Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins.

Intratumoral similarities and differences between large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) are determined partially by the Notch signaling pathway, which controls the switch from neuroendocrine to slