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.

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.

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.

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.

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.

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.

Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy?

A randomised trial of screening for lung cancer using CT showed a survival benefit with screening, but issues surrounding risks arising from screening remain. The appropriate treatment of early-stage lung cancer detected in this way is receiving increasing attention. This Review discusses treatment-related issues for such tumours and explores the merits of surgery versus stereotactic ablative radiotherapy (SABR), both of which are effective treatments but have different risks for acute toxicity. Although surgery is widely deemed to be the preferred treatment for patients who are fit, growing evidence suggests that SABR achieves similar local control rates, but without the risks associated with surgery. Choice of local treatment should also be made with consideration of the high rates of disease recurrence and second primary lung tumours in patients after curative therapy for early-stage lung cancer. Careful collaborative evaluation by pulmonologists, interventional radiologists, thoracic surgeons, and radiation oncologists should guide decision making for each patient with a screen-detected early-stage lung cancer.

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.

Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), (n-3) fatty acids from fish oil, have immune-modulating effects and may improve nutritional status in cancer. The objective of this study was to investigate the effects of an oral nutritional supplement containing (n-3) fatty acids on nutritional status and inflammatory markers in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment. In a double-blind experiment, 40 patients with stage III NSCLC were randomly assigned to receive 2 cans/d of a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids (2.0 g EPA + 0.9 g DHA/d) or an isocaloric control supplement. EPA in plasma phospholipids, energy intake, resting energy expenditure (REE), body weight, fat free mass (FFM), mid-upper arm circumference (MUAC), and inflammatory markers were assessed. Effects of intervention were analyzed by generalized estimating equations and expressed as regression coefficients (B). The intervention group (I) had a better weight maintenance than the control (C) group after 2 and 4 wk (B = 1.3 and 1.7 kg, respectively; P < 0.05), a better FFM maintenance after 3 and 5 wk (B = 1.5 and 1.9 kg, respectively; P < 0.05), a reduced REE (B = -16.7% of predicted; P = 0.01) after 3 wk, and a trend for a greater MUAC (B = 9.1; P = 0.06) and lower interleukin-6 production (B = -27.9; P = 0.08) after 5 wk. After 4 wk, the I group had a higher energy and protein intake than the C group (B = 2456 kJ/24 h, P = 0.03 and B = 25.0 g, P = 0.01, respectively). In conclusion, a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids beneficially affects nutritional status during multimodality treatment in patients with NSCLC.

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.

Rupture of the right main bronchus: a case of a 4-year-old girl.

Tracheobronchial rupture after a blunt chest trauma is rare, especially in children. If the diagnosis is overlooked, severe ventilatory complications or mediastinitis may occur. We describe a case of a 4-year-old girl with a rupture of the right main bronchus after she was hit by a frame of steel (like a mini goal) that fell down while she was playing. The diagnosis was initially missed owing to a variety of symptoms. Difficulty with ventilation and persistent air leak after insertion of a chest tube in the case of a pneumothorax is suspect for a tracheobronchial rupture. This emphasizes once again the importance of the concept of rechecking and searching for the underlying cause when a pneumothorax persists. Bronchoscopy is the gold standard in establishing the diagnosis. Surgical treatment is in most cases the best option, especially in a ventilated patient. Without treatment mortality rates are up to 30%. In conclusion, tracheobronchial rupture should be excluded if mediastinal emphysema or a persistent air leak is present after a blunt thoracic trauma.

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.

An unusual cause of hematemesis: Goiter.

Downhill varices are located in the upper part of the esophagus and are usually related to superior vena cava obstruction. Bleeding from these varices is extremely rare. We describe a 77-year-old patient with hematemesis due to downhill varices as a result of recurrent goiter. A right lobe thyroidectomy was carried out with disappearance of the varices.

The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis.

Positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) seems to be superior to computed tomography (CT) in staging the mediastinum in patients with non-small-cell lung cancer (NSCLC). However, recent results suggest that FDG-PET performance characteristics are conditional for nodal size as shown by CT: FDG-PET is more sensitive but less specific with lymph node enlargement on CT. The association between size and the probability of malignancy needs to be known to predict the post-test probabilities after PET, and finally, stratify patients for mediastinoscopy or thoracotomy depending on the PET and CT results. Therefore, we performed a meta-analysis of available studies reporting on the prevalence of metastatic involvement for different size categories of enlarged lymph nodes in patients with NSCLC and were able to include 14 studies. The prevalence of metastatic involvement and conditional test performance of CT and FDG-PET were calculated for lymph nodes measuring 10-15 mm, 16-20 mm and >20 mm. We found a post-test probability for N2 disease of 5% for lymph nodes measuring 10-15 mm on CT in patients with a negative FDG-PET result, suggesting that these patients should be planned for thoracotomy because the yield of mediastinoscopy will be extremely low. For patients with lymph nodes measuring > or =16 mm on CT and a negative FDG-PET result a post-test probability for N2 disease of 21% was found, suggesting that these patients should be planned for mediastinoscopy prior to possible thoracotomy to prevent too many unnecessary thoracotomies in this subset.