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Objectives Assessment of proliferation by the Ki-67 labelling index ( Ki67- LI) is an important parameter of pancreatic neuroendocrine tumour ( pNET) prognosis on resection specimens. Ki67- LI values for grading are not fully established on endoscopic ultrasound-guided fine needle aspiration ( EUS- FNA). The aim of the study was to determine the accuracy of Ki67- LI on EUS- FNA to predict a final grade of p NET and to analyse the relationship between cytological grading and progression-free survival ( PFS). Methods Between 1996 and 2010, 46 pNETs (33 were resected) from 45 patients were diagnosed by EUS- FNA. Ki67-LI was evaluated on cytological and histological material for each tumour and classified according to the 2010 WHO grading system. Results A very good inter-observer agreement for Ki67- LI on EUS- FNA and surgical specimens, respectively, were obtained. Discrepancies were observed between histology and cytology, especially in grade 2 ( G2) tumours, where cytology underestimated grading owing to tumour heterogeneity. Still, EUS- FNA was able to distinguish a poor prognostic group, as the actuarial PFS of cytological (c) G3 tumours was 10 ± 4 months versus 29 ± 7 and 68 ± 10 for c G2 and c G1 tumours, respectively ( P < 0.0001). Conclusion This study attests the reproducibility of Ki67- LI of pNETs whether counted on cytology or histology with a very good inter-observer correlation. Determination of Ki67- LI on EUS- FNA of pNETs should be included systematically in their prognostic work-up. [ABSTRACT FROM AUTHOR]

Objectives: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a routine technique to assess solid pancreatic lesions. The aim of this study was to analyse the effect of optimizing laboratory procedures for specimen preparation on the rate and accuracy of the procedure. Methods: All EUS-FNAs of solid pancreatic lesions performed during the year 2000 (Period 1) and from May 2003 to May 2004 (Period 2) were analysed. During Period 1, one experienced gastroenterologist performed all EUS-FNAs, making direct smears and retrieving small fragments if present on the smear for histology. In Period 2, two endoscopists performed the EUS-FNAs and all the material was emptied into a vial containing a fixative. Slide preparation was carried out in the pathology laboratory: one slide was processed using cytocentrifugation and cell blocks were made from left-over material. Neither period utilized rapid on-site evaluation. Results: During the two periods, 67 and 102 FNAs were analysed and showed significantly different ( P < 0.001) non-diagnostic rates of 22.8% and 4.2%, respectively. The increased diagnostic yield can be explained by the modified laboratory procedures and to a lesser extent by the increased experience of the gastroenterologists. Sensitivity, specificity, PPV, NPV and accuracy in the second time period were, respectively, 90.6%, 100%, 100%, 81.8% and 93.4%, not significantly different from the first time period. Conclusion: This study shows that accurate EUS-FNA results may be obtained with a low non-diagnostic rate comparable to those reported for rapid on-site evaluation by optimizing laboratory specimen processing in a setting of solid pancreatic lesions. [ABSTRACT FROM AUTHOR]

Clin Microbiol Infect 2010; 16: 671–675 The present study aimed to validate ThermoFisher’s (Thermo Fisher Scientific, Runcorn, Cheshire, UK) Papspin (PS) for human papillomavirus (HPV) testing by in-house PCR and by the Hybrid Capture II (HC2) assay and to compare the results with those obtained using Specimen Transport Medium (STM) (Digene Diagnostics, Gaithersburg, MD, USA). Forty-five patients underwent conization for known lesions ranging from atypical squamous cells of undetermined significance (ASC-US) with high-risk HPV (hr-HPV) to high-grade squamous intraepithelial lesion (H-SIL/CIN2+) or adenocarcinoma. Two negative controls were included: one patient with post-menopausal bleeding and another from whom an inflammatory cervical sample was taken without conization. Prior to conization, a gynaecologist collected two cervical samples, fixed in PS or STM, from each patient. All but four cases were tested for panHPV (GP5+/GP6+) and specific hr-HPV subtypes (HPV16, 18, 31,33) by PCR using both media and all were processed for HC2. This study demonstrates that both HPV detection techniques work with PS, showing a specificity of 78.3% for HC2 and 92.8% for PCR compared to 83.8% for HC2 and 92% for PCR using STM. The efficacy of detecting HPV in PS-preserved H-SIL/CIN2+ was very high (96% for PCR using PS and 86% for HC2 using PS), which was in the same range as for PCR using STM, and which was only slightly lower than for HC2 using STM (96% and 89%, respectively). The differences were not statistically significant. It is concluded that ThermoFisher’s PS is a valid liquid-based cytology medium for cervical samples, convenient for HPV testing by PCR with GP5+/GP6+ primers and by the HC2 assay. [ABSTRACT FROM AUTHOR]

