The Importance of Stromal Endometriosis in Thoracic Endometriosis.

Thoracic endometriosis (TE) is a rare type of endometriosis, where endometrial tissue is found in or around the lungs and is frequent among extra-pelvic endometriosis patients. Catamenial pneumothorax (CP) is the most common form of TE and is characterized by recurrent lung collapses around menstruation. In addition to histology, immunohistochemical evaluation of endometrial implants is used more frequently. In this review, we compared immunohistochemical (CPE) with histological (CPH) characterizations of TE/CP and reevaluated arguments in favor of the implantation theory of Sampson. A summary since the first immunohistochemical description in 1998 until 2019 is provided. The emphasis was on classification of endometrial implants into glands, stroma, and both together. The most remarkable finding is the very high percentage of stromal endometriosis of 52.7% (CPE) compared to 10.2% (CPH). Chest pain, dyspnea, right-sided preference, and diaphragmatic endometrial implants showed the highest percentages in both groups. No significant association was found between the recurrence rate and the various appearances of endometriosis. Sometimes in CPE (6.8%) and CPH (30.6%) no endometrial implants were identified underlining the importance of sensitive detection of endometriosis during and after surgery. We suggest that immunohistochemical evaluation should become mandatory and will improve diagnosis and classification of the disease.

Mesenchymal folliculin is required for alveolar development: implications for cystic lung disease in Birt-Hogg-Dubé syndrome.

BACKGROUND: Pulmonary cysts and spontaneous pneumothorax are presented in most patients with Birt-Hogg-Dubé (BHD) syndrome, which is caused by loss of function mutations in the folliculin (FLCN) gene. The pathogenic mechanisms underlying the cystic lung disease in BHD are poorly understood. METHODS: Mesenchymal Flcn was specifically deleted in mice or in cultured lung mesenchymal progenitor cells using a Cre/loxP approach. Dynamic changes in lung structure, cellular and molecular phenotypes and signalling were measured by histology, immunofluorescence staining and immunoblotting. RESULTS: Deletion of Flcn in mesoderm-derived mesenchymal cells results in significant reduction of postnatal alveolar growth and subsequent alveolar destruction, leading to cystic lesions. Cell proliferation and alveolar myofibroblast differentiation are inhibited in the Flcn knockout lungs, and expression of the extracellular matrix proteins Col3a1 and elastin are downregulated. Signalling pathways including mTORC1, AMP-activated protein kinase, ERK1/2 and Wnt-ß-catenin are differentially affected at different developmental stages. All the above changes have statistical significance (p<0.05). CONCLUSIONS: Mesenchymal Flcn is an essential regulator during alveolar development and maintenance, through multiple cellular and molecular mechanisms. The mesenchymal Flcn knockout mouse model provides the first in vivo disease model that may recapitulate the stages of cyst development in human BHD. These findings elucidate the developmental origins and mechanisms of lung disease in BHD.

Pleura revisited: From histology and pathophysiology to pathology and molecular biology.

Pleural cavity has an interesting physiology that when impaired gives rise to pleural effusions a rather frequent problem in respiratory medicine practice. Their aetiology varies widely producing distinct pathological lesions with different prognosis and treatment. The basic morphological features of pleural diseases, neoplastic and non-neoplastic, will be analysed in this review with an emphasis to their pathophysiology, differential diagnosis and clinicopathological correlations.

Use of endo-bronchial end-tidal CO2 test for location of the pleural air leakage in patients with intractable pneumothorax.

BACKGROUND: Location of the affected bronchus of pleural air leaks is the most important step of trans-bronchoscopic bronchial occlusion for the treatment of intractable pneumothorax. The balloon occlusion test is the most commonly used technique, but has failed in some cases. The aim of the present study was: (1) to determine if endo-bronchial end-tidal CO2 (EtCO2) measurement can identify the affected bronchus that is the source of a persistent pleural air leak; and (2) to establish a methodology for endo-bronchial EtCO2 testing in locating affected bronchus in intractable pneumothorax. METHODS: A total of 28 patients with intractable pneumothorax underwent bronchoscopy with (1) the balloon occlusion test for the identification of the affected bronchus; and (2) endo-bronchial EtCO2 measurement (EtCO2 test) at the orifices of the bronchus of the affected lung. The effectiveness of these two methods of affected bronchus identification were compared. The threshold EtCO2 (T-EtCO2) was determined. RESULTS: The positive rates of locating the affected bronchus by the endo-bronchial EtCO2 test, balloon occlusion test, and combination of the two techniques were 60.7% (17/28), 64.3% (18/28) and 96.4% (27/28), respectively. The average differences in EtCO2 between the affected bronchus and the main carina, main bronchus, and non-affected bronchus were (in mmHg) 4.41 ± 1.99 (95% confidence interval: 3.5, 5.3), 4.73 ± 2.10 (3.80, 5.66 ) and 5.57 ± 2.53 (4.45, 6.69), respectively. CONCLUSIONS: (1) The endo-bronchial EtCO2 test is complementary to the balloon occlusion test of the leading bronchus. (2) A threshold (T-EtCO2) value of >5 mmHg is optimal for this technique.

