Omalizumab in Severe Asthma: Effect on Oral Corticosteroid Exposure and Remodeling. A Randomized Open-Label Parallel Study.

INTRODUCTION: Data on the clinical efficacy and remodeling of omalizumab therapy in patients on oral corticosteroids (OC) are limited. OBJECTIVE: The purpose of the study is to show that in patients with corticosteroid-dependent asthma, omalizumab is a corticosteroid-sparing therapy able to inhibit airway remodeling and to reduce disease burden (lung function impairment, exacerbations). METHODS: This study is a randomised open-label study evaluating the addition of omalizumab to the standard of care in patients with severe asthma receiving oral corticosteroids. The primary endpoint was represented by the change in OC monthly dose by the end of treatment and secondary endpoints included spirometry changes, airway inflammation (FeNO), number of exacerbations and airways remodelling assessed by bronchial biopsies studied by transmission electron microscopy. As a safety variable, adverse effects were recorded. RESULTS: Efficacy was assessed for 16 patients in the omalizumab group and 13 in the control group. The final cumulative mean monthly OC doses were 34.7 mg and 217 mg for the omalizumab and control group, respectively; the mean difference between groups adjusted for baseline was -148.1 [95% confidence interval (CI) -243.6, -52.5; p = 0.004]. OC withdrawal of 75% versus 7.7% (p = 0.001) was observed in the omalizumab and control group, respectively. Omalizumab provided a slowing of forced expiratory volume in one second (FEV1) loss (70 mL versus 260 mL), a significant decrease in FeNO values and a reduction in the annual relative risk of clinically significant exacerbations of 54%. The treatment was well tolerated. The morphological study showed a significant decrease in basement membrane thickness in the omalizumab group (6.7 µm versus 4.6 µm) compared with controls (6.9 µm versus 7 µm) [mean difference between groups adjusted for baseline was -2.4 (95% CI -3.7, -1.2; p < 0.001], as well as a decrease in intercellular spaces (1.18 µm versus 0.62 µm and 1.21 µm versus 1.20 µm, p = 0.011, respectively). A qualitative improvement was also observed in the treated group. CONCLUSIONS: Omalizumab showed a marked OC-sparing capacity and was associated with an improvement in clinical management that correlated with bronchial epithelial repair. In OC-dependent asthma, reversibility of remodelling is possible; the concepts that basement membrane enlargement is detrimental and that chronic airway obstruction is systematically irreversible are outdated (EudraCT: 2009-010914-31).

Adenoid cystic carcinoma and basaloid carcinoma of the breast: A clinicopathological study.

Adenoid cystic carcinoma of the breast (ACCB) is a rare triple negative tumor (TNT) with an excellent prognosis in most cases. Three different histologic types are recognized: classic ACCB, solid basaloid ACCB (SB-ACCB), and ACCB with high-grade transformation. A majority of these tumors show characteristic molecular and immunohistochemical (IHC) features, with fusion of MYB and NFIB genes and overexpression of MYB, respectively. Basaloid carcinomas of the breast (BCB) are infrequently described. They resemble SB-ACCB and TNT of no special type (TNT-NST). We have studied the clinicopathological features of 17 ACCB and 9 BCB, investigating the expression of MYB by IHC and the rearrangements of MYB by fluorescence in situ hybridization (FISH). MYB was expressed by IHC in 15 ACCB and in 3 BCB. MYB FISH detected rearrangements in 11 ACCB and in 2 BCB. After a mean follow-up of 90 months, with a range of 12-204 months, 2 patients with ACCB with high-grade transformation and 1 patient with BCB developed metastases and died of disease. In summary, most ACCB have a good prognosis, but tumors with adverse histopathological features may metastasize. BCB may overlap with ACCB and TNT-NST, and their prognosis should be further studied.

