Presence of focal usual interstitial pneumonia is a key prognostic factor in progressive pulmonary fibrosis.

AIMS: Progressive pulmonary fibrosis (PPF) is a newly recognised clinical phenotype of interstitial lung diseases in the 2022 interstitial pulmonary fibrosis (IPF) guidelines. This category is based entirely on clinical and radiological factors, and the background histopathology is unknown. Our objective was to investigate the histopathological characteristics of PPF and to examine the correlation between usual interstitial pneumonia (UIP) and prognosis in this new disease type. We hypothesised that the presence of UIP-like fibrosis predicts patients' survival in PPF cases. METHODS AND RESULTS: We selected 201 cases fulfilling the clinical criteria of PPF from case archives. Cases diagnosed as IPF by a multidisciplinary team were excluded. Whole slide images were evaluated by three pathologists who were blinded to clinical and radiological data. We measured areas of UIP-like fibrosis and calculated what percentage of the total lesion area they occupied. The presence of focal UIP-like fibrosis amounting to 10% or more of the lesion area was seen in 148 (73.6%), 168 (83.6%) and 165 (82.1%) cases for each pathologist, respectively. Agreement of the recognition of UIP-like fibrosis in PPF cases was above κ = 0.6 between all pairs. Survival analysis showed that the presence of focal UIP-like fibrosis correlated with worsened survival under all parameters tested (P < 0.001). CONCLUSIONS: The presence of UIP-like fibrosis is a core pathological feature of clinical PPF, and its presence within diseased areas is associated with poorer prognosis. This study highlights the importance of considering the presence of focal UIP-like fibrosis in the evaluation and management of PPF.

Impact of time interval between donor brain death and cold preservation on long-term outcome in lung transplantation.

OBJECTIVES: Brain death (BD) is associated with various systemic responses and a cascade of inflammatory reactions. It is still unknown how the time interval from BD to cold preservation (CP) affects outcome after lung transplantation (LTx). This report investigates the impact of the time interval from BD to CP on long-term outcome in LTx. METHODS: We reviewed 250 consecutive recipients who underwent LTx at our institution between January 2000 and December 2011. In Group I (n = 212), the time interval from BD to CP was <24 h, and in Group II (n = 38) >24 h. Cox proportional hazard regression analysis was performed to determine the risk factors affecting survival. RESULTS: The median time from BD to CP was 18.6 h (range 9-65). The rate of postoperative complications was comparable (P = 0.8). The 30-day mortality rate was 7.5% in Group I and 0% in Group II. The 5-year survival rate was better in Group II [70% (95% CI: 48.5-83.8%)] than in Group I [66% (95% CI: 58.3-72.5%)] without statistical significance (P = 0.3). Intraoperative extracorporeal membrane oxygenation (ECMO) use was identified as a significant risk factor for survival [HR = 1.7, (95% CI: 1.1-2.6), P = 0.01]. CONCLUSION: In our cohort, the time interval from BD to CP had no impact on long-term outcome after LTx.

The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation.

OBJECTIVES: Macrophages (M) are one of the most important cells of the innate immune system for first line defense. Upon transplantation (Tx), M play a prominent role during lung ischaemia reperfusion (I/R) injury. Here, we hypothesize that the depletion of donor M ameliorates the post-transplant lung I/R injury. METHODS: Orthotopic single-lung Tx was performed between syngeneic BALB/c mice after a cold ischaemic time of 8 h and a reperfusion time of 10 h. Prior to graft implantation, alveolar macrophages of donor lungs were selectively depleted applying the 'suicide technique' by intratracheal application of clodronate liposomes (experimental, n = 6) vs the application of empty liposomes (control, n = 6). Cell count (number of F4/80(+)-macrophages) and graft injury were evaluated by histology and immunohistochemistry, and levels of lactat dehydrogenase (LDH) (apoptosis assay), enzyme linked immunosorbent assay for nuclear protein high-mobility-group-protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α) and transforming growth factor beta1 (TGF-ß1) in plasma were analysed. RESULTS: Clodronate liposomes successfully reduced 70% of M from donor lungs when compared with grafts treated with empty liposome only. M-depleted transplants showed improved histology and revealed considerably less graft damage when compared with control recipients (LDH, P = 0.03; HMGB1, P = 0.3). Oxygenation capacity was ameliorated in M-depleted transplants, if not significant (P = 0.114); however, wet/dry ratio did not differ between groups (P = 0.629). The inflammatory response was significantly reduced in M-depleted mice when compared with control recipients (TNF-α, P = 0.042; TGF-ß1, P = 0.039). CONCLUSIONS: The selective depletion of M in donor lung transplants can be successfully performed and results in a sustained anti-inflammatory response upon I/R-injury. The beneficial effect of this preconditioning method should be further evaluated as a promising tool for the attenuation of I/R prior to graft implantation in clinical Tx.