Childhood pneumothorax in Birt-Hogg-Dubé syndrome: A cohort study and review of the literature.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported. METHODS: To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed. RESULTS: In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified. CONCLUSION: Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance.

High Nrf2 expression in alveolar type I pneumocytes is associated with low recurrences in primary spontaneous pneumothorax.

Recurrent primary spontaneous pneumothorax (PSP) is a troublesome problem and a major concern for the patients. This study examined whether nuclear factor erythroid 2-related factor 2 (Nrf2) expression in alveolar type I pneumocytes was associated with the clinical manifestations of PSP patients including disease recurrence. Eighty-eight PSP patients who were managed with needlescopic video-assisted thoracoscopic surgery (NVATS) were included in this study. Immunohistochemistry (IHC) was assessed to determine Nrf2 expression in resected lung tissues and the results were correlated with clinicopathological characteristics by the chi-square or the Fisher's exact test. The prognostic value of Nrf2 for overall recurrence was evaluated by univariate and multivariable Cox regression model. The expression of Nrf2 was observed in type I pneumocytes of lung tissues from PSP patients by IHC. We found that low Nrf2 expression in PSP patients, especially in young (age ≤ 20, p = 0.033) and body mass index (BMI) ≥18 kg/m2 (p = 0.019) groups, was significantly correlated with PSP recurrence. In the univariate and multivariate analyses, high Nrf2 expression was a significant protective factor for overall recurrence in PSP patients (univariate: p = 0.026; multivariate: p = 0.004). The expression level of Nrf2 in alveolar type I pneumocytes was a potential factor involved in PSP recurrence. Our findings suggest that elevated Nrf2 expression in PSP patients may be a promising way for reducing PSP recurrence.

Needle Decompression of Tension Pneumothorax with Colorimetric Capnography.

BACKGROUND: The success of needle decompression for tension pneumothorax is variable, and there are no objective measures assessing effective decompression. Colorimetric capnography, which detects carbon dioxide present within the pleural space, may serve as a simple test to assess effective needle decompression. METHODS: Three swine underwent traumatically induced tension pneumothorax (standard of care, n = 15; standard of care with needle capnography, n = 15). Needle thoracostomy was performed with an 8-cm angiocatheter. Similarly, decompression was performed with the addition of colorimetric capnography. Subjective operator assessment of decompression was recorded and compared with true decompression, using thoracoscopic visualization for both techniques. Areas under receiver operating curves were calculated and pairwise comparison was performed to assess statistical significance (P < .05). RESULTS: The detection of decompression by needle colorimetric capnography was found to be 100% accurate (15 of 15 attempts), when compared with thoracoscopic assessment (true decompression). Furthermore, it accurately detected the lack of tension pneumothorax, that is, the absence of any pathologic/space-occupying lesion, in 100% of cases (10 of 10 attempts). Standard of care needle decompression was detected by operators in 9 of 15 attempts (60%) and was detected in 3 of 10 attempts when tension pneumothorax was not present (30%). True decompression, under direct visualization with thoracoscopy, occurred 15 of 15 times (100%) with capnography, and 12 of 15 times (80%) without capnography. Areas under receiver operating curves were 0.65 for standard of care and 1.0 for needle capnography (P = .002). CONCLUSIONS: Needle decompression with colorimetric capnography provides a rapid, effective, and highly accurate method for eliminating operator bias for tension pneumothorax decompression. This may be useful for the treatment of this life-threatening condition.

Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease.

Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.

Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P-gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc-sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes ± 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes ± 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc-sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in the lungs. (©) RSNA, 2016.

Highly sensitive monitoring of chest wall dynamics and acoustics provides diverse valuable information for evaluating ventilation and diagnosing pneumothorax.