Basaloid squamous cell carcinoma of the breast / Carcinoma escamoso basaloide de mama

Basaloid squamous cell carcinoma (BSCC) is a subtype of squamous cell carcinoma that characteristically occurs in the head and neck, may be related to HPV infection and is usually considered to be aggressive. We present the first description of BSCC of the breast. The tumor exhibited characteristic histologic features of BSCC, including nests of basaloid squamous cells with comedonecrosis, abrupt keratinization, and abundant hyaline basement membrane-like material deposition. The tumor showed immunohistochemical features of triple negativity, diffuse p63 positivity, p16 positivity, and Rb negativity. HPV immunogenotyping was negative. The patient was free of disease after treatment with breast conserving surgery, chemotherapy and radiotherapy. BSCC of the breast should be distinguished from basaloid adenoid cystic carcinoma, triple-negative basal-like breast cancer and nonbasaloid squamous cell carcinoma of the breast based on histology and immunohistochemistry. The prognostic implications of BSCC of the breast should be further studied in larger series

El carcinoma escamoso basaloide (CEB) es un subtipo de carcinoma escamoso que se origina normalmente en cabeza y cuello, que puede guardar relación con la infección por el virus del papiloma humano (VPH), y que normalmente se considera agresivo. Presentamos la primera descripción de CEB de la mama. El tumor mostró características histológicas de CEB, incluyendo los nidos de células escamosas basaloides con comedonecrosis, queratinización abrupta y abundante material de depósito tipo membrana basal hialina. El tumor mostró características inmunohistoquímicas de triple negatividad, positividad para p63 difusa, positividad para p16 y negatividad para Rb. La inmunofenotipificación para VPH fue negativa. La paciente estaba libre de enfermedad tras el tratamiento con cirugía conservadora de mama, quimioterapia y radioterapia. El CEB de mama deberá distinguirse del carcinoma adenoide quístico basaloide, del cáncer de mama de tipo basal triple-negativo y del carcinoma no basaloide escamoso de mama, basado en histología e inmunohistoquímica. Además, las implicaciones pronósticas del CEB de mama deberán estudiarse en series adicionales de mayor tamaño

Basaloid squamous cell carcinoma of the breast.

Basaloid squamous cell carcinoma (BSCC) is a subtype of squamous cell carcinoma that characteristically occurs in the head and neck, may be related to HPV infection and is usually considered to be aggressive. We present the first description of BSCC of the breast. The tumor exhibited characteristic histologic features of BSCC, including nests of basaloid squamous cells with comedonecrosis, abrupt keratinization, and abundant hyaline basement membrane-like material deposition. The tumor showed immunohistochemical features of triple negativity, diffuse p63 positivity, p16 positivity, and Rb negativity. HPV immunogenotyping was negative. The patient was free of disease after treatment with breast conserving surgery, chemotherapy and radiotherapy. BSCC of the breast should be distinguished from basaloid adenoid cystic carcinoma, triple-negative basal-like breast cancer and nonbasaloid squamous cell carcinoma of the breast based on histology and immunohistochemistry. The prognostic implications of BSCC of the breast should be further studied in larger series.

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

INTRODUCTION: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. METHODS: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). RESULTS: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). CONCLUSIONS: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.

Cáncer de pulmón en pacientes con combinación de fibrosis pulmonar y enfisema y fibrosis pulmonar idiopática. Estudio descriptivo en una serie española / Lung Cancer in Patients With Combined Pulmonary Fibrosis and Emphysema and Idiopathic Pulmonary Fibrosis. A Descriptive Study in a Spanish Series

Introducción: La información sobre la asociación del cáncer de pulmón (CP) y combinación de fibrosis pulmonar y enfisema (CFPE) es limitada y procedente casi exclusivamente de series asiáticas. El objetivo principal del estudio fue valorar el impacto del CP en la supervivencia en la CFPE y en pacientes diagnosticados de fibrosis pulmonar idiopática (FPI). Métodos: Se realizó un estudio retrospectivo con los datos de pacientes con CFPE y FPI diagnosticados en nuestro centro en un periodo de 5 años. Resultados: Se incluyó a 66 pacientes, 29 en el grupo de CFPE y 37 pacientes con FPI. Nueve tenían un diagnóstico de CP (6 con CFPE y 3 con FPI); 6 pacientes (67%) recibieron tratamiento paliativo a pesar de que 3 de ellos presentaban estadios I y II. No hubo diferencias significativas en la mortalidad global de los 2 grupos; sin embargo, en los pacientes con CP la supervivencia fue significativamente menor con respecto a los que no tenían CP (p = 0,044). Las causas más frecuentes de muerte fue la insuficiencia respiratoria secundaria a la exacerbación de la fibrosis pulmonar (44%). En el análisis multivariante, la odds ratio de morir en los pacientes con CP respecto a los pacientes sin CP fue de 6,20 (p = 0,037, intervalo de confianza [IC] del 95%: 1,11 a 34,48). Conclusión: El CP empeora la supervivencia de estas 2 entidades. El manejo diagnóstico y terapéutico del CP se ve dificultado por el mayor riesgo de complicaciones posteriores al tratamiento elegido, incluso tras el tratamiento paliativo (AU)