Single institutional experience with primary mediastinal cysts: clinicopathological study of 108 resected cases.

PURPOSE: To review our institutional surgical outcomes with primary mediastinal cysts (PMCs) and elucidate the clinicopathological differences among several histological PMC variants. METHODS: We retrospectively reviewed 108 patients who underwent surgery for PMC at our institution between 1997 and 2012. RESULTS: There were 54 thymic cysts (TCs), 26 bronchogenic cysts (BCs), 16 mature cystic teratomas (MCTs), 11 pericardial cysts (PCs), and 1 esophageal duplication cyst. Surgical approach was via thoracoscopy in 44, thoracotomy in 24, median sternotomy in 39, and hemiclamshell incision in 1. Pathological complete resection was achieved in all patients. Postoperative complications occurred in 13 patients. There was no postoperative mortality. All patients were recurrence-free after a mean follow up of 41 ± 26 months. MCT was significantly associated with larger cyst size (p <0.001) more frequent combined resection of invaded organs (p <0.001), more intraoperative bleeding (p = 0.005), and longer duration of operation (p = 0.022) than the 3 other groups (TC, BC, and PC). CONCLUSION: Surgical treatment for PMC is safe and efficacious regardless of approach. Patients with MCT may require more aggressive surgeries than those with other histological variants, reflecting their potential for invasion into surrounding structures and larger cyst size.

Assessing lung transplantation ischemia-reperfusion injury by microcomputed tomography and ultrashort echo-time magnetic resonance imaging in a mouse model.

PURPOSE: Ischemia-reperfusion injury (I/R) is a common early complication after lung transplantation. The purpose of this study was to compare ultrashort echo-time (UTE) sequences in magnetic resonance imaging (MRI) with a microcomputed tomography (micro-CT) reference standard for detection of I/R injury in a lung transplantation mouse model. MATERIALS AND METHODS: Six mice (C57BL/6) underwent orthotopic lung transplantation using donor grafts that were exposed to 6-hour cold ischemia. Imaging was performed within 24 hours after the transplantation with high-resolution micro-CT (tube voltage, 50 kV; current, 500 mA; aluminum filter, 0.5 mm; voxel size, 35 × 35 × 35 µm³) and small-animal MRI at 4.7 T with a linearly polarized whole-body mouse coil. The imaging protocol comprised radial 3-dimensional UTE sequences with different echo times (repetition time, 8 milliseconds; echo time, 50/75/100/500/1500/3000/4000/5000 µs; voxel size, 350 × 350 × 350 µm³). Images were assessed visually and through calculation of contrast-to-noise ratio (CNR) values. Calculated S0 values and T2* transverse relaxation times (MRI) of lung parenchyma were compared with Hounsfield unit (HU) density in micro-CT images. Receiver operating characteristic curves and area under the curve values were calculated for comparison of diagnostic power. All samples underwent a histologic examination. RESULTS: The results of both UTE MRI and micro-CT showed an excellent depiction of pulmonary infiltration due to I/R injury, with MRI exhibiting a significantly higher CNR (mean [SD] CNR MRI, 19.7 [8.0]; mean [SD] CNR micro-CT, 10.3 [2.5]; P < 0.001). Measured parametrical values were as follows: mean (SD) HU, -416 (120); mean (SD) S0 value, 1655 (440); mean (SD) T2*, 895 (870) µs for the non-transplanted right lung and mean (SD) HU, 29 (35); mean (SD) S0 value, 2310 (300); and mean (SD) T2*, 4550 (3230) µs for the transplanted left lung. Slight infiltration could be better discriminated with micro-CT, whereas, in strong infiltration, a better contrast was provided by UTE MRI. The area under the curve values resulting from the receiver operating characteristic curve analysis were 0.99 for HU density, 0.89 for S0, 0.96 for T2*, and 0.98 for the combination of S0 and T2*. CONCLUSIONS: Results show that MRI of the lung has a similar diagnostic power compared with that of micro-CT regarding the detection of I/R injury after experimental lung transplantation. Both modalities provide complementary information in the assessment of dense and slight infiltration in the early phase after lung transplantation. Therefore, UTE MRI seems to be a promising addition to computed tomographic imaging in the assessment of I/R injury after lung transplantation.

Tumour standardized uptake value on positron emission tomography is a novel predictor of adenocarcinoma in situ for c-Stage IA lung cancer patients with a part-solid nodule on thin-section computed tomography scan.

OBJECTIVES: Adenocarcinoma in situ (AIS), which is considered to be pathologically non-invasive in the new International Association for the Study of Lung Cancer/the American Thoracic Society/the European Respiratory Society classification, might be present in patients who show a part-solid nodule on thin-section computed tomography (CT) scan. METHODS: Between 2008 and 2011, 556 clinical Stage IA (c-Stage IA) lung cancer patients underwent pulmonary resection. For all the patients, the findings obtained by preoperative thin-section CT were reviewed and categorized as pure ground-glass nodule (GGN), part-solid nodule or pure-solid nodule based on the findings on thin-section CT, i.e. based on the consolidation/tumour ratio (CTR). A part-solid nodule was defined as a tumour with 0 < CTR < 1.0, which indicated focal nodular opacity that contained both solid and GGN components. All the patients were evaluated by positron emission tomography (PET), and the maximum standardized uptake value (SUVmax) was recorded. Several clinicopathological features were investigated to identify predictors of AIS in clinical Stage IA lung cancer patients with a part-solid nodule radiologically, using multivariate analyses. RESULTS: One-hundred and twelve c-Stage IA lung cancer patients showed a part-solid appearance on thin-section CT. Among them, AIS was found in 10 (32%) of the tumours with 0 < CTR ≤ 0.5, in contrast to 3 (5%) with 0.5 < CTR < 1.0. According to multivariate analyses, SUVmax and CTR significantly predicted AIS in patients with a part-solid nodule (P = 0.04, 0.02). The mean SUVmax of the patients with AIS was 0.57 (0-1.6). Moreover, in the subgroup of part-solid nodule with a SUVmax of ≤1.0 and a CTR of ≤0.40, which were calculated as cut-off values for AIS based on the results for a receiver operating characteristic curve, 6 (40%) patients with these criteria showed a pathological non-invasive nature, even patients with a part-solid nodule. CONCLUSIONS: Among c-Stage IA adenocarcinoma with a part-solid nodule on thin-section CT scan, an extremely low level of SUVmax could reflect a pure GGN equivalent radiologically and AIS pathologically. The preoperative tumour SUVmax on PET could yield important information for predicting non-invasiveness in patients with a part-solid nodule.

Mastering mouse lung transplantation from scratch--a track record.

BACKGROUND: Mouse lung transplantation has evolved into an established scientific model that is currently used by an increasing number of research groups. Acquiring this technique without previous microsurgical knowledge is considered very difficult. Disclosing all the intraoperative failures and mistakes during the model's evolution will encourage all researchers who lack microsurgical skills that overcoming and eventually succeeding in this model is possible. METHODS: Inbred (C57BL/6, BALB/c, SVG129) and CD1-outbred mice served as the transplant donors and recipients. The training procedure was performed by a surgeon not experienced in microsurgery, and arranged as follows: donor preparation until proof of functionality, graft implantation into deceased recipients, and graft implantation into surviving recipients until stable performance was achieved. The transplant's viability was controlled using micro-computed tomography imaging. RESULTS: Donor preparation complications decreased from 43% after 1 month to 0% after 2 mo. The first functional donor was implanted at day 28, and the first successful implantation into a surviving recipient was performed at day 60 after six training recipients. Micro-computed tomography confirmed a ventilated and perfused graft. Intraoperative complications, mainly due to anastomosis failure, decreased from 58% after the first month to 15% at the latest assessment. The most recent implantation time was 75 ± 4.8 min, and the transplantation success rate was 82% ± 2.8%. A modified forceps considerably improved completion of the venous anastomosis. CONCLUSIONS: Consistent success in the mouse lung transplantation model can be achieved even without pre-existing microsurgical skills. The surgery can be mastered within a reasonable period using a limited number of training animals. Procedure-related complications can be restricted to a minimum by applying key corrective steps at critical phases. This should encourage investigators without pre-expert knowledge in microsurgery to start to learn this research model.

New technique for lung segmentectomy using indocyanine green injection.

