Real-time and non-invasive acute lung rejection diagnosis using confocal LASER Endomicroscopy in lung transplant recipients: Results from the CELTICS study.

BACKGROUND AND OBJECTIVE: Traditionally, the diagnosis of acute rejection (AR) relies on invasive transbronchial biopsies (TBBs) to obtain histopathological samples. We aimed to evaluate the diagnostic yield of probe-based confocal laser endomicroscopy (pCLE) as a complementary and non-invasive tool for ACR screening, comparing its results with those obtained from TBBs. METHODS: Between January 2015 and April 2022, we conducted a retrospective study of all lung transplant recipients aged over 18 years at Toulouse University Hospital (France). All patients who underwent bronchoscopies with both TBBs and pCLE imaging were included. Two experienced interpreters (TV and MS) reviewed the pCLE images independently, blinded to all clinical information and pathology results. RESULTS: From 120 procedures in 85 patients, 34 abnormal histological samples were identified. Probe-based confocal laser endomicroscopy revealed significant associations between both alveolar (ALC) and perivascular (PVC) cellularities and abnormal histological samples (p<0.0001 and 0.003 respectively). Alveolar cellularity demonstrated a sensitivity (Se) of 85.3 %, specificity (Spe) of 43 %, positive predictive value (PPV) of 37.2 % and negative predictive value (NPV) of 88.1 %. For PVC, Se was 70.6 %, Spe 80.2 %, PPV 58.5 % and NPV 87.3 %. Intra-interpreter correlation (TV) was 88.3 % for the number of vessels (+/-1), 98.3 % for ALC and 90 % for PVC. Inter-interpreter correlation (TV and MS) was 80 % for vessels (+/-1), 97.5 % for ALC and 83.3 % for PVC. CONCLUSION: Our study demonstrates the feasibility of incorporating pCLE into clinical practice, demonstrating good diagnostic yield and reproducible outcomes in the screening of AR in lung transplant recipients.

[A case of bronchiectasis due to light chain deposition disease]. / Histoire naturelle d'une forme bronchectasiante de la maladie à dépôts de chaînes légères.

INTRODUCTION: The natural history of orphan lung diseases is often unclear. We report the long-term follow-up of a case of bronchiectasis due to pulmonary non amyloid light chain deposition disease (LCDD). CASE REPORT: A 50-year-old woman who was a smoker, was diagnosed with diffuse thin walled bronchiectasis of uncertain origin after presenting with a respiratory tract infection. Ten years later, the combination of bronchiectasis, the appearance of pulmonary cysts and the identification of increased kappa free light chains evoked the diagnosis of pulmonary LCDD. The diagnosis was confirmed by lung biopsy. No immunoproliferative disorder was identified. During the 12 years follow-up, dyspnea worsened progressively and bronchiectasis and lung cysts extended leading to multicystic lung disease. Pulmonary function tests did not show any ventilatory defect but a small decrease in carbon monoxide transfer factor occurred. CONCLUSION: We describe the evolution of a rare presentation of isolated pulmonary LCDD, characterized by cystic diffuse atypical bronchiectasis with thin walls, associated with progressive cystic destruction of the lung parenchyma. The possibility of pulmonary LCDD should be considered in cases of atypical bronchiectasis of unknown etiology.

[Proteomics, a new tool for an accurate typing of amyloidosis]. / La protéomique, une nouvelle technique pour un typage optimal des amyloses.

Amyloidosis is a rare group of diseases related to extracellular deposition of proteins in an insoluble beta-pleated sheet structure presenting a characteristic apple-green birefringence under polarized light after Congo red staining. Thirty types of proteins are known to cause amyloidosis. The accurate identification of the amyloid protein is of paramount importance since it is a key step for the clinical management and personalized treatment. Amyloid typing is usually based on immunohistochemistry and immunofluorescence on tissular sections. This approach has several limits leading to a subtyping failure rate of 15 to 58% of cases. To overcome these difficulties, proteomic methods have been developed to characterize directly the amyloid protein. The most advanced technique carried out on fixed and paraffin-embedded tissue consists of laser microdissection followed by mass spectrometry. The type of amyloidosis can be determined in more than 95% of cases. However, the experience for this technique is very limited apart from the Mayo Clinic (Rochester, United States). In France, a very close proteomic assay has been implemented in the department of pathology of Foch Hospital with similar results. The introduction of proteomics in clinical practice represents a major improvement for typing amyloidosis. In this article, we discuss the benefits and limits of the different techniques used for amyloid classification and we briefly report our proteomic results.

