Cyclosporine A drives a Th17- and Th2-mediated posttransplant obliterative airway disease.

Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.

Coronary microcirculatory dysfunction is associated with left ventricular dysfunction during follow-up after STEMI.

BACKGROUND: Coronary microvascular resistance is increased after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), which may be related in part to changed left ventricular (LV) dynamics. Therefore we studied the coronary microcirculation in relation to systolic and diastolic LV function after STEMI. METHODS: The study cohort consisted of 12 consecutive patients, all treated with primary PCI for a first anterior wall STEMI. At 4 months, we assessed pressure-volume loops. Subsequently, we measured intracoronary pressure and flow velocity and calculated coronary microvascular resistance. Infarct size and LV mass were assessed using magnetic resonance imaging. RESULTS: Patients with an impaired systolic LV function due to a larger myocardial infarction showed a higher baseline average peak flow velocity (APV) than the other patients (26 ± 7 versus 17 ± 5 cm/s, p = 0.003, respectively), and showed an impaired variable microvascular resistance index (2.1 ± 1.0 versus 4.1 ± 1.3 mmHg cm(-1)∙s(-1), p = 0.003, respectively). Impaired diastolic relaxation time was inversely correlated with hyperaemic APV (r = -0.56, p = 0.003) and positively correlated with hyperaemic microvascular resistance (r = 0.48, p = 0.01). LV dilatation was associated with a reduced variable microvascular resistance index (r = 0.78, p = 0.006). CONCLUSION: A larger anterior myocardial infarction results in impaired LV performance associated with reduced coronary microvascular resistance variability, in particular due to higher coronary blood flow at baseline in these compromised left ventricles.

Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature.

The characteristics of 8 episodes of leishmaniasis with atypical manifestations in 2 Italian kidney transplant recipients are analyzed and contextualized among those of 52 other episodes of leishmaniasis observed in 19 transplant recipients found through a systematic review of the international literature. In all the patients, the initial episode was visceral leishmaniasis, which was associated with mucocutaneous involvement in 2 cases. With the exception of 1 case of post kala-azar dermal leishmaniasis, 2 episodes of Leishmania endophthalmitis, and 3 episodes of mucocutaneous leishmaniasis, all the recurrences were characterized by visceral involvement. The potential role of polymerase chain reaction in monitoring the infection, the importance of a long follow-up, the potential benefit of chemoprophylaxis, and the therapeutic challenges are discussed.

Localized malignant lymphohistiocytoid pleural mesothelioma.

We report a case of a 42-year-old man with a right pleural mesothelioma. This neoplasm has 3 rare features. Firstly, it was a localized form: suspected by imaging, visualized by video-assisted thoracoscopy, at the time of the curative-thoracotomy and confirmed by the pathological analysis. The second characteristic is its histological type: "malignant lymphohistiocytoid mesothelioma". This rare subtype has been reported in only 4 papers. Third, after pleuro-pneumonectomy, our patient is alive after 6 years and 5 months postoperatively without any sign of recurrence. Only one case with a long follow-up has been reported but with recurrence at 5 years postoperatively.

[Pulmonary granulomatous necrotizing vasculitis: an extra-intestinal manifestation of ulcerative colitis or Wegener's granulomatosis?]. / Vasculite granulomateuse nécrosante pulmonaire : une manifestation extra-intestinale de la rectocolite ulcéro-hémorragique ou une maladie de Wegener isolé ?

Respiratory symptoms are rare manifestations of ulcerative colitis as well as intestinal manifestations in Wegener granulomatosis. We report the case of a 17-year old man previously diagnosed as having ulcerative colitis who presented with diffuse thoracic pain. Hypermetabolic pulmonary nodules were discovered at the positron emission tomographic scan. Necrotizing granulomatous vasculitis was demonstrated at lung biopsy. In this paper, we describe the association between pulmonary nodules and ulcerative colitis and we discuss the possibility of an overlap syndrome between ulcerative colitis and Wegener granulomatosis.

Fibroma of the tendon sheath of the neck.

INTRODUCTION: Fibroma of the tendon sheath (FTS) is a rare benign tumour typically occurring in the extremities, but very rarely involving in the neck. CASE REPORT: A 22-year-old male presented with a large painless mass of the right oropharynx. Magnetic resonance imaging (MRI) showed a well-circumscribed 7cm lesion in the right prestyloid space. The lesion was completely removed surgically. Histopathological examination revealed a fibroma of the tendon sheath of the stylohyoid muscle. DISCUSSION: These tumours generally arise in the extremities of adults. To our knowledge, this is the first reported case of FTS in the neck.