Current practice of monitoring lung ventilation in neonatal intensive care units, utilizing endotracheal tube pressure and flow, end-tidal CO2, arterial O2 saturation from pulse oximetry, and hemodynamic indexes, fails to account for asymmetric pathologies and to allow for early detection of deteriorating ventilation. This study investigated the utility of bilateral measurements of chest wall dynamics and sounds, in providing early detection of changes in the mechanics and distribution of lung ventilation. Nine healthy New Zealand rabbits were ventilated at a constant pressure, while miniature accelerometers were attached to each side of the chest. Slowly progressing pneumothorax was induced by injecting 1 ml/min air into the pleural space on either side of the chest. The end of the experiment (tPTX) was defined when arterial O2 saturation from pulse oximetry dropped <90% or when vigorous spontaneous breathing began, since it represents the time of clinical detection using common methods. Consistent and significant changes were observed in 15 of the chest dynamics parameters. The most meaningful temporal changes were noted for features extracted from subsonic dynamics (<10 Hz), e.g., tidal amplitude, energy, and autoregressive poles. Features from the high-frequency band (10-200 Hz), e.g., energy and entropy, exhibited smaller but significant changes. At 70% tPTX, identification of asymmetric ventilation was attained for all animals. Side identification of the pneumothorax was achieved at 50% tPTX, within a 95% confidence interval. Diagnosis was, on average, 34.1 ± 18.8 min before tPTX. In conclusion, bilateral monitoring of the chest dynamics and acoustics provide novel information that is sensitive to asymmetric changes in ventilation, enabling early detection and localization of pneumothorax.

Immunohistochemical analysis of thoracic endometriosis.

Thoracic endometriosis is a rare disease responsible for catamenial pneumothorax. The immunohistochemical features of thoracic endometriosis are not well understood. An immunohistochemical examination of 84 diaphragmatic specimens of catamenial pneumothorax using antibodies against estrogen receptor (ER), progesterone receptor (PgR), CD10 and smooth muscle actin (SMA) was conducted. The endometrial tissue was small, and focally located around the chasm of the tendon on the side of the thoracic cavity. Endometrial stroma were detected in 84/84 (100%) of the specimens, endometrial glands were detected in 21/84 (25%) and smooth muscle was detected in 1/84 (1.2%). The endometrial stroma exhibited positive staining for ER in 74/84 (88.1%) of the specimens, PgR in 84/84 (100%), CD10 in 74/84 (88.1%) and SMA in 46/84 (54.8%). Because thoracic endometriosis is small in size, and only 25% of the resected tissue specimens were accompanied with the endometrial gland, an immunohistochemical analysis can be useful for their detection. The fact that over half of the thoracic endometrial stroma showed positive staining for SMA, and the existence of thoracic endometriosis accompanied by smooth muscle, indicated that some part of the thoracic endometriosis may have the ability to differentiate into smooth muscle, although further studies are needed to confirm this hypothesis.

Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors and pulmonary cysts with repeated pneumothorax. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is known to be involved in the signaling of mammalian target of rapamycin (mTOR). We investigated the lung of a BHD patient who presented with a unique mutation. A 33-year-old woman visited our hospital due to repeated pneumothorax. Histopathologic study of the resected lung demonstrated multiple epithelial cysts. An increase of blood vessels was observed in the vicinity of subpleural cysts. Genomic DNA analysis revealed heterozygous mutation at the 3' end of intron 5 of the FLCN gene. Total mRNA and protein were extracted from the resected lung tissue. RT-PCR and sequence analysis demonstrated the production of exon 6-skipped FLCN mRNA. In Western blotting, the band intensities of phospho-mTOR, phospho-S6, phospho-Akt, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were increased in the BHD lung compared with normal lungs. Histopathologic analysis demonstrated strong immunostainings of mTOR signaling molecules in cyst-lining cells. Collective data indicates that dysregulation of mTOR signaling facilitates S6-mediated protein synthesis and HIF-1α-mediated angiogenesis, which may contribute to the development of pulmonary cysts in this disorder.

Birt-Hogg-Dube syndrome: clinicopathological features of the lung.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited disorder characterised by fibrofolliculomas, renal tumours, pulmonary cysts and pneumothorax. The pulmonary cysts and repeated episodes of pneumothorax are the clinical hallmarks for discovering families affected by the syndrome. This disorder is caused by mutations in the gene coding for folliculin (FLCN). FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 (also known as FNIPL), and the complex cross-talks with signalling molecules such as 5'-AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). Heterozygous Flcn knockout mice and rats with Flcn gene mutations develop renal cysts, adenomas and/or carcinomas. These findings suggest that FLCN functions as a tumour suppressor that inhibits renal carcinogenesis. However, the mechanisms of the formation of pulmonary cysts and pneumothorax associated with heterozygous mutations in FLCN are poorly understood. Resected lung specimens from patients with BHD are often misdiagnosed by pathologists as non-specific blebs or bullae or emphysema, and patients with BHD who have pulmonary cysts and repeated pneumothorax frequently do not receive appropriate medical investigations. This review discusses the clinical and pathological features of lungs of patients with BHD, focusing on the diagnostic pathology and possible mechanisms of cyst formation.

Anesthetic management of a horse with traumatic pneumothorax.

A traumatic pneumothorax and severe hemorrhage were present in a mare with a large thoracic wall defect, lung perforation, and multiple rib fractures. General anesthesia was induced to allow surgical exploration. We describe the anesthetic technique, and discuss the management of the ventilatory, hemodynamic, and metabolic disturbances encountered.