Immunohistochemical study of HLA-G expression in lung transplant recipients.

Human leukocyte antigen-G (HLA-G), a nonclassical HLA class I protein, promotes immune tolerance of solid-organ allografts, yet its role in lung transplantation (LTx) is unknown. We examined the expression of HLA-G in lung allografts through immunohistochemistry by a cross-sectional study of 64 LTx recipients, classified into four groups (stable patients, acute rejection [AR], bronchiolitis obliterans syndrome [BOS] and symptomatic viral shedders). A marked expression of HLA-G in bronchial epithelial cells (BEC) was frequently observed in stable recipients (n = 18/35 [51%]), but not in patients with AR (n = 14) or with BOS (n = 8). HLA-G was also expressed by 4 of 7 symptomatic viral shedders. In addition, HLA-G-positive patients from the stable group (n = 35) experienced lower incidence of resistant AR and/or BOS during long-term follow-up, as compared with their HLA-G-negative counterparts. Finally, in vitro data showed that interferon-gamma, a cytokine present in lung allograft microenvironment, upregulated HLA-G mRNA and protein expression in primary cultured human BEC. We conclude that HLA-G expression in the bronchial epithelium of lung allograft is elevated in some LTx recipients in association with their functional stability, suggesting a potential role of HLA-G as a tolerance marker.

Pathomechanisms of cyst formation in pulmonary light chain deposition disease.

Cystic lung light chain deposition disease (CL-LCDD) is a recently described rare disorder characterised by numerous cysts and diffuse monoclonal nonamyloid light chain deposits surrounded by macrophagic giant cells. The mechanisms responsible for cyst development remain unknown. The objectives of the present study were to analyse the major components of the pulmonary extracellular matrix in CL-LCDD and to determine the influence of metalloproteinases (MMPs) by comparison with other cystic lung disorders. A virtually complete degradation of the elastic network was found in CL-LCDD. To a lesser degree, loss of fibrillar and basement membrane collagens was also observed. Macrophagic giant cells expressed MMP-1, MMP-2, MMP-9, MMP-12 and MMP-14 and in situ zymography highlighted a strong gelatinolytic activity. As in CL-LCDD, cystic lesions in Langerhans' cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM) were characterised by the lack of elastic fibres. Similarly, MMP were expressed in CL-LCDD and LCH but the labelled cells were different. In contrast, few MMPs were detected in LAM. In conclusion, elastolysis is common to cystic lung light chain deposition disease and other cystic lung disorders, suggesting its implication in cyst formation. Moreover, in cystic lung light chain deposition disease, a role of metalloproteinases in elastolysis is strongly indicated by the metalloproteinase expression and activity pattern.

Light chain deposition disease involving the airways: diagnosis by fibreoptic bronchoscopy.

Light chain deposition disease (LCDD) infrequently affects the lungs and usually causes damage to the parenchyma, while bronchial involvement appears to be very rare. The present authors report the case of a 64-yr-old female with LCDD characterised by asymptomatic airway involvement. Ten months after excision of a poorly differentiated vaginal carcinoma, a routine chest computed tomography (CT) scan revealed two lung cysts, several bilateral nodules and diffuse bronchial thickening. Pulmonary function tests were normal. Fibreoptic bronchoscopy showed marked diffuse mucosal thickening with highly conspicuous vascular plexuses. Nonamyloidal deposits were found in the bronchial wall, but no definite diagnosis could be proposed. On follow-up, the patient was still asymptomatic and the CT scan and endoscopic appearance remained unchanged. The final diagnosis of kappa LCDD was established 18 months later by another series of bronchial biopsies with frozen samples. Interestingly, electron microscopy showed dense granular deposits associated with nonamyloidal fibrils. An increased number of lung cysts were observed 32 months after identification of bronchial abnormalities, confirming the progressive nature of the disease. No extrapulmonary deposits or immunoproliferative disorder were found. In conclusion, light chain deposition disease, which may remain latent for several years, can entirely involve large airways and may be diagnosed by bronchial biopsy.