Post-infectious bronchiolitis obliterans (PIBO) forms a chronic obstructive lung disease in children following a severe viral respiratory infection. Subsequent dysanaptic lung growth, with differential development of the alveolar compartment over the airway compartment, was clinically described, but remains elusive. We therefore performed a detailed 3D airway characterization in PIBO compared to bronchiolitis obliterans syndrome (BOS) after lung transplantation and discarded donor lungs. Explant lungs from matched adult patients who underwent lung transplantation for end-stage PIBO (n=5), redo lung transplantation patients with end-stage BOS (n=5), and discarded donor lungs (n=5) were included. Lungs were air-inflated and frozen in fumes of liquid nitrogen. Ex vivo computed tomography (CT) scans (resolution 700 µm) were obtained and used for radiologic scoring and semi-automated 3D airway segmentation. Next, frozen lungs were sampled on matched locations (n=4/lung) and scanned with microCT (resolution 10 µm). Radiologic scoring indicated more airway wall thickening (p=0.079), bronchial dilatation (p=0.087), and pleural thickening (p=0.071) in PIBO vs BOS. The number of airways per generation was similar between groups (p=0.53), but airway diameters were increased in PIBO (generation 6-11) and in BOS lungs (generation 7-10) compared to controls, without differences between PIBO and BOS. Significantly more airways ended in BO lesions in BOS vs PIBO (p=0.016, mean 25.60% vs 12.60%), although the size of the BO lesions was increased in PIBO vs BOS (p=0.032, median 27.23mm³ vs 5.01mm³). Subsequent micro CT assessment revealed a significant lower number of terminal bronchioles (TB) in PIBO (p=0.0009, PIBO: mean 3131 TB/lung, BOS: 8360 TB/lung, controls: 10342 TB/lung), although diameters of TB were similar across groups (p=0.37). In addition, alveolar spaces tended to be larger in PIBO (p=0.070). 3D micro CT analysis confirmed that in BOS, BO lesions are only segmental with preserved TBs, while in PIBO, the airway is completely lost following the obstruction. PIBO lungs displayed a more than two-fold decrease in TB compared to BOS, with fewer but larger BO lesions and non-reopening of airways distal from BO. Our findings provide potential pathophysiologic evidence of dysanaptic lung growth in PIBO. [ABSTRACT FROM AUTHOR]

Puumala virus (PUUV) is considered a classic Old World etiologic agent of nephropathia epidemica (NE), or hemorrhagic fever with renal syndrome (HFRS). HFRS is considered to be distinct from hantavirus (cardio-)pulmonary syndrome (HPS or HCPS), described in the New World. Here, we report a severe case, which fulfilled most, if not all, Centers for Disease Control and Prevention (CDC) criteria for HPS, needing non-invasive ventilation and subsequent acute hemodialysis. However, the etiological agent was PUUV, as proved by serological testing, real-time polymerase chain reaction (PCR), and sequencing. Viral antigen was detected by specific anti-PUUV immunostaining, showing, for the first time, greenish intracytoplasmic inclusions in bronchoalveolar lavage (BAL) macrophages. This case definitely confirms that HPS can be encountered during PUUV infections. Interestingly, special findings could render the diagnosis easier, such as greenish homogeneous cytoplasmic inclusions, surrounded by a fine clear halo in BAL macrophages. Therefore, although the diagnosis remains difficult before the onset of renal involvement, the occurrence of severe respiratory failure mimicking community-acquired pneumonia must alert the clinician for possible HPS, especially in endemic areas. [ABSTRACT FROM AUTHOR]

Donor organ shortage, in combination with a 70% decline rate of offered donor lungs, results in significant wait list mortality and time with poor quality of life. Assessing donor lungs for transplant suitability is based on donors' history, gas exchange, chest X-ray, bronchoscopy, and in situ visual inspection; but donor lung acceptance remains subjective. We performed an in depth histopathologic and radiologic assessment of retrieved but unused donor lungs. We assessed 62 donor lungs not used for transplantation for various reasons between 2010 and 2019. These lungs were air-inflated, frozen, scanned with computed tomography, systematically sampled on 4 different locations, assessed macroscopically and microscopically by two experienced lung pathologists and by an experienced thoracic radiologist, all blinded for the reason of decline. Reasons for non-use are summarized in the figure. Thirty-nine (63%) lungs were not used for allograft-related reasons. In 13/39 (33%) lungs, the reason for decline could not be confirmed by histologic assessment (emboli, n=7; pneumonia, n=3; contusion, n=2; emphysema, n=1), in an additional 8/39 (21%) lungs, histologic abnormalities were only considered focal and mild (emphysema, n=5; pneumonia, n=3). In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) of 62 unused donor lungs were not transplanted due to extra pulmonary causes, of which 3 (13%) lungs displayed severe histologic abnormalities (pneumonia, n=2; emphysema, n=1), in addition to mild emphysema in 9 (39%) lungs and mild bronchopneumonia in 1 lung (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) of these donor lungs. Histologic and radiologic assessment of unused donor lungs revealed substantial discrepancy with the clinical reason for decline. Prior chest CT imaging and frozen sections in selected cases might contribute to adequate donor assessment and augment current yield of donor lungs. [ABSTRACT FROM AUTHOR]

Acanthamoeba infection is a rare, difficult-to-treat, and often fatal, opportunistic parasitic infection in immunocompromised hosts, such as patients infected with HIV. We describe an aggressive nasal and sinus infection by Acanthamoeba spp. in a person with AIDS. The resolution of this Acanthamoeba infection was secondary to a multidisciplinary treatment approach involving a combination of surgery as well as high-dose amphotericin B plus 5-fluorocytosine. In the era of the HIV/AIDS pandemic, the present report underscores the need for early identification and prompt aggressive treatment to ensure successful management of this rare but potentially fatal opportunistic infection. [ABSTRACT FROM AUTHOR]

Acanthamoeba infection is a rare, difficult-to-treat, and often fatal, opportunistic parasitic infection in immunocompromised hosts, such as patients infected with HIV. We describe an aggressive nasal and sinus infection by Acanthamoeba spp. in a person with AIDS. The resolution of this Acanthamoeba infection was secondary to a multidisciplinary treatment approach involving a combination of surgery as well as high-dose amphotericin B plus 5-fluorocytosine. In the era of the HIV/AIDS pandemic, the present report underscores the need for early identification and prompt aggressive treatment to ensure successful management of this rare but potentially fatal opportunistic infection. [ABSTRACT FROM AUTHOR]

Motilin-secreting neuroendocrine tumours have been rarely described. Immunohistochemical, biochemical and motility investigations were performed in a 62-year-old man with liver and bone metastases of a motilin-secreting neuroendocrine tumour originating from a rectal polyp removed 14 years previously. Symptoms related to liver metastases were reduced by a right hepatectomy whereas plasma motilin levels were decreased. The patient also underwent two operations for spinal cord decompression and survived 6 more years under medical treatment, mainly octreotide. Immunohistochemistry revealed predominant expression of motilin-containing cells, with rare cells expressing somatostatin and pancreatic polypeptide, and staining for only one panendocrine marker, neurone-specific enolase. A liver tumour extract contained 17.9 μg motilin per gram of tissue, which permitted to isolate and characterize human motilin, which was identical to porcine motilin. Plasma column gel chromatography revealed a main peak corresponding apparently to porcine motilin. The patient had no symptoms of disturbed motility. Gastric emptying and gastroduodenojejunal motility were found within normal limits. The absence of alterations of gut motility was perhaps related to sustained autonomous motilin production. The long evolution of this type of tumour suggests that plasma motilin determination should be added to the investigations for neuroendocrine tumours.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Bacillary angiomatosis is an infection caused by Bartonella, which has first been described in human immunodeficiency virus (HIV)–infected patients. We report an unusually located lesion, in a totally asymptomatic kidney transplant recipient. The diagnosis was strongly suggested based on the iconography and our histological analysis, but was not confirmed using polymerase chain reaction (PCR) and immunohistochemical studies. We illustrate our difficult way to the diagnosis as well as the course of the disease and our therapeutic strategy. [Copyright &y& Elsevier]