Introduction: Information on the association of lung cancer (LC) and combined pulmonary fibrosis and emphysema (CPFE) is limited and derived almost exclusively from series in Asian populations. The main objective of the study was to assess the impact of LC on survival in CPFE patients and in patients with idiopathic pulmonary fibrosis (IPF). Methods: A retrospective study was performed with data from patients with CFPE and IPF diagnosed in our hospital over a period of 5 years. Results: Sixty-six patients were included, 29 with CPFE and 37 with IPF. Nine had a diagnosis of LC (6 with CPFE and 3 with IPF). Six patients (67%) received palliative treatment even though 3 of them were diagnosed atstage I-II. Overall mortality did not differ significantly between groups; however, in patients with LC, survival was significantly lower compared to those without LC (P =.044). The most frequent cause of death was respiratory failure secondary to pulmonary fibrosis exacerbation (44%). In a multivariate analysis, the odds ratio of death among patients with LC compared to patients without LC was 6.20 (P =.037, 95% confidence interval: 1.11 to 34.48). Conclusions: Lung cancer reduces survival in both entities. The diagnostic and therapeutic management of LC is hampered by the increased risk of complications after any treatment modality, even after palliative treatment (AU)

Lung Cancer in Patients With Combined Pulmonary Fibrosis and Emphysema and Idiopathic Pulmonary Fibrosis. A Descriptive Study in a Spanish Series. / Cáncer de pulmón en pacientes con combinación de fibrosis pulmonar y enfisema y fibrosis pulmonar idiopática. Estudio descriptivo en una serie española.

INTRODUCTION: Information on the association of lung cancer (LC) and combined pulmonary fibrosis and emphysema (CPFE) is limited and derived almost exclusively from series in Asian populations. The main objective of the study was to assess the impact of LC on survival in CPFE patients and in patients with idiopathic pulmonary fibrosis (IPF). METHODS: A retrospective study was performed with data from patients with CFPE and IPF diagnosed in our hospital over a period of 5 years. RESULTS: Sixty-six patients were included, 29 with CPFE and 37 with IPF. Nine had a diagnosis of LC (6 with CPFE and 3 with IPF). Six patients (67%) received palliative treatment even though 3 of them were diagnosed atstage i-ii. Overall mortality did not differ significantly between groups; however, in patients with LC, survival was significantly lower compared to those without LC (P=.044). The most frequent cause of death was respiratory failure secondary to pulmonary fibrosis exacerbation (44%). In a multivariate analysis, the odds ratio of death among patients with LC compared to patients without LC was 6.20 (P=.037, 95% confidence interval: 1.11 to 34.48). CONCLUSIONS: Lung cancer reduces survival in both entities. The diagnostic and therapeutic management of LC is hampered by the increased risk of complications after any treatment modality, even after palliative treatment.

Gliosarcoma: A rare primary CNS tumor. Presentation of two cases.

INTRODUCTION: Gliosarcoma is a very rare primary mixed tumor in the central nervous system, with a biphasic pattern consisting of glial and malignant mesenchymal elements. Its onset is between the fourth and sixth decade of life, and it has a male/female ratio of 1.8/1. Here we present two cases of Gliosarcoma treated in our department. DISCUSSION: The monoclonal or biclonal origin of its biphasic nature is still subject to debate; hence the importance of its diagnosis and histogenesis. RESULTS: Standard treatment consists in surgical resection of the tumor followed in some cases by external radiotherapy and chemotherapy.