Fibulin-5 protein is reduced in the lung of patients with spontaneous pneumothorax who are under 25 years old.

PURPOSE: To clarify whether fibulins-5 is associated with primary spontaneous pneumothorax (PSP) in young PSP patients. METHODS: Forty-six surgically resected, fresh lung specimens were used. Patients were divided into 3 groups: younger than 25 years with pneumothorax (group Y), 25 years or older with pneumothorax (group O), and without pneumothorax (group C). Chest X-ray, computed tomography data, height/width ratio (H/W) and anteroposterior/transverse diameter ratio (a/b) were measured. Elastica van Gieson staining and immunofluorescence staining for fibulin-5 were performed. Fibulin-5 mRNA expression and protein levels were measured by real-time PCR and western blotting. Direct sequences of the fibulin-5 gene in PSP patients were performed. RESULTS: The mean H/W ratio in group Y was significantly larger than that in the other groups (p <0.01). The mean a/b ratio in group Y was significantly smaller than that in the other groups (p = 0.02). Fibulin-5 mRNA expression was not significantly different among the groups (p = 0.64). The relative intensity of fibulin-5 protein in group Y was significantly lower than that in group O (p = 0.006), with no significant differences between groups O and C (p = 0.14). CONCLUSIONS: We showed that fibulin-5 is reduced in patients with PSP who are younger than 25 years.

Assessment of control tissue for gene and protein expression studies: a comparison of three alternative lung sources.

The use of an appropriate control group in human research is essential in investigating the level of a pathological disorder. This study aimed to compare three alternative sources of control lung tissue and to determine their suitability for gene and protein expression studies. Gene and protein expression levels of the vascular endothelial growth factor (VEGF) and gelatinase families and their receptors were measured using real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The gene expression levels of VEGFA, placental growth factor (PGF), and their receptors, fms-related tyrosine kinase 1 (FLT1), and kinase insert domain receptor (KDR) as well as matrix metalloproteinase-2 (MMP-2) and the inhibitors, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 were significantly higher in lung cancer resections. The gene expression level of MMP-9 was significantly lower in the corresponding samples. Altered protein expression was also detected, depending on the area assessed. The results of this study show that none of the three control groups studied are completely suitable for gene and protein studies associated with the VEGF and gelatinase families, highlighting the need for researchers to be selective in which controls they opt for.

Hemodynamics in the pulmonary artery of a patient with pneumothorax.

Pneumothorax is characterized by lung collapse and an alteration of lung geometry, resulting in alterations of the pulmonary artery blood flow. Though many clinical studies and animal experiments have investigated the effects of pneumothorax on the hemodynamics of pulmonary arteries, its precise effects remain unclear. In this patient-specific study, we investigated the effects of lung deformation and vascular resistance increases due to pneumothorax on the pulmonary blood flow during the acute phase and after recovery. Arterial geometry was extracted up to the fifth generation from computed tomography images, and reconstructed. Computational fluid dynamic analysis was performed, for an unsteady laminar flow with resistance at the outlets, in a reconstructed domain. The results demonstrated a change in flow structure during systole between the acute phase and recovery, and were associated with variations in the flow rate ratio between the right and left lungs. We observed a parabolic-like decrease of the volume flow rate ratio in the affected lung as the resistance increased. Thus, the systemic artery blood oxygenation will rely more on the unaffected lung leading to improved oxygenation of the blood under high resistance in the affected lung. These findings are significant in our understanding of ventilation function under a pneumothorax.

Microarray detection of gene overexpression in primary spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP) often occurs after the rupture of small bullae or subpleural blebs in otherwise normal lungs. The underlying mechanism(s) remain unclear. The aim of this study was to identify genes potentially involved in the development of PSP. Microarray analysis was performed to identify specific gene expression patterns. Expression levels of genes identified to be significantly up- or down-regulated in association with PSP were confirmed by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Immunohistochemistry was performed to identify lung cell types highly expressing these genes. Microarray analysis revealed that expression levels of hypoxia-inducible factor-3 alpha (HIF-3alpha) and caspase-8 were significantly up-regulated in tissue from patients with PSP, whereas interferon-gamma, interleukin (IL)-6, and IL-8 were down-regulated (all P < .05). These genes are related to hypoxia, apoptosis, and inflammation. HIF-3alpha and caspase-8 protein levels were increased in samples from patients with PSP. HIF-3alpha and caspase-8 were localized in mesothelial cells, alveolar type II pneumocytes, and bronchoalveolar epithelial cells in samples from patients with PSP. Our findings, although obviously preliminary given the small sample size, suggest that hypoxia, inflammation, and apoptosis may play important roles in the pathogenesis of PSP.