• Discordant ALK immunohistochemistry positive (IHC) FISH negative NSCLC occurs at low frequency. • Not all locally performed ALK IHC and FISH test were centrally confirmed. • Prognosis of concordant ALK IHC and FISH positive NSCLC is similar as literature. • Prognosis of validated discordant ALK IHC positive FISH negative NSCLC is significantly lower. • In NSCLC a positive ALK IHC screentest should be followed by ALK FISH. Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78–7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2–15.9; p=0.010. ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. [ABSTRACT FROM AUTHOR]

We report a case of crizotinib effectiveness in a heavily pretreated patient with a metastatic NSCLC initially considered IHC-positive and FISH-negative for ALK rearrangement. After repeated analyses of tumor samples, borderline ALK FISH-positivity (18.5% positive cells) was demonstrated. [ABSTRACT FROM AUTHOR]

Donor-transmitted vascular tumors are a rare complication after lung transplantation. A 35-year-old woman underwent bilateral lung transplantation for primary ciliary dyskinesia. Three years post-transplant, a nodule in the right upper lung lobe was detected on routine computer tomography. Wedge resection showed a hemangioma. One year later, two new lung nodules, as well as two liver lesions appeared, and vascular lesions without signs of malignancy were diagnosed on laparoscopic liver biopsies. After switching from tacrolimus to sirolimus, the volume of the lesions significantly decreased. However, two years later, mixed solid tissue lesions developed in both ovaries, while the lung and liver lesions gradually increased in volume again. Histological examination after bilateral salpingectomy was compatible with bilateral angiosarcoma. Tumor analysis by haplotyping and human leukocyte antigen typing showed mixed donor-chimerism, proving that the tumoral lesions in the lungs and ovaries were of donor origin. In retrospect, the donor became brain death following brain surgery complications for a previously biopsy-proven cerebral hemangioma, which is believed to have been a precursor lesion of this vascular malignancy. Our case highlights a unique course of donor-related angiosarcoma, finally diagnosed 6 years after lung transplantation. Donor-origin of tumors detected in solid organ recipients should always be suspected in case of uncommon disease course or histology, and proper tissue-based diagnosis using sensitive techniques should be pursued, given the possible implications for treatment and outcome of other organ recipients in case of multi-organ donation. [ABSTRACT FROM AUTHOR]

Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD) by analyzing CTGF expression in broncho-alveolar lavage (BAL) fluid, plasma and lung tissue. Sixty matched lung transplant patients were included (stable, n=20; bronchiolitis obliterans syndrome (BOS), n=20, restrictive allograft syndrome (RAS), n=20). CTGF expression was analyzed in BAL 3m post-transplant, 1y post-transplant, and at CLAD diagnosis or 2y post-transplant for stable patients. Explant lung tissue of CLAD (BOS, n=20; RAS, n=20), pulmonary GHVD (n=9), and discarded donor lungs (n=20) was immunohistochemically stained for CTGF. BAL CTGF protein expression was significantly higher at 3m post-transplant in patients who later developed RAS compared to stable or BOS patients (ANOVA p=0.028); while CTGF expression was similar at 1y post-transplant (ANOVA p=0.20). At CLAD diagnosis, CTGF expression was significantly increased in RAS compared to stable (p=0.0007) and BOS (p=0.042). Serial analysis revealed no difference in CTGF values between time points for stable and BOS patients (ANOVA p=0.84, p=0.92), whereas CTGF levels were significantly higher in RAS at CLAD diagnosis compared to 1y post-transplant (ANOVA p=0.029). CTGF plasma values were similar between BOS, RAS, and stable (ANOVA p=0.74). Immunohistochemistry revealed a higher percentage and intensity of CTGF positive respiratory epithelial cells in BOS and RAS lungs compared to controls (ANOVA p<0.0001), without significant difference between BOS and RAS (p=0.47). There was consistent strong CTGF positivity in BO lesions. CTGF expression in endothelial cells was significantly higher in BOS and RAS compared to controls (p=0.011 and p=0.0005). Fibroblasts in fibrotic regions of RAS were strongly CTGF positive. Pulmonary GVHD displayed similar CTGF staining as in CLAD. Higher CTGF expression is present in BAL from RAS patients at CLAD diagnosis. Lung tissue CTGF expression is increased in end-stage RAS, BOS and pulmonary GVHD. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD, which warrants further investigation of CTGF and its potential therapeutic modulation in these conditions. [ABSTRACT FROM AUTHOR]

Background To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Cetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls. Results Cetuximab given 24 h before surgery was safe. Ninety percent of patients had 18FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than −25% or less than −50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003). Conclusions Short-course pre-operative administration of cetuximab is safe and shows a high rate of 18FDG-PET response. 18FDG-PET response was correlated with residual tumour cellularity suggesting that 18FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN. [ABSTRACT FROM PUBLISHER]

Fine needle aspiration cytology (FNAC) is practised widely throughout Europe. The majority of countries have dedicated cytopathologists as well as histopathologists practicing cytology. Despite this, FNAC is performed mostly by clinicians and radiologists except in the larger centres with dedicated staff with a special interest in cytopathology. The advent of One-Stop diagnostic services and image-guided procedures are prompting further development of FNAC clinics where cytopathologists take their own samples, issue reports in the same clinical session and take extra material for ancillary tests to complete the diagnosis. The volume of FNAC work varies accordingly; in dedicated centres FNAC represents up to 80% of the workload whilst, in the majority of countries, it represents one quarter or less. Hence, the rate of inadequate FNAC varies widely, depending on the local sampling policies and the organ, but does not exceed 25% in any of the countries. The most sampled organs are breast and thyroid, followed by lymph nodes. Most countries have dedicated training in cytopathology for pathology trainees, the duration varying between 6 months and 2 years of the total training time. This discussion, focusing on European practices, highlights the heterogeneity of FNAC activity but also its success in many centres where it is practiced to a high standard, particularly in breast, thyroid and lymph node pathology. The relatively high rate of inadequate material in some centres reflects local policies and calls for greater uniformity of FNAC practice, particularly specimen sampling. To achieve this, the future direction should concentrate on specialist training, to include performing as well as interpreting FNAC, as part of the curriculum. Current emphasis on web-based training may not provide first hand experience of the FNAC procedure and should be supplemented by attending FNAC clinics and developing the technique to its full potential. [ABSTRACT FROM AUTHOR]

Comments on the state of the study and practice of cytopathology in Belgium in 2005. Progress of the work started by cytopathologists in the country; Explanation of why there is no institution in the country that provides training for psychopathologists; Directions for the future.

Reports on the the discussion during the symposium on the topic related to pleural lesions. Cases related to synovial sarcoma of the pleura; Description of mucin positive mesotheliomas; Morphological diversity of malignant mesothelioma.

