F. Calabrese

Noneosinophilic asthma in children: relation with airway remodelling

Noneosinophilic asthma is increasingly recognised as an important clinical–pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling – basement membrane thickening, epithelial loss and angiogenesis – and immune activation – inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-&bgr;, TGF-&bgr; receptor type II – were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-&bgr; receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life.

Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors

BACKGROUND To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.BACKGROUND To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.

Transforming growth factor-β type II receptor in pulmonary arteries of patients with very severe COPD

A mild-to-moderate increase in pulmonary arterial pressure is often associated with severe chronic obstructive pulmonary disease (COPD). Transforming growth factor (TGF)-β is a cytokine involved in the maintenance of integrity of vasculature. The aim of the study was to investigate whether the TGF-β pathway might be involved in the development of pulmonary hypertension associated with COPD. Surgical specimens from 14 patients undergoing lung transplantation for very severe COPD (forced expiratory volume in one second 17±2% of the predicted value) and from seven donors were examined. The expression of TGF-β1 and TGF-β type II receptor (TGF-βRII), cell proliferation index and structural changes in pulmonary arteries were quantified immunohistochemically. In severe COPD patients, increased expression of TGF-βRII was observed in both the tunica media and intima, which was associated with a normal proliferation index in both layers. Conversely, significant thickening of the tunica intima, which was not present in the tunica media, was observed, suggesting that mechanisms other than cell proliferation may be involved in intimal thickening. In conclusion, in the pulmonary arteries of patients with severe chronic obstructive pulmonary disease, there is upregulation of transforming growth factor-β type II receptor expression associated with a normal proliferation index. These findings suggest the activation of an antiproliferative pathway, which might explain the relatively low degree of pulmonary hypertension observed in these subjects.

Is lobectomy really more effective than sublobar resection in the surgical treatment of second primary lung cancer

OBJECTIVES Sublobar resection for early-stage lung cancer is still a controversial issue. We sought to compare sublobar resection (segmentectomy or wedge resection) with lobectomy in the treatment of patients with a second primary lung cancer. METHODS From January 1995 to December 2010, 121 patients with second primary lung cancer, classified by the criteria proposed by Martini and Melamed, were treated at our Institution. We had 23 patients with a synchronous tumour and 98 with metachronous. As second treatment, we performed 61 lobectomies (17 of these were completion pneumonectomies), 38 atypical resections and 22 segmentectomies. Histology was adenocarcinoma in 49, squamous in 38, bronchoalveolar carcinomas in 14, adenosquamous in 8, large cells in 2, anaplastic in 5 and other histologies in 5. RESULTS Overall 5-year survival from second surgery was 42%; overall operative mortality was 2.5% (3 patients), while morbidity was 19% (22 patients). Morbidity was comparable between the lobectomy group, sublobar resection and completion pneumonectomies (12.8, 27.7 and 30.8%, respectively, P = 0.21). Regarding the type of surgery, the lobectomy group showed a better 5-year survival than sublobar resection (57.5 and 36%, respectively, P = 0.016). Compared with lobectomies, completion pneumonectomies showed a significantly less-favourable survival (57.5 and 20%, respectively, P = 0.001). CONCLUSIONS From our experience, lobectomy should still be considered as the treatment of choice in the management of second primary lung cancer, but sublobar resection remains a valid option in high-risk patients with limited pulmonary function. Completion pneumonectomy was a negative prognostic factor in long-term survival.

Superior sulcus tumors (Pancoast tumors)

Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horners syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach.

Pulmonary inflammatory myofibroblastic tumour with unusual octreoscan uptake: two reports.

To the Editors: Inflammatory myofibroblastic tumour (IMT) is a relatively uncommon lesion and occurs in nearly every site of the body. Patients with IMT are usually asymptomatic, with a solitary nodule or mass detected by routine chest radiograph 1. Many diagnostic procedures can be applied to make the diagnosis: computed tomography (CT) scan to outline nodule growth and perfusion, [18F]-2-fluoro-deoxy-D-glucose (FDG)-PET/CT scan to evaluate metabolic activity and 111In-Diethylene triamine pentaacetic acid (DTPA)-D-Phe1 scan (octreoscan) to investigate somatostatin analogue receptors, often present in a variety of neuroendocrine tumours (NETs). We present two cases of pulmonary IMT clinically misdiagnosed as carcinoid tumours due to a positive octreoscan. Case 1 was a 52-yr-old female former smoker who was admitted to our hospital with thoracic pain. The electrocardiogram was completely negative for angina or myocardial infarction. Chest radiograph and CT revealed a left hilar nodule, sharply circumscribed, slightly lobulated, with a mild homogeneous increase of density after enhancement. A whole-body FDG-PET/CT scan showed increased tracer uptake of the lung mass (standardised uptake value (SUV) 25) compatible with a malignant lesion. SUVmax was calculated 50 min after injection and normalised for body weight. After intravenous administration of 111 mBq of [111In]-octreotide, an abnormal, although low, uptake was present in the left lung hilar region (fig. 1a⇓). Bronchoscopy was negative. On the basis of the CT, FDG-PET/CT and octreoscan, a clinical/radiological diagnosis of a carcinoid tumour, most probably atypical, was postulated. The intraoperative frozen specimen excluded the diagnosis of …

Higher Risk of Acute Cellular Rejection in Lung Transplant Recipients with Cystic Fibrosis.

BACKGROUND Acute cellular rejection (ACR) affects up to 40% of recipients within the first year after lung transplant (LTx). The aim of this study was to determine the frequency of ACR and associated major risk factors in cystic fibrosis (CF) recipients. Bronchiolitis obliterans syndrome (BOS) and 1-year/long-term survival were also evaluated. MATERIAL AND METHODS ACR was reviewed in 643 scheduled biopsies from 44 CF (Group 1) versus 89 other recipients (Group 2). We performed univariate/multivariate analyses of risk factors for ACR and BOS, and survival analysis. RESULTS Group 1 showed higher ACR frequency, especially for ACR ≥ A2. Multivariable generalized linear models considering both native lung disease and age showed that higher values of ACR index were significantly related to the pretransplant diagnosis of CF. BOS and long-term survival were not influenced by the increased incidence of ACR. Poorer long-term survival was observed in Group 2. CONCLUSIONS CF recipients have a higher ACR risk, which may be due to enhanced immune activation related to a genetic disorder, and younger age.

Pediatric chronic lower respiratory disorders: Microbiological and immunological phenotype†‡§

The role of infectious agents in children with recurrent/chronic lower respiratory disorders (R/CLRDs) is not clear, whereas it has been largely studied in acute respiratory diseases. The purpose of the study was to evaluate the frequency of infections, in particular viral infections, in children with R/CLRDs correlating their presence with clinical/biohumoral parameters.

Acute cellular rejection and Epstein–Barr virus-related post-transplant lymphoproliferative disorder in a pediatric lung transplant with low viral load

F. Calabrese, M. Loy, F. Lunardi, D. Marino, S.M.L. Aversa, F. Rea. Acute cellular rejection and Epstein–Barr virus‐related post‐transplant lymphoproliferative disorder in a pediatric lung transplant with low viral load.
Transpl Infect Dis 2010: 12: 342–346. All rights reserved.

Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman

Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.