Preclinical tolerance evaluation of the addition of a cisplatin-based dry powder for inhalation to the conventional carboplatin-paclitaxel doublet for treatment of non-small cell lung cancer.

Despite the advances in targeted therapies and immunotherapy for non-small cell lung cancer (NSCLC) patients, the intravenous administration of carboplatin (CARB) and paclitaxel (PTX) in well-spaced cycles is widely indicated for the treatment of NSCLC from stage II to stage IV. Our strategy was to add a controlled-release cisplatin-based dry-powder for inhalation (CIS-DPI-ET) to the conventional CARB-PTX-IV doublet, administered during the treatment off-cycles to intensify the therapeutic response while avoiding the impairment of pulmonary, renal and haematological tolerance of these combinations. The co-administration of CIS-DPI-ET (0.5 mg/kg) and CARB-PTX-IV (17-10 mg/kg) the same day showed a higher proportion of neutrophils in BALF (35 ± 7% vs 1.3 ± 0.8%), with earlier regenerative anaemia than with CARB-PTX-IV alone. A first strategy of CARB-PTX-IV dose reduction by 25% also induced neutrophil recruitment, but in a lower proportion than with the first combination (20 ± 6% vs 0.3 ± 0.3%) and avoiding regenerative anaemia. A second strategy of delaying CIS-DPI-ET and CARB-PTX-IV administrations by 24 h avoided both the recruitment of neutrophils in BALF and regenerative anaemia. Moreover, all these groups showed higher cytotoxicity (LDH activity, protein content) with no higher renal toxicities. These two strategies seem interesting to be assessed in terms of antitumor efficacy in mice.

Pulmonary and renal tolerance of cisplatin-based regimens combining intravenous and endotracheal routes for lung cancer treatment in mice.

Despite recent advances, platinum-based chemotherapy (partially composed of cisplatin, CIS) remains the backbone of non-small-cell lung cancer treatment. As CIS presents a cumulative and dose-limiting nephrotoxicity, it is currently administered with an interruption phase of 3-4 weeks between treatment cycles. During these periods, the patient recovers from the treatment side effects but so does the tumour. Our strategy is to increase the treatment frequency by delivering a cisplatin controlled-release dry powder for inhalation (CIS-DPI) formulation during these off-cycles to expose the tumour environment for longer to CIS, increasing its effectiveness. This is promising as long as the pulmonary and renal toxicities remain acceptable. The aim of the present investigation was to evaluate the pulmonary and renal tolerance of CIS-DPI (three times per cycle) and CIS using the intravenous (IV) route (CIS-IV) (one time per cycle) as monotherapies and to optimize their combination in terms of dose and schedule. At the maximum tolerated dose (MTD), combining CIS-DPI and CIS-IV impaired the pulmonary and the renal tolerance. Therefore, pulmonary tolerance was improved when the CIS-IV dose was decreased by 25% (to 1.5 mg/kg) while maintaining the MTD for CIS-DPI. In addition to this dose adjustment, a delay of 24 h between CIS-DPI and CIS-IV administrations limited the acute kidney injury.

Correlations between clinical presentations of adult trigger digits and histologic aspects of the A1 pulley.

PURPOSE: We aimed to report by light microscopy the normal histology of the A1 pulley, describe the histologic abnormalities of A1 pulleys in trigger digits, and look for possible correlations between these findings and the severity of the disease. METHODS: In a series of 104 trigger digits operated on in 80 adult patients, the A1 pulleys were removed and histologically studied. The findings were compared with 55 normal A1 pulleys obtained from fresh-frozen cadaveric specimens. RESULTS: The normal A1 pulley was composed of 3 layers: layer I, an inner, avascular, concave unicellular or bicellular gliding layer containing cartilage-like cells; layer II, a middle layer, also avascular, characterized by spindle-shaped fibroblasts; and layer III, an outer, richly vascularized layer, continuous with the membranous tendons sheath. We used a 3-grade classification, increasing in severity, to describe the histologic abnormalities observed in trigger digit A1 pulleys. Mild abnormalities (grade 1) were those with a fibrocartilaginous gliding surface almost intact. The margin between the fibrocartilaginous and membranous portions of the pulley was well delineated. In moderate abnormalities (grade 2), the avascular fibrocartilaginous gliding surface appeared fissured and thinner. The inner layer (I) was interrupted and replaced by fibrous tissue, with fissures that did not cross through the middle layer (II). A mild vascular network hyperplasia was observed in the outer layer (III), which began to invade the fibrocartilage. In severe abnormalities (grade 3), the fibrocartilaginous gliding surface was thin, discontinuous, or even completely destroyed. The vascular network hyperplasia became excessive and reached the synovial space of the flexor tendon sheath. The histologic features were correlated with the severity of the clinical symptoms (p < .001). CONCLUSIONS: The histologic abnormalities observed in the A1 pulley of trigger digits are characteristic and not related to inflammation. As the trigger digit worsens, the gliding surface begins to wear and is gradually replaced by a secondary invasive hyperplasia from the outer layer. These abnormalities could be caused by a modification or an increase of the mechanical stresses along the flexor tendons.