[Exogenous lipoid pneumonia associated with pulmonary and hepatic sarcoidosis]. / Pneumopathie lipidique exogène associée à une sarcoïdose systémique avec atteinte hépatique nodulaire.

INTRODUCTION: In a patient with basal alveolar shadowing the diagnosis of exogenous lipoid pneumonia (ELP) requires a past history of chronic ingestion of liquid paraffin and the presence of numerous macrophages containing oil droplets in the bronchial lavage (BL). Additional radiological abnormalities suggest an associated disease, notably infection or cancer, as has been described in the literature. CASE REPORT: We report the case of a 50 year old woman presenting with alveolar shadowing in the left lung associated with ipsilateral mediastinal nodes and a pleural effusion in addition to two hepatic nodules. As the diagnosis of ELP did not explain the radiological features a thoracotomy and liver biopsies were performed. Histological examination of the hepatic, pulmonary and lymph node biopsies excluded cancer and mycobacterial disease and showed a florid granulomatous foreign body reaction associated with pulmonary and hepatic sarcoidosis. After a 3 month course of oral corticosteroids the mediastinal lymphadenopathy, pleural effusion and hepatic nodules resolved. The patient has maintained her recovery without further treatment for 4 years. CONCLUSION: The final diagnosis was ELP and systemic sarcoidosis with nodular hepatic involvement.

From humoral rejection to generalized thrombotic microangiopathy--role of acquired ADAMTS13 deficiency in a renal allograft recipient.

A 9-year-old renal transplant recipient presented with elevated serum creatinine levels 4 years post-transplant renal biopsy revealed humoral rejection including lesions suggestive for thrombotic microangiopathy (TMA). He received methylprednisolone pulses followed by a normalization of serum creatinine. Two more steroid responsive acute rejection episodes occurred. Two months later he presented rapidly progressive life threatening symptoms including bilateral pyramidal syndrome and hemoptysis. Serum haptoglobin became undetectable at this time and platelet count decreased (70000/microl), suggesting TMA. Cerebral MRI revealed generalized ischemic white matter lesions. ADAMTS13 activity decreased to < 5%. Daily plasma exchanges (PE) resulted in immediate improvement. All attempts to discontinue PE were unsuccessful. Transplantectomy resulted in normalization of generalized symptoms, hemolysis and ADAMTS13 activity (110%). Multi-organ involvement has never been reported in acquired ADAMTS13 deficiency post-transplant. Rapid resolution after transplantectomy might suggest that renal TMA was responsible for acquired ADAMTS13 deficiency and thereby triggered the generalization of TMA lesions.

Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) remains the leading cause of morbidity/mortality following lung transplantation. In recipients with BOS, markers predicting the decline in lung function are needed. The aim of this longitudinal study was to determine whether exhaled nitric oxide fraction (FeNO) measurements provide useful information for discriminating patients with unstable BOS from those with stable BOS. During a 14-month period, 145 FeNO measurements were performed in 50 lung transplant recipients. Among them, 16 recipients with BOS (32 FeNO measurements) were analysed. For each FeNO measurement, the patients were classified into three groups according to the decline in forced expiratory volume in one second (FEV1) within the following 6 months: 1) stable BOS free; 2) stable BOS (decline in FEV1 of <5%); and 3) unstable BOS (decline in FEV1 of > or =15%). The mean FeNO in patients with unstable BOS was significantly increased compared with that in stable BOS-free patients (18.4+/-5.7 versus 9.7+/-3.7 ppb) and that in patients with stable BOS (18.4+/-5.7 versus 9.7+/-3.3 ppb). The present findings suggest that, in patients with bronchiolitis obliterans syndrome, a raised exhaled nitric oxide fraction may predict the development of worrisome functional impairment during long-term follow-up.

[Intraosseous meningioma of the skull: radiologic pathologic correlation]. / Méningiome intra-osseux de la voûte du crâne: confrontation anatomo-radiologique.