Carcinoma microinvasivo de mama: estudio clinicopatológico de 18 casos / Microinvasive breast carcinoma: a clinicopathological profile of 18 cases

Introducción: La definición exacta del carcinoma microinvasivo de mama sigue siendo problemática, y su comportamiento clínico incierto. Hemos estudiado de forma retrospectiva 38 casos con el diagnostico de carcinoma microinvasivo realizado en diversas instituciones, según los criterios de Silver y Tavassoli. Material y métodos: Describimos las características clinicopatológicas y la reproducibilidad del diagnostico de microinvasion, siguiendo los criterios predeterminados. También estudiamos el valor de la p63 y de la calponina, para establecer la integridad de la capa mioepitelial. Resultados: Los casos fueron revisados por dos de los autores (FG, VM) y reclasificados como carcinoma microinvasivo en 18 casos (47%), microinvasión dudosa, 1 caso, carcinoma ductal in situ (DCIS) con el pseudoinvasión, 11 casos (28,9%), y carcinoma ductal invasor pT1a y pT1b en 8 casos (21,6%). El tamaño del DCIS asociado varió entre 7 y 80 mm. En once casos solo había un foco de microinvasión, los otros casos demostraron dos o tres focos de microinvasión. Dos casos mostraron invasión vascular como la única evidencia del microinvasión. El estudio immunohistoquímico con la calponina y la p63 fue útil en la diagnosis en el 50% de los casos. La axila se extirpó en 15 casos, con un solo ganglio positivo (6,6%). El seguimiento ha oscilado entre 3-120 meses (promedio de 42 meses) con sólo una recidiva local sobre la cicatriz por CDIS a los 9 meses. Conclusiones: El sobrediagnóstico histológico es uno de los problemas de esta entidad. Unos criterios morfológicos estrictos y el uso de la inmunohistoquímica es útil en el diagnóstico diferencial con el CDIS y el carcinoma ductal infiltrante. La incidencia de las recurrencias locales y la metástasis ganglionar son bajas y usualmente se asocian a CDIS de alto grado con necrosis. La extirpación del ganglio centinela puede estar indicada en casos de CDIS con microinvasión

Introduction: The exact definition of microinvasive breast carcinoma remains problematic, and its clinical behavior is uncertain. We have studied retrospectively 38 cases with the diagnosis of microinvasive carcinoma made in different institutions, according to the criteria of Silver and Tavassoli. Material and Methods: We describe the clinico-pathologic characteristics and the reproducibility of the diagnosis of microinvasion, following predetermined criteria. We also study the value of immunohistochemical stains with p63 and calponin, to establish the integrity of the myoepithelial layer. Results: The cases were reviewed by two of the authors (FG, VM) and reclassified as microinvasive carcinoma, 18 cases (47%), doubtful microinvasion, 1 case, ductal carcinoma in situ (DCIS) with pseudoinvasion, 11 cases (28.9%), and invasive ductal carcinoma pT1a and pT1b, 8 cases (21.6%).The size of the associated DCIS varied between 7 and 80 mms. In eleven cases one single focus of microinvasion was found, the other cases showed two or three foci of microinvasion. Two cases showed angiolymphatic invasion, as the only evidence of microinvasion. Immunohistochemistry with calponin and p63 was helpful in the diagnosis of microinvasion in 50% of the cases. Axillary lymph nodes were obtained in 15 cases, and a single positive lymph node was found. One patient recurred as DCIS in the surgical scar nine months after surgery. The other patients were disease free after a variable follow-up, between 3 and 120 months (average 42 months). Conclusions: Microinvasive breast carcinoma is often overdiagnosed histologically. The implementation of strict morphological criteria and the use of immunohistochemistry may be helpful in the differential diagnosis with DCIS and invasive ductal carcinoma. The incidence of local recurrence and lymph node metastases is low, and it is usually associated with the presence of high grade DCIS with necrosis. Sentinel lymph node biopsy may be indicated in cases of DCIS with microinvasion (AU)