Salvage Surgery for Patients With Local Recurrence or Persistent Disease After Treatment With Chemoradiotherapy for SCLC.

INTRODUCTION: The role of salvage surgery for patients with locoregional (LR) recurrence or persistent SCLC after radical chemoradiotherapy (CRT) for limited-stage disease is not well established. We evaluated our experience. METHODS: We conducted a retrospective study of consecutive patients who underwent salvage pulmonary resection for LR-recurrent or persistent SCLC between 2008 and 2020 at the Amsterdam University Medical Center. RESULTS: A total of 10 patients were identified. Median age at initial diagnosis of limited-stage SCLC was 58.5 years (48-71 y). All patients had radical-intent concurrent CRT. Of the 10 patients, 9 were diagnosed with LR-recurrent or persistent disease with a median of 18 months (3-78 y) after CRT. All patients underwent an anatomical radical resection and mediastinal lymph node dissection. No 90-day mortality was recorded. In addition, one patient developed a LR recurrence 7 months after resection. Distant progression was found in three patients at 6, 32, and 61 months after surgery, all of whom subsequently died of progressive SCLC. Median follow-up was 22.5 months (2-86 mos). Disease-free survival was 34 months; overall survival was not reached. CONCLUSIONS: For highly selected patients with LR-recurrent or persistent SCLC after CRT, salvage surgery is feasible and can result in clinically meaningful survival. Such patients should be presented to the multidisciplinary tumor board.

In-Hospital Mobilization, Physical Fitness, and Physical Functioning After Lung Cancer Surgery.

BACKGROUND: Apart from clinical experience and theoretical considerations, there is a lack of evidence that the level of adherence to in-hospital mobilization protocols is related to functional recovery in patients after resection for lung cancer. The objectives of the study were to determine (1) the relationship between adherence to the in-hospital mobilization protocol and physical fitness at hospital discharge and (2) the value of physical fitness measures at discharge in predicting physical functioning 6 weeks and 3 months postoperatively. METHODS: This observational study included 62 patients who underwent surgical resection for lung cancer. Adherence to the in-hospital mobilization protocol was abstracted from patients' records. Physical fitness measures before the operation and at hospital discharge included handgrip strength, 30-second sit-to-stand test, and 6-minute walk test (6MWT). Self-reported physical functioning was assessed preoperatively and 6 weeks and 3 months postoperatively, using the Medical Outcome Study 36-Item Short Form (SF-36) Physical Function subscale (RAND Corp, Santa Monica, CA). Linear regression analyses were used to estimate the relationships of interest, adjusting for potential confounders. RESULTS: Level of adherence to the mobilization protocol was significantly and independently related to handgrip strength, sit-to-stand test, and 6MWT at discharge. Handgrip strength and 6MWT at discharge significantly predicted SF-36 Physical Function at 6 weeks and 3 months postoperatively. The sit-to-stand test only predicted SF-36 Physical Function at 6 weeks. CONCLUSIONS: Suboptimal postoperative mobilization after surgical resection for lung cancer negatively affects physical fitness at discharge. Our results underline the importance of adherence to early postoperative mobilization protocols. Measuring physical fitness at discharge may be useful to inform clinicians on elective referral of patients for postdischarge rehabilitation.

[Salvage surgery for locally recurrent lung cancer: options for patients who have been treated with high dose radiotherapy]. / 'Salvage'-chirurgie voor lokaal recidief longcarcinoom.

A combination of chemotherapy and high dose radiotherapy is the cornerstone of the treatment of locally-advanced non-small cell lung cancer (NSCLC). For selected patients with early stage NSCLC, stereotactic body radiation therapy (SBRT, also known as SABR, stereotactic ablative radiotherapy) is a good option. Unfortunately, metastases can occur in patients following these treatments. However, in some patients, the recurrence remains localized to the previous irradiated area, so-called local recurrence. For selected patients with such a recurrence, radical salvage surgery - a treatment modality with curative intent - is an option. In this article we describe two patients with local recurrence after high dose radiotherapy, who were subsequently treated operatively. We also discuss which subset of lung cancer patients should be selected for this type of surgery.

Positive End-Expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers.

RATIONALE: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown. OBJECTIVES: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers. METHODS: We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance. MEASUREMENTS AND MAIN RESULTS: PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H2O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy. CONCLUSIONS: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.

Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill.

RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency and increases morbidity, duration of hospital stay, and health care costs. The mechanisms underlying diaphragm weakness are unknown, but might include mitochondrial dysfunction and oxidative stress. OBJECTIVES: We hypothesized that weakness of diaphragm muscle fibers in critically ill patients is accompanied by impaired mitochondrial function and structure, and by increased markers of oxidative stress. METHODS: To test these hypotheses, we studied contractile force, mitochondrial function, and mitochondrial structure in diaphragm muscle fibers. Fibers were isolated from diaphragm biopsies of 36 mechanically ventilated critically ill patients and compared with those isolated from biopsies of 27 patients with suspected early-stage lung malignancy (control subjects). MEASUREMENTS AND MAIN RESULTS: Diaphragm muscle fibers from critically ill patients displayed significant atrophy and contractile weakness, but lacked impaired mitochondrial respiration and increased levels of oxidative stress markers. Mitochondrial energy status and morphology were not altered, despite a lower content of fusion proteins. CONCLUSIONS: Critically ill patients have manifest diaphragm muscle fiber atrophy and weakness in the absence of mitochondrial dysfunction and oxidative stress. Thus, mitochondrial dysfunction and oxidative stress do not play a causative role in the development of atrophy and contractile weakness of the diaphragm in critically ill patients.

Surgical Treatment of Complications After High-Dose Chemoradiotherapy for Lung Cancer.

BACKGROUND: There are limited published reports on the indications for, and outcomes of, a surgical intervention for complications arising after high-dose chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). We report on our institutional experience with such cases. METHODS: Patients who underwent operations for any complication after CRT (≥60 Gy) for NSCLC between 2009 and 2015 were identified. All operations were performed at a tertiary referral center. RESULTS: In the 15 patients identified, the median time between the last day of radiotherapy and first radiologic confirmation of the complication was 8 months (range, 0 to 102 months). Complicated pulmonary cavitation was the most frequent indication for surgical intervention (n = 11 in 9 patients), followed by esophagorespiratory fistula (n = 3), hemorrhage (n = 3), bronchial stenosis (n = 2), esophageal stenosis (n = 1), and bronchiectasis (n = 1). Four patients had more than two complications diagnosed, and 9 patients underwent more than one surgical intervention. Surgical procedures performed included thoracostomy (n = 11 in 9 patients) with seven vascularized muscle flaps used in 6 patients, pulmonary resection (n = 5 in 4 patients) and esophageal resection with gastric tube reconstruction (n = 3). The 30- and 90-day mortality rates were 20% (n = 3) and 27% (n = 4), respectively. Median survival was 19 months (95% confidence interval [CI]: 3.9 to 34.1 months). CONCLUSIONS: An Operation is often the only treatment option when irreversible complications arise after high-dose CRT for NSCLC. It is infrequently performed, technically challenging, and associated with high perioperative risk and even death. Therefore, we suggest that such patients should be managed by a multidisciplinary team, including experienced thoracic surgeons.

Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer.

INTRODUCTION: The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence following SABR for early stage non-small cell lung cancer (NSCLC). METHODS: Patients who underwent surgical salvage for a local recurrence following SABR for NSCLC were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification. RESULTS: Nine patients who underwent surgery for a local recurrence were identified. Median time to local recurrence was 22 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with four patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during two resections, requiring conversion from a thoracoscopic procedure to thoracotomy during one of these procedures. Three patients experienced complications post-surgery; grade 2 (N = 2) and grade 3a (N = 1), respectively. All resection specimens showed viable tumor cells. Median length of hospital stay was 8 days (range 5-15 days) and 30-day mortality was 0 %. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. CONCLUSIONS: Our experience with nine surgical procedures for local recurrences post-SABR revealed two grade IIIa complications, and a 30-day mortality of 0 %, suggesting that salvage surgery can be safely performed after SABR.

Population-Based Patterns of Surgical Care for Stage IIIA NSCLC in the Netherlands between 2010 and 2013.

INTRODUCTION: Current guidelines include both induction therapy plus an operation and chemoradiotherapy (CRT) as options for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) after multidisciplinary evaluation. We explored the use of operations for cIIIA NSCLC in the Netherlands. METHODS: Data about the primary treatment of patients with cIIIA NSCLC (according to the seventh edition of the Tumour, Node, and Metastasis Classification of Malignant Tumours) between 2010 and 2013 were extracted from the Netherlands Cancer Registry. Mortality information was obtained from the automated civil registry. RESULTS: A total of 4816 patients with cIIIA NSCLC (stage cN2, 3240 [67%]; stage T4, 1252 [26%]) were identified. CRT was used in 45% of patients and an operation was a component of treatment in 15%, with 28% of the latter having induction therapy. The 4-year survival rate was highest with induction therapy plus an operation (51%), followed by an operation plus adjuvant therapy (39%) and CRT (27%). Patients receiving induction therapy plus an operation were younger than those receiving CRT (median age 60 versus 66 years). The 30- and 90-day postoperative mortality rates after induction therapy plus lobectomy were 0.6% and 3.7% compared with 4.2% and 12.5% after induction therapy plus bilobectomy or pneumonectomy. Factors associated with poorer survival after induction therapy plus an operation were age older than 69 years, histological findings of nonsquamous cell carcinoma, and bilobectomy or pneumonectomy. Pathological stage IIIA NSCLC was present in only 51% of patients with cIIIA NSCLC who underwent an operation with or without adjuvant therapy, and the disease was of a lower stage in most of the remaining patients. CONCLUSIONS: In the Netherlands between 2010 and 2013, 15% of patients with cIIIA NSCLC received an operation, with the minority of these patients receiving induction therapy. In those receiving induction therapy, 90-day mortality after bilobectomy or pneumonectomy was more than three times higher than that for lobectomy. The discrepancy between clinical and pathological stage in patients receiving an upfront operation merits further investigation.

Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage.

RATIONALE: Altered pulmonary hemodynamics and fluid flow-induced high shear stress (HSS) are characteristic hallmarks in the pathogenesis of pulmonary arterial hypertension (PAH). However, the contribution of HSS to cellular and vascular alterations in PAH is unclear. OBJECTIVES: We hypothesize that failing shear adaptation is an essential part of the endothelial dysfunction in all forms of PAH and tested whether microvascular endothelial cells (MVECs) or pulmonary arterial endothelial cells (PAECs) from lungs of patients with PAH adapt to HSS and if the shear defect partakes in vascular remodeling in vivo. METHODS: PAH MVEC (n = 7) and PAH PAEC (n = 3) morphology, function, protein, and gene expressions were compared with control MVEC (n = 8) under static culture conditions and after 24, 72, and 120 hours of HSS. MEASUREMENTS AND MAIN RESULTS: PAH MVEC showed a significantly delayed morphological shear adaptation (P = 0.03) and evidence of cell injury at sites of nonuniform shear profiles that are critical loci for vascular remodeling in PAH. In clear contrast, PAEC isolated from the same PAH lungs showed no impairments. PAH MVEC gene expression and transcriptional shear activation were not altered but showed significant decreased protein levels (P = 0.02) and disturbed interendothelial localization of the shear sensor platelet endothelial cell adhesion molecule-1 (PECAM-1). The decreased PECAM-1 levels were caused by caspase-mediated cytoplasmic cleavage but not increased cell apoptosis. Caspase blockade stabilized PECAM-1 levels, restored endothelial shear responsiveness in vitro, and attenuated occlusive vascular remodeling in chronically hypoxic Sugen5416-treated rats modeling severe PAH. CONCLUSIONS: Delayed shear adaptation, which promotes shear-induced endothelial injury, is a newly identified dysfunction specific to the microvascular endothelium in PAH. The shear response is normalized on stabilization of PECAM-1, which reverses intimal remodeling in vivo.

Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage IA non-small-cell lung cancer: Results from the ROSEL multicenter randomized trial.

We report quality of life and indirect costs from patient reported outcomes from the ROSEL randomized control trial comparing stereotactic ablative radiotherapy (SABR, also known as stereotactic body radiotherapy or SBRT) versus surgical resection for medically operable stage IA non-small cell lung cancer. ROSEL closed prematurely after accruing and randomizing 22 patients. This exploratory analysis found the global health related quality of life and indirect costs to be significantly favorable and cheaper, with SABR.

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials.

BACKGROUND: The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS: Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS: 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION: SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING: Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients.

RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

Long-term follow-up after first-line bronchoscopic therapy in patients with bronchial carcinoids.

BACKGROUND: Carcinoid of the lung is considered to be a low-grade malignancy. A subgroup presents as an endobronchial tumour. Surgical resection is considered the standard approach because of its metastatic potential and the possibility of an iceberg phenomenon for the endobronchial subgroup. Advances in non-invasive and minimally invasive technologies seem to justify a more lung parenchyma-sparing approach. METHODS: In patients presenting with bronchial carcinoids, initial bronchoscopic treatment (IBT) is first attempted for complete tumour eradication and sufficient tissue sampling for the proper differentiation of typical (TC) versus atypical (AC) histological type. Furthermore in cases with postobstruction problems the desobstruction is aimed at improving the patient's condition and by that alleviate surgery if that is needed. High resolution CT is performed 6 weeks post IBT to determine local tumour growth. Surgical resection follows in case of extraluminal disease, residual carcinoid inaccessible for IBT, or late recurrences not salvaged by repeat IBT. RESULTS: Minimum follow-up was 5 years from start of treatment for 112 patients (65 women, 47 men), with a median age of 47 years (range 16-77 years). Eighty-three patients (74%) had TC, and 29 (26%) AC. IBT only was ultimately curative in 42% of the cases (47/112): 42 TC, 5 AC. Disease-specific mortality including surgical mortality has been 2.6% (3/112) in patients with extraluminal carcinoids (3 AC). CONCLUSIONS: IBT, if with unsuccessful rescue surgery, is justifiable with excellent long-term outcome. IBT made surgery unnecessary in 42% of the cases. Iceberg phenomenon and metastatic potential in this group of patients with bronchial carcinoids are clinically insignificant.