Intraosseous meningiomas are rare ectopic meningiomas. The authors report the case of a hyperostotic intraosseous meningioma of the parietal bone without dural extension. The preoperative imaging findings, as well as imaging features of the surgical specimen and pathologic findings are discussed.

Diffusion-weighted MR imaging and pathologic findings in adult cerebellar medulloblastoma.

UNLABELLED: OBJECTIVES, MATERIALS AND METHODS: The authors present the diffusion-weighted MR imaging and pathologic findings in two adult patients with cerebellar medulloblastoma. RESULTS: Both presented with a vermian mass of the posterior fossa with low signal on SE T1 weighted images, and moderate enhancement of the mass after gadolinium injection. The tumors were of high intensity on diffusion-weighted images with low ADC value. The ADC values (x10(-3) mm2/s) were respectively 0.60 +/- 0.06 and 0.59+/-0.11 (tumor), and 0.65 +/- 0.04 and 0.67 +/- 0.07 (cerebellar white matter). Tumors were highly cellular and composed of densely packed small round cells with hyperchromatic nuclei and scanty cytoplasm. CONCLUSION: diffusion-weighted MR imaging may be useful for the diagnosis of cerebellar medulloblastoma, due to their high cellularity and high nuclear-to-cytoplasmic ratio.

[Diagnostic strategy when confronted with a moderate and prolonged increase of transaminases]. / Démarche diagnostique devant une augmentation modérée et prolongée des transaminases.

TWO TYPES OF SITUATIONS: Measurement of transaminase serum activity is a common biological test. Although the etiological scope of acute and severe hyper-aminotransferase is codified and limited, that of prolonged and moderate hyper-aminotransferase is much broader. IN THE CASE OF PROLONGED AND MODERATE INCREASE IN TRANSAMINASE SERUM ACTIVITY: The discovery of this abnormality during systematic biological controls is a frequent situation, and its management is relatively well standardised. It requires a rigorous diagnostic strategy, which includes the search for consumption of alcohol, overweight, chronic hepatic disease of viral origin and the nature of the medicinal products ingested. FROM AN ETIOLOGICAL POINT OF VIEW: The most frequent causes of moderate and prolonged hyper-aminotransferase are alcohol abuse, overweight, non-insulin-dependent diabetes, dyslipaemia, viral hepatitis and medicinal products. However, less frequent hepatic or extra-hepatic causes must not be neglected.

Intrahepatic cholangiocarcinoma and hepatolithiasis: an unusual association in Western countries.

Hepatolithiasis is uncommon in Western countries and the relationship with cholangiocarcinoma is unusual. We report the association of hepatolithiasis and a cholangiocarcinoma in a Caucasian patient with a 17-year history of recurrent pancreatitis associated with hepatolithiasis. We discuss work-up and surgical treatment, and stress the need to keep in mind the possible association between hepatolithiasis and cholangiocarcinoma even in Western countries.

[Cellular angiofibroma. A rare vulvar tumor. Report of a case]. / L'angiofibrome cellulaire, une tumeur vulvaire rare. A propos d'un cas.

Cellular angiofibroma is a rare tumor. We report a vulvar case in a 37 year old woman. This nodular, well circonscribed tumor consists of bland spindle cells, numerous thin or thick often hyalinized vessels and adipocytes. The stromal cells are positive for vimentin and negative for CD34, protein S100, smooth muscle actin, desmin, epithelial membrane antigen and cytokeratin. Cellular angiofibroma is a benign tumor that has to be differentiated from aggressive angiomyxoma, angiomyofibroblastoma, glomangiopericytoma, spindle cell lipoma, solitary fibrous tumor and perineurioma.

[Epithelioid leiomyosarcoma of the uterine cervix. Report of a case]. / Léiomyosarcome épithélioïde du col utérin. A propos d'un cas.

We report a case of an epithelioid leiomyosarcoma of the uterine cervix in a 42 year-old woman. This is a very rare tumor. Usually, the presenting symptoms are vaginal bleeding and abdominal pain. Two problems have to be solved by the microscopy: to prove the smooth muscle differentiation of the tumor and to assert the malignancy. Surgery remains the basis of therapy. Prognosis is poor.