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.

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.

[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.

[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.

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.

[Asbestosis still exists ]. / L'asbestose existe encore

A diagnosis of asbestosis, lung fibrosis due to asbestos exposure, was proposed in 2003 in a 64-year-old woman on the basis of the history, computed tomography appearances, lung function studies, and biometric data. This diagnosis was confirmed by the pathological examination of a lung lobe resected surgically for bronchial carcinoma in 2010. The diagnosis of asbestosis is now rarely made as a result of a substantial decrease in dust exposure over the past decades and mainly because of the interdiction of asbestos use in western countries. Currently, the most frequent thoracic manifestations of asbestos exposure are benign pleural lesions and mesothelioma. It has also become exceptional to have pathological confirmation of the diagnosis, obtained in this woman thanks to the surgical treatment of another complication of her occupational exposure.

[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.

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.

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.

Biclonal low grade B-cell lymphoma confirmed by both flow cytometry and karyotypic analysis, in spite of a normal kappa/lambda Ig light chain ratio.

Composite low grade lymphoma with two subpopulations in a same site is uncommon. We herewith report the case of an 80-year-old woman who presented with isolated bilateral dacryoadenomegaly. Pathological examination of an incisional biopsy of her right lacrimal gland was consistent with a marginal zone lymphoma. Flow cytometry immunophenotyping showed two distinct clonal B-cell populations expressing sIg D lambda or sIg M kappa restriction in the lacrimal gland, blood, and bone marrow. Both B-cells populations were sorted from peripheral blood for molecular biology investigations and comparison with molecular data performed on tumor and bone marrow cells. IgH PCR performed on purified blood populations disclosed two monoclonal peaks: 98 bp-sized peak in the sIg M kappa and a 107 bp in the sIg D lambda clones, respectively. The lacrimal gland tumor expressed mainly sIg M kappa population, and showed a major 98 bp-sized peak coexisting with a very minor 107 bp peak. Cytogenetic studies showed a 46, XX,del (7) (q22q32) karyotype. Bone marrow examination at diagnosis revealed the same B-cell clones distribution than the one observed in blood with a dominant sIg D lambda population, a Genescan profile showing a major peak of 107 bp and a minor peak of 98 bp. Chromosomal analysis disclosed a 46,XX,del (10) (?p14) karyotype without detectable 7q deletion. To our knowledge, this observation represents the first reported case of biclonal low grade lymphoma hidden behind a normal classical kappa/lambda Ig light chain ratio in blood, but clearly demonstrated by the combination of three ancillary techniques (flow cytometry both analytical and cell sorting, molecular biology, and cytogenetics) and analysis of different tissues (i.e., in this case, lacrimal gland biopsy, blood, and bone marrow).

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.

[External auditory meatus adenocarcinoma]. / Un adénocarcinome du méat acoustique externe.

We report the case of a man presenting a deafness and a hemorrhagic ear discharge since one year. CT scanner and MRI reveal an invasive tumoral lesion of the external auditory meatus (EAM) expending into the posterior fossa. After surgery the diagnosis of high grade ceruminal gland adenocarcinoma is established whereas the malignancy was not obvious on earlier biopsy. Cancers arising in the EAM are uncommon and are essentially representating by squamous cell cancers and basal cell cancers. The precise diagnosis of a glandular tumor is a challenge for the pathologist because the limits between benign and malignant tumors are not obvious. Integration of clinical and radiological behavior and the histology of the tumor is necessary for a early diagnosis and a complete surgery.

[Primary pulmonary hemangiopericytoma: 2 new cases]. / L'hémangiopéricytome pulmonaire primitif: deux nouvelles observations.

We describe two new resected cases of primary pulmonary hemangiopericytoma and the review of cases published in the period 1954-2002. The first patient has a large pulmonary mass of the right apex revealed by scapular pain. The right upper lobectomy with free margins reveals hemangiopericytoma. Pelvic and pulmonary metastases appear two years after surgery, treated by two series of chemotherapy without clinical response. After acute nephrotoxicity controlled by hemodialysis, the patient dies with distant metastases three years and an half after thoracotomy. The second patient develops dry cough and thoracic pain with discovery of a cavitary mass in the right pulmonary field. Fine needle aspiration cytology suggests a mesenchymatous lesion. Three months after extended pneumonectomy, the intrathoracic tumour relapses and regresses partially under chemotherapy. Femoral and brain metastases are irradiated. The patient dies 22 months after thoracotomy. Histology and immunohistochemistry of both tumours closely related to solitary fibrous tumour confirm malignant hemangiopericytoma. Primary pulmonary hemangiopericytoma is rare and may be benign or malignant. Radical resection is the best treatment. Chemotherapy and radiotherapy may improve the prognosis. Compared with lung cancer, the tumour is a slow growing mass, often voluminous, with delayed symptoms, very few lymph node dissemination, rare brain metastasis, more frequent cutaneous or retroperitoneal dissemination, often after long-term and requiring indeed a 10 to 20 years follow-up.

[The pathology department]. / Le Service d'Anatomie Pathologique.

The evolution of the Laboratory of Pathology at Erasmus Hospital is directly related to the morphological diagnosis integration in the medico-surgical organization of the Hospital. Such integration is based on the creation of links between the Laboratory of Pathology and the clinical departments and necessitates permanent adaptations to new complementary technology. Immunohistochemical methods were gradually included in the surgical morphological diagnosis. Currently, new markers from molecular biology are needed to obtain accurate pathological diagnosis. We observe an increasing hyperspecialization of the morphological classification with complete integration of such biological markers leading to the necessity of carrying out collegial diagnosis. The development of the telepathology technology permits international collegial diagnosis. According to its central position the Laboratory of Pathology plays an important part in the development of the clinical and fundamental research. The research subjects of the Laboratory of Pathology concern diagnostic and prognostic evaluation in colic cancers, sarcomas, brain tumors and HPV related tumors endometriosis.

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.

Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts.

The toxic galactoside-specific lectin from mistletoe, a component of proprietary extracts with unproven efficacy in oncology, exhibits capacity to trigger enhanced secretion of proinflammatory cytokines at low doses (ng/ml or ng/kg body weight) and reductions of cell viability with increasing concentrations. To infer any tumor selectivity of this activity, cytofluorimetric and cell growth assays with a variety of established human tumor cell lines were performed. Only quantitative changes were apparent, and the toxicity against tumor cells was within the range of that of the tested fibroblast preparations from 5 donors. No indication for any tumor selectivity was observed. In kinetic studies with 8 sarcoma and 4 melanoma lines, this evidence for quantitative variability of the response in interindividual comparison was further underscored. At 50 pg lectin/ml x 10(5) cells, even a growth-stimulatory impact was noted in 5 of 12 tested cases. To mimic in vivo conditions with presence of cytokine-secreting inflammatory and stromal cells, exposure to the lectin was extended to histotypic cultures established from 30 cases of surgically removed tumor. As salient result, 5 specimens from 4 of the 8 tested tumor classes responded with a significant increase of [3H]-thymidine incorporation relative to controls during the culture period of 72 hours, when the lectin was present at a concentration in the described immunomodulatory range (1 ng/ml). A relation of this activity to the extent of the actual proliferative status of the reactive samples could not be delineated. Therefore, a non-negligible percentage of the established tumor cell lines (e.g., 3 from 8 sarcoma lines) can be markedly stimulated by the lectin at a very low dose and with dependence on the cell type. Furthermore, the feasibility to elicit a significant growth enhancement is likewise documented for human tumor explants in 16.6% of the examined cases. In view of the uncontrolled application of lectin-containing extracts in alternative/complementary medicine, the presented results on unquestionably adverse lectin-dependent effects in two culture systems call for rigorous examination of the clinical safety of this unconventional, scientifically entirely experimental treatment modality.

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.

Discrimination between dysplastic and malignant epithelium of the ampulla of vater based on quantitative image cytometric data.

OBJECTIVE: To assess the ability to associate histopathologic grading with objective criteria obtained by nuclear image cytometry in epithelium of the ampulla of Vater. STUDY DESIGN: Forty-one resected ampullary specimens were studied, including 8 dysplastic ampullomas together with 22 well-differentiated and 11 poorly differentiated ampullary adenocarcinomas. The nuclei were Feulgen stained and analyzed using a computer-assisted microscope, which generated 38 quantitative variables describing chromatin texture and nuclear DNA content (DNA ploidy level). These variables were explored by discriminant analysis to determine the most stable and informative variables. Univariate analysis was performed on the four most informative ones. The whole set of variables was also subjected to principal component analysis in order to characterize intragroup and intergroup heterogeneity. RESULTS: The univariate analysis defined two morphonuclear variables (related to nuclear chromatin distribution) discriminating between dysplasia and well-differentiated cancers. Aneuploidy occurrence was associated with discrimination between well-differentiated and poorly differentiated cancers. CONCLUSION: While alterations in chromatin distribution may be an early event in the malignant degeneration of this epithelium, alterations in nuclear DNA content should correspond to a later phenomenon. Quantification of these features can be exploited to assist in diagnosis.