tool in restaging non-small cell lung cancer after induction therapy for mediastinal nodal involvement as it provides pathological evidence of response and may select patients for subsequent thoracotomy. However, long-term survival data after remediastinoscopy are scarce. METHODS: From November 1994 to April 2003, a remediastinoscopy was performed in 32 patients (29 men, 3 women) after induction therapy for locally advanced non-small cell lung cancer. Mean age was 67.8 years (range, 47-83). Neoadjuvant chemotherapy was given in 26 patients and chemoradiotherapy in 6. Follow-up data were completed in January 2005. RESULTS: Remediastinoscopy was technically feasible in all patients. There were five false-negative remediastinoscopies, resulting in a sensitivity of 71%, specificity of 100% and accuracy of 84%. Follow-up was complete in all patients. Median survival time for the whole group was 21 months (95% confidence interval [CI] 9-33). Median survival time in patients with a positive remediastinoscopy was 7 months (95% CI 5-9), with a negative remediastinoscopy 41 months (95% CI 13-69), and with a false-negative remediastinoscopy 24 months (95% CI 5-43). The difference between positive and negative remediastinoscopies was highly significant (p=0.003). In the combined group of patients with positive and false-negative remediastinoscopies (n=17), median survival time was 8 months (95% CI 3-13). The difference with negative remediastinoscopy remained significant (p=0.012). In a multivariate analysis, including sex, age, histology and nodal status at repeat mediastinoscopy, only nodal status was a significant independent prognostic factor (p=0.015). CONCLUSIONS: Remediastinoscopy is a valuable restaging procedure after induction therapy. Prognosis is poor in patients with persisting mediastinal nodal involvement, proven at repeat mediastinoscopy.

Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients.

Our objective was to describe the clinical signs of 'possible' Creutzfeldt-Jakob disease (CJD) and to investigate whether current diagnostic criteria can accurately differentiate between different forms of dementia. We studied clinical data of 'definite' CJD, Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VD) patients. Two subgroups were used: the first consisted of patients with clinical signs compatible with 'possible' CJD but in whom another final diagnosis was made and a second group with a typical evolution of the respective dementia. More focal neurological deficits were observed in AD, DLB or VD patients initially classified as 'possible' CJD than in typical patients. A typical electroencephalogram showing periodic sharp wave complexes was observed in 26 (50%) CJD and 6% of other dementia patients. The 14-3-3 protein was detected in all CJD and 8% of other dementia patients. In patients with rapidly progressive dementia and focal neurological signs, CJD should be considered. When faced with the triad: dementia, myoclonus, and initial memory problems AD should be considered if the disease duration is longer than 1 year. The diagnosis of DLB is suggested, if Parkinsonism or fluctuations are present, whereas a focal onset and compatible brain imaging can indicate VD. Findings suggestive of CJD on EEG, brain imaging, and CSF do not exclude other dementias but make them very unlikely. These observations cannot only assist in the differential diagnosis of CJD but also with the identification of AD, DLB or VD patients with atypical clinical history.

Fibromuscular dysplasia of the brachial artery associated with unilateral clubbing.

A 46-year old male patient was admitted with a history of an extremely painful right upper arm, associated with unilateral clubbing. Duplex scanning and magnetic resonance imaging were suggestive of a pseudo-aneurysm of the brachial artery. Digital angiography showed an irregular brachial artery, associated with a small pseudo-aneurysm. The brachial artery was partially resected and reconstructed with a venous interposition graft. Pathological examination provided the final diagnosis of fibromuscular dysplasia. Although more encountered in women, this case report describes the occurrence of fibromuscular dysplasia in an unusual location in a male patient with a long-term follow-up.

Remediastinoscopy.

Indications for remediastinoscopy include recurrent and second primary lung cancer, an inadequate first procedure, lung cancer occurring after an unrelated disease such as lymphoma, and restaging after induction therapy. Nowadays, restaging is the most frequent indication for remediastinoscopy. Only patients with proven mediastinal downstaging will benefit from a subsequent surgical resection. In contrast to imaging or functional studies, remediastinoscopy provides pathologic evidence of response after induction therapy. Although technically more challenging than a first procedure, remediastinoscopy can select patients for subsequent thoracotomy and provides prognostic information. In most recent series, sensitivity of remediastinoscopy is higher than 70% with an accuracy of approximately 85%. Survival also depends on the findings at remediastinoscopy, with patients with persisting mediastinal involvement having a poor prognosis. An alternative approach consists of the use of minimally invasive staging procedures as endobronchial or endoscopic esophageal ultrasonography to obtain initial proof of mediastinal nodal involvement. Mediastinoscopy is subsequently performed after induction therapy to evaluate response. In this way, a technically more difficult remediastinoscopy can be avoided.

Extracellular protein deposition correlates with glial activation and oxidative stress in Creutzfeldt-Jakob and Alzheimer's disease.

The relation of protein deposition with glial cells and oxidative stress was studied in Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD) and neurologically healthy control patients. Three neocortical areas, the hippocampus, and the cerebellum of 20 CJD, 10 AD and 10 control patients were immunohistochemically examined for the presence of astroglia, microglia, and protein depositions. To investigate the level of oxidative stress the percentage of neurons with cytoplasmic hydroxylated DNA was determined. Astroglia, microglia and oxidative stress were located around amyloid-beta depositions and a clear quantitative relation was identified. These markers were only increased in the hippocampus of AD compared to controls. Quantitative analysis in these groups showed a correlation between the oxidative stress level and the number of microglia in the grey matter. All markers were increased in the grey matter and the cerebellum of CJD when compared to AD and controls. The highest numbers of lesions were observed in a CJD population with a rapid disease progression. Quantitative analysis showed a correlation between the oxidative stress level and all glial cells. Further analysis showed that the number of microglia was related to the intensity of the prion depositions. Glial cells in the brain are thought to be the main producers of oxidative stress, resulting in neuronal death. Our results confirm that this close relationship exists in both AD and CJD. We also show that an increased number of glial cells and therefore possibly oxidative stress is associated with the disease progression.