One of the most difficult aspects of complete segmentectomy of the lung is the identification of the intersegmental plane. Instead of a conventional residual segment inflation method, we have developed a new technique for detecting intersegmental planes using indocyanine green medium. The technique is simple and consists of (1) ligation of the segmental vein to prevent loss of the indocyanine green and (2) injection of indocyanine green through the segmental bronchus. These two steps result in easy identification of intersegmental planes by a change of color not only of the surface but also of the parenchyma of the lung. This technique can be indicated for atypical segmentectomy.

Is limited resection appropriate for radiologically "solid" tumors in small lung cancers?

BACKGROUND: Small lung cancers showing a wide area of ground-grass opacity (GGO) on thin-section computed tomography (CT) are considered good candidates for limited surgical resection because of its minimally invasive nature. Conversely, the validity of limited resection for radiologically "solid" tumors is still controversial in small non-small cell lung carcinomas. METHODS: Between 2008 and 2010, 680 consecutive patients underwent pulmonary resection for lung cancer. The findings obtained by preoperative CT were reviewed for all 680 patients and categorized as pure GGO, mixed GGO, or purely solid. All patients were evaluated by positron emission tomography (PET) and the maximum standardized uptake value (SUV(max)) was recorded. Several clinicopathologic features were investigated to identify predictors of hilar or mediastinal lymph node metastasis using univariate or multivariate analysis. RESULTS: Two hundred twenty-seven of the patients with clinical stage IA lung cancer showed a solid or mixed GGO appearance on thin-section CT. Among them, nodal involvement was found pathologically in 42 (26%) patients with pure solid tumors, but in only 4 (6%) patients with mixed GGO tumors (p = 0.0002). Among the 131 patients with stage T1a disease, 94 (71.8%) had solid tumors, and nodal involvement was observed in 15 (16.0%). Among the 94 pure solid stage T1a tumors, the carcinoembryonic antigen (CEA) level and SUV(max) were significant predictors of lymph node involvement by tumor based on a multivariate analysis. The frequency of lymph node metastasis was approximately 27% for patients with pure "solid" lung cancer and high SUV(max), even for stage T1a tumor. CONCLUSIONS: Lymph node metastasis is frequently observed for pure solid lung cancer, especially for tumors that show a high SUV(max). If limited resection is indicated for solid lung cancer, a thorough intraoperative evaluation of lymph nodes is needed to prevent locoregional failure.

Diagnostic performance of PET/CT in differentiation of malignant and benign non-solid solitary pulmonary nodules.

OBJECTIVE: To evaluate whether [F-18] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can distinguish benign from malignant solitary pulmonary nodules (SPNs) with non-solid components. METHODS: [F-18] FDG-PET/CT scans were performed on 53 consecutive patients (30 men, 23 women; mean age 65 years) who had SPNs with non-solid components identified by CT screening for lung cancer. All patients underwent surgical resection, and all lesions were pathologically proved. Visual score, maximal, and mean standardized uptake value (SUV), and maximal and mean lesion-to-normal tissue count density ratio (LNR) were calculated in all lesions. In addition, clinical characteristics, laboratory test results, and CT findings were assessed. RESULTS: Benign SPNs with non-solid components had a higher uptake on [F-18] FDG-PET/CT. Visual score, maximal and mean SUV, and maximal and mean LNR were significantly higher in the benign when compared with the malignant SPNs (P < 0.001). When the cutoff of 1.5 was assigned for maximal SUV, the diagnostic performance of [F-18] FDG-PET/CT in predicting benign SPN revealed 100.0% sensitivity, 96.4% specificity, and 100.0% accuracy. CONCLUSIONS: [F-18] FDG-PET/CT is useful for the differential diagnosis of SPNs with non-solid components.

Multiple lung adenocarcinomas showing ground-glass opacities on thoracic computed tomography.

It is difficult to distinguish multiple primary lung cancers from pulmonary metastasis. We experienced a case of surgically resected lung tumors that showed multiple ground-glass opacities on thoracic computed tomographic scan. There were eight nonsolid and two part-solid ground-glass opacities in the bilateral lungs. Surgical resection was performed because all tumors had a ground-glass opacity appearance on computed tomographic scan, which is compatible with a finding of primary lung adenocarcinoma. The postoperative pathologic diagnoses were two cases of invasive adenocarcinoma, six cases of bronchioloalveolar carcinoma, and eight cases of atypical adenomatous hyperplasia. The patient remains alive without any evidence of recurrence 40 months after surgery. A ground-glass opacity appearance on computed tomographic scan could be interpreted as supportive evidence for multiple primary lung adenocarcinoma rather than pulmonary metastases.