Does hyperbaric oxygen therapy prevent airway anastomosis from breakdown?

Ischemia with subsequent necrosis of anastomoses, after central airway resection and reconstruction, remains a feared complication for thoracic surgeons and their patients. To date, there is no evidence to support the use of hyperbaric oxygen in the prevention of necrosis of airway reconstructions in humans. We present a patient who underwent central airway surgery with postoperative ischemia of an end-to-side anastomosis. Repeat visit to a hyperbaric oxygen chamber seemed to prevent the anastomosis from subsequent necrosis and dehiscence with complete healing as a result. In conclusion, hyperbaric oxygen treatment can be considered when ischemia or necrosis is observed in central airway anastomoses during postoperative bronchoscopic surveillance.

Second primary lung cancers following a diagnosis of primary head and neck cancer.

OBJECTIVES: Second primary lung cancers (SPLC) are not uncommon in survivors of squamous cell head and neck cancer (HNSCC), and carry a worse prognosis than when patients present with a primary lung cancer. We reviewed our institutional experience on the treatment and prognosis of SPLC patients, both at the time of diagnosis, and following treatment of HNSCC, in order to explore treatment outcomes. MATERIALS AND METHODS: Our institutional database was queried for patients with a diagnosis of HNSCC and lung cancer, between 2000 and 2013. Only HNSCC patients with tumors of the oral cavity, oropharynx, hypopharynx and larynx were eligible. Patients were stratified between synchronous and metachronous HNSCC and SPLC. Cox regression analysis was performed to determine factors predictive of overall survival (OS) in metachronous presentations. RESULTS: 181 eligible patients were identified for analysis, comprising 40 synchronous and 141 metachronous HNSCC-SPLC. Patients presenting with synchronous SPLC were more likely to have early-stage disease, as compared to patients with metachronous SPLC (45% vs. 28%, respectively; p=0.036). Patients with early stage SPLC had a significantly better survival compared to those with locally advanced (p<0.001) and metastatic disease (p<0.001), with a median OS of 95.4 months vs. 11.0 and 4.6 months, respectively. CONCLUSIONS: Although the survival of patients treated for early-stage NSCLC were good, the OS of the entire cohort of SPLC after HNSCC was poor as a majority of patients presented with advanced disease. The use of CT screening strategies in this patient population warrants further investigation.

Detecting resistance in EGFR-mutated non-small-cell lung cancer after clonal selection through targeted therapy.

Tumor heterogeneity plays an important role in the development of treatment-resistance, especially in the current era of targeted therapies. Although tumor heterogeneity is a widely recognized phenomenon, it is at present unclear how this knowledge should be incorporated into daily clinical practice. In this report, we describe an innovative nuclear imaging method that may play a role in detecting tumor heterogeneity in the future.

Unaffected contractility of diaphragm muscle fibers in humans on mechanical ventilation.

Several studies have indicated that diaphragm dysfunction develops in patients on mechanical ventilation (MV). Here, we tested the hypothesis that the contractility of sarcomeres, i.e., the smallest contractile unit in muscle, is affected in humans on MV. To this end, we compared diaphragm muscle fibers of nine brain-dead organ donors (cases) that had been on MV for 26 ± 5 h with diaphragm muscle fibers from nine patients (controls) undergoing surgery for lung cancer that had been on MV for less than 2 h. In each diaphragm specimen we determined 1) muscle fiber cross-sectional area in cryosections by immunohistochemical methods and 2) the contractile performance of permeabilized single muscle fibers by means of maximum specific force, kinetics of cross-bridge cycling by rate of tension redevelopment, myosin heavy chain content and concentration, and calcium sensitivity of force of slow-twitch and fast-twitch muscle fibers. In case subjects, we noted no statistically significant decrease in outcomes compared with controls in slow-twitch or fast-twitch muscle fibers. These observations indicate that 26 h of MV of humans is not invariably associated with changes in the contractile performance of sarcomeres in the diaphragm.

Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited disorder caused by germline mutations in the folliculin (FLCN) gene. Clinical manifestations of BHD include skin fibrofolliculomas, renal cell cancer, lung cysts and (recurrent) spontaneous pneumothorax (SP). All clinical manifestations usually present in adults > 20 years of age. CASE PRESENTATIONS: Two non-related patients with (recurrent) pneumothorax starting at age 14 accompanied by multiple basal lung cysts on thoracic CT underwent FLCN germline mutation analysis. A pathogenic FLCN mutation was found in both patients confirming suspected BHD. The family history was negative for spontaneous pneumothorax in both families. CONCLUSION: Although childhood occurrence of SP in BHD is rare, these two cases illustrate that BHD should be considered as cause of SP in children.