Purpose Chronic pulmonary graft versus host disease (cpGvHD) is a diverse and underestimated complication following allogenic hematopoietic stem cell transplantation (alloHCT). We aimed to compare the airway architecture with chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). Methods Inflated explant lungs from cpGvHD patients, retrieved at lung transplantation, were compared to lungs with CLAD following LTx and unused donor lungs as controls, matched according to age and gender, using a combination of CT, whole lung microCT (80µm resolution), tissue microCT (10µm resolution) and histopathology (n=6 per group), aiming to quantify histopathologic findings in (small) airways. Results Following alloHCT, 3 patients presented as BOS and 3 patients showed interstitial changes and restriction. CT analysis demonstrated a strong similarity between BOS after LTx and post- alloHCT, evidenced by a similar airway count compared to controls but severe (>50%) airway obstruction from generation 7, with whole lung microCT demonstrating that 70.8% of the airways ended in obstruction (figure). Further analysis indicated that bronchioles either collapsed or accumulated matrix along a segment of the airway (figure). In patients with restriction and interstitial changes following alloHCT, the degree of airway obstruction was lower compared to BOS post-alloHCT, but similar to RAS post-LTx, showing a lower proportion of airway obstruction (±35%), decreased number of terminal bronchioles per lung (p<0.01) and parenchymal fibrosis (p<0.01) as evidenced by microCT analysis. Conclusion We observed similarities in airway pathology in chronic pulmonary GvHD and CLAD following LTx, suggesting similar pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Purpose Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), have been identified as main phenotypes of chronic lung allograft dysfunction (CLAD), however patients can change phenotype. We aimed to describe incidence, prognosis, radiology, pulmonary function and pathology in this mixed group of CLAD. Methods We retrospectively assessed the chest CT-scans of all double lung patients transplanted between 2001 and 2015 with a FEV1 decline >20% of baseline. The diagnosis of RAS was made using a decline in TLC>10% compared to baseline or a decline in FVC>20% compared to baseline. A mixed group of CLAD was defined as patients developing a TLC or FVC decline with persistent CT opacities after initial CLAD diagnosis (without TLC or FVC drop) or vice versa. Results 44% of the patients developed CLAD (268/608) of which 77 developed persistent CT opacities (29%). 45 patients were immediately diagnosed with RAS. We found twenty-seven patients with a mixed phenotype of CLAD (25 BOS to RAS, 2 RAS to BOS). In 5 patients persistent pleuroparenchymal opacities were found without an additional decrease in FVC or TLC. The median time between CLAD and mixed diagnosis was 2Y (IQR 0.9-4.8Y). Median survival after CLAD diagnosis was longer in the mixed group compared to the RAS group (4.3Y vs 1.17, p=0.0052), however survival after the appearance of opacities was similar in both groups (p=0.39). We found significantly more emphysema patients in the mixed group (p=0.0062), with a lower FEV1 (p<0.0001) and lower FEV1/FVC (p=0.0002) at diagnosis. In the mixed group, TLC was decreased by 10% in all patients, while the FVC was only decreased in a minority of the patients (36%). Radiology at diagnosis in the mixed group showed a significant apical predominance of the opacities, whereas there was no specific preponderance of CT opacities in the RAS group (p=0.0029). Pathology of explant specimens at autopsy or redo-transplantation showed a predominant pattern of organising pneumonia in the RAS group (55% vs 22%, p=0.13) and pleuroparenchymal fibro-elastosis in the mixed group (67% vs 40%; p=0.25). Conclusion We demonstrated that 35% of patients showed a mixed phenotype of CLAD, which showed difference in survival, demographics, pulmonary function, radiology and pathology compared to RAS patients. [ABSTRACT FROM AUTHOR]

Purpose Acute fibrinous and organizing pneumonia (AFOP) after lung transplantation has recently gained attention as it may result in a rapid decline in respiratory function and death; or chronic lung allograft dysfunction (CLAD) in patients surviving the acute onset. We investigated the effect of fibrin deposition and organizing pneumonia (OP) in transbronchial biopsies (TBB) from lung transplant patients on graft survival and CLAD-free survival. Methods We reviewed all pathology reports of TBB obtained from 468 patients who underwent lung transplantation in the University Hospital Leuven between 2011 and 2017 (follow-up until 9/2018). The presence of intra-alveolar fibrin deposition or OP was assessed and defined as early (< 3 months) or late (> 3 months). CLAD was defined as a persistent FEV1 decline (<80%); restrictive allograft syndrome (RAS) was defined by an additional >10% decline in total lung capacity and the presence of persistent radiological opacities. Results The presence of early and late fibrin deposition or OP was detected in 23 (5%) and 28 (6%) patients, respectively. CLAD was diagnosed in 107 (22.9%) of 468 patients (median time to CLAD = 2.90y, IQR [1.41-4.78]), in 4 of 23 patients (17.4%) with early fibrin or OP (1 RAS +), and in 16 of 28 patients (57.1%) with late fibrin or OP (12 RAS +). CLAD-free survival was significantly lower in patients with late fibrin or OP (p<0.0001, median survival 2.64y) compared to patients without or with early fibrin or OP (median survival >7.68y and >7.64y, respectively). The presence of late fibrin or OP significantly increased the risk of later RAS (OR: 13.31; CI [3.871 - 40.2], p<0.0001), whereas early fibrin or OP showed no correlation with RAS (p=0.57). Similarly, graft survival was significantly lower in patients with late fibrin or OP (p=0.0008, median survival 4.46y) compared to patients without or with early fibrin or OP (median survival >7.81y and >7.77y, respectively). Patients with late fibrin or OP mostly died from CLAD (n=10, 9 RAS +), humoral rejection (n=2), sepsis (n=1), or tuberculosis (n=1). Conclusion The pathologist should actively search for fibrin and OP in TBB, as it is associated with worse prognosis and a high risk of subsequent CLAD development, specifically RAS. This indicates that the presence of late fibrin and OP in TBB could be an early pathologic manifestation of later RAS development. [ABSTRACT FROM AUTHOR]