Atypical acute rejection after hand transplantation.

Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse, patchy or focal, and distributed over forearms and dorsum of the hands. This 'classical' pattern of rejection usually spares the skin of the palm and does not affect the nails. Herein, we report the experience on four cases presenting with an 'atypical' pattern of rejection that is novel in involving the palmar skin and the nails. All patients were young and exposed to repetitive and persistent mechanical stress of the palm. Characteristic features of rejection included a desquamative rash associated with dry skin, red papules, scaling and lichenification localized to the palm. Skin lesions were associated with nail dystrophy, degeneration, deformation or loss. Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells (CD3+, CD4+ and CD8+), with small numbers of B cells (CD20+ and CD79a+) and a low number of Forkhead transcription factor 3 (FOXP3)-positive cells in one patient. The lesions persisted over weeks to months, responded poorly to steroid treatment and were managed with antithymocyte globulin (ATG; Thymoglobulin, Genzyme, Cambridge, MA), alemtuzumab and/or intensified maintenance immunosuppression.

The Banff 2007 working classification of skin-containing composite tissue allograft pathology.

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruna, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs.

[Difficulties and limitations in conducting translational research in thoracic oncology. A practical example]. / Difficultés et limites dans la conduite d'une étude translationnelle en oncologie thoracique. Un exemple pratique.

INTRODUCTION: In a first study, we identified signatures of 3 mRNAs (semaphorin 3D [SEMA3D], cytokeratin 16 [KRT16] and UL16 binding protein 2 [ULBP2]) associated to response to a cisplatin-vinorelbin chemotherapy and to survival of advanced non-small cell lung cancers (NSCLC). MATERIAL AND METHODS: The aim of this study was to develop immunohistochemistry tests for KRT16, ULBP2 and SEMA3D and to test proteins expression for prediction of response and survival in biopsies of the same patients. RESULTS: We were not able to reproduce by the protein expression study the signature predicting response to chemotherapy in advanced NSCLC. CONCLUSION: We highlight the difficulties of translational research in thoracic oncology emphasizing the complexity in obtaining adequate tissue samples and the difficulties in conduction and transposing in routine practice high throughput technique for transcriptomic analyses.

The differential expression of Galectin-1 and Galectin-3 in normal lymphoid tissue and non-Hodgkin's and Hodgkin's lymphomas.

The WHO classification of lymphomas was established on the basis of clinical, morphological, immunohistochemical and genetic criteria. However, each entity displays its own spectrum of clinical aggressiveness. Treatment success varies widely and is not predictable. Since galectins are involved in oncogenesis and the physiology of immune cells, we investigated whether galectin-1 and galectin-3 immunohistochemical expression could differ in 25 normal lymphoid tissues, 42 non-Hodgkins and 14 Hodgkins lymphomas. Immunohistochemical galectin expression was submitted to semi-quantitative and quantitative (computer-assisted microscopy) evaluations. This study is completed by an analysis (by means of quantitative RT-PCR) of galectin-3 mRNA expression in 3 normal lymph nodes, 3 follicular lymphomas (FLs) and 3 diffuse large B-cell lymphomas (DLBCLs). The data show that in normal lymphoid tissue, lymphocytes do not express galectin-1 and rarely express galectin-3. In contrast, galectin-3 was expressed in 8 of the 16 DLBCL cases and in 1 of the 8 FL cases. Furthermore, galectin-3 mRNA was expressed 3 times more in the DLBCLs than in the FLs. While the blood vessel walls of the lymphomas expressed galectin-1, the vessel walls of normal lymphoid tissues did not. This expression of galectin-1 in blood vessel walls was correlated with vascular density. The present study thus shows that DLBCL can be distinguished from normal lymphoid tissue and other lymphomas on the basis of galectin-3 expression.

[Techniques and strategy of pathological sampling in the diagnostic and therapeutic management of lung cancer]. / Techniques et stratégie de prise en charge des prélèvements anatomopathologiques dans le cadre de l'approche diagnostique et thérapeutique du cancer bronchique.

Histopathology is key to the diagnosis and staging of lung cancer. This analysis requires tissue sampling from primary and/or metastatic lesions. The choice of sampling technique is intended to optimize diagnostic yield while avoiding unnecessarily invasive procedures. Recent developments in targeted therapy require increasingly precise histological and molecular characterization of the tumor. Therefore, pathologists must be economical with tissue samples to ensure that they have the opportunity to perform all the analyses required. More than ever, good communication between clinician, endoscopist or surgeon, and pathologist is essential. This is necessary to ensure that all participants in the process of lung cancer diagnosis collaborate to ensure that the appropriate number and type of biopsies are performed with the appropriate tissue sampling treatment. This will allow performance of all the necessary analyses leading to a more precise characterization of the tumor, and thus the optimal treatment for patients with lung cancer.

Characterization of nuclear DNA content, proliferation index, and nuclear size in a series of 181 meningiomas, including benign primary, recurrent, and malignant tumors.

The characterization of nuclear area, the proliferation index, and nuclear DNA content was carried out by means of digital cell image analysis, which makes it possible to compute morphometric and densitometric features on Feulgen-stained nuclei from archival, that is, formalin-fixed, paraffin-embedded materials. The 181 meningiomas studied included 173 classic (41 meningotheliomatous, 27 fibroblastic, 82 transitional, nine psammomatous, eight angiomatous and six hemangioblastic tumors) and eight malignant meningiomas (three hemangiopericytomas and five tumors that we labeled HFM, that is, tumors exhibiting evidence of histological features of malignancy). The results reveal a strong relationship between incomplete surgical resection and recurrence on the one hand and between the probability of recurrence and histopathological type on the other. Whereas neither nuclear area nor nuclear DNA content assessments were helpful in distinguishing the six classic and the two malignant meningioma subgroups, a statistically significant increase in proliferative activity was observed in the malignant meningiomas as compared with classic ones, excepting hemangioblastomas that proliferate at the same rate as the malignant meningiomas. Furthermore, the multiple meningiomas definitely proliferated more actively than the single ones, but a similar proliferative activity was observed in the nonrecurrent and recurrent meningiomas. Proliferation analyses might be therefore helpful for determining aggressive meningiomas and for planning adjuvant therapy in these cases.

Fatal primary infection due to human herpesvirus 6 variant A in a renal transplant recipient.

We describe a fatal primary human herpesvirus 6 (HHV-6) variant A infection in a kidney transplanted adult woman. On day 20 post transplantation (TX), after rejection therapy, the patient presented an acute hemophagocytic syndrome with hepatitis and central nervous system involvement. HHV-6 IgG and IgM antibodies seroconversion was demonstrated. HHV-6 variant A was the sole pathogen detected by nested PCR and/or culture in blood, bone marrow aspiration, liver biopsy, cerebrospinal fluid and bronchoalveolar lavage. The graft was HHV-6 seropositive and the patient was not transfused before day 28 post TX, suggesting that the virus was transmitted by the graft. Despite immunoglobulins, ganciclovir and foscarnet therapy, the HHV-6 infection progressed and led to severe aplasia. The patient developed Aspergillus fumigatus pneumonia and died from fulminant candidemia. This case demonstrated for the first time that HHV-6 variant A primary infection can cause life-threatening disseminated infection in immunosuppressed patients.

Computer-assisted quantitative description of chromatin pattern and DNA-ploidy level in ependymomas and choroid-plexus tumors.

Computer-assisted microscope analyses of Feulgen-stained nuclei were used to quantitatively describe the chromatin pattern and to determine the DNA ploidy level in a series of 70 cases including 46 low-grade (benign) ependymomas, 17 anaplastic (malignant) ependymomas, 3 choroid plexus papillomas (benign) and 4 choroid plexus carcinomas (malignant). While the quantitative description of the chromatin pattern was carried out by means of 14 morphonuclear parameters relating to geometric, densitometric and textural features, the DNA ploidy level was assessed by means of DNA histogram typing. Of these 70 cases, proliferative activity was assessed on 24, for which tissue was still available after the digital cell image analyses. This assessment was carried out by means of the determination of the immunohistochemical MIB-1 staining relating to the Ki-67 antigen. The results show that the determination of morphonuclear characteristics did not make it possible to distinguish between ependymal and choroid plexus tumours. Furthermore, neither the computer-assisted microscope analyses of morphonuclear characteritics nor the DNA ploidy level determination made it possible to distinguish between low-grade and anaplastic ependymomas. In sharp contrast, the determination of proliferative activity by means of the Ki-67 antigen immunohistochemical staining enabled such a distinction to be made.

The contribution of image cytometry to the characterization of clinical subgroups of lipomas.

The aim of the present study was to investigate whether biological features determined through image cytometry are able to characterize clinical subpopulations of lipomas. Forty lipomas excised from 36 patients were studied. On the one hand, the tumors were clinically characterized by means of patient-related and pre- and post-operative features. On the other, the tumors were analyzed by means of the computer-assisted microscopy analysis of Feulgen-stained nuclei. This analysis generated 3 groups of biological quantitative variables describing morphonuclear aspects (i.e. the chromatin pattern of the cell nuclei), the nuclear DNA content (DNA ploidy level), and architectural features (such as the cell density and the topographical cell nuclei organization). Possible relations between the clinical and the biological features of the lipomas were investigated by means of univariate and multivariate statistical analyses. The results show the existence of such relations, in particular between the morphonuclear and architectural features of lipomas, on the one hand, and their consistency, volume and weight, on the other. Furthermore, multivariate analysis made it possible to distinguish two subpopulations of lipomas exhibiting different biological characteristics in terms of morphonuclear patterns.

The characterization of biological features in dedifferentiated liposarcomas by means of principal components and discriminant analyses of 25 computer-generated variables from Feulgen-stained nuclei and histological slides.

Several groups of lipomatous tumors are not yet clearly characterized on the biological level. In order to attempt to classify the dedifferentiated liposarcomas with respect to other types of malignant liposarcomas, 80 adipose tumors were submitted to the combination of two computer-assisted methodologies. These two methodologies consisted of i) the determination of 25 variables, and ii) the analysis of the diagnostic information contributed by these 25 variables by means of two complementary techniques, i.e. principal components and discriminant analyses. The 25 variables were computed by means of image cytometry on Feulgen-stained nuclei and histological slides, quantitatively describing distinct biological characteristics relating to morphonuclear (chromatin pattern) features (14 variables), nuclear DNA content distribution (9 variables), and tissue architecture pattern (2 variables). The 80 adipose tumors included 21 typical lipomas, 7 atypical lipomas (defined as extremity adipose tumors with a histopathological pattern of well-differentiated liposarcomas), 16 retroperitoneal and 5 non-retroperitoneal abdominal well-differentiated liposarcomas, 9 dedifferentiated liposarcomas, 8 myxoid (intermediate-grade tumor) and 14 pleomorphic (high-grade tumor) liposarcomas. The data strongly suggest that the dedifferentiated liposarcomas exhibit biological characteristics which are distinct from those of low- and high-grade liposarcomas, but similar to those of intermediate ones. The results also show that typical and atypical lipomas are two distinct biological entities. In contrast, the atypical lipomas and the well-differentiated retroperitoneal and non-retroperitoneal liposarcomas exhibited a high number of similar biological characteristics. Computer-assisted methods contribute valuable information to characterize lipomatous tumor biology.

Lectin histochemistry, ploidy level, and proliferative activity in rhabdomyosarcoma subtypes.

The glycohistochemical expression of binding sites for eight lectins is characterized in a series of 8 embryonal, 4 alveolar and 4 pleomorphic rhabdomyosarcomas. The correlation between lectin staining and either the proliferation index or the ploidy level was also investigated. The data show that rhabdomyosarcomas exhibit heterogeneous lectin binding expressions. A comparable level of lectin labeling is observed in euploid and aneuploid tumours. In contrast to other neoplasms, lectin staining has proved to be of doubtful value in distinguishing between different RMS subtypes. The data also reveal that a significantly lower level of proliferative activity was observed in the pleomorphic group as compared to the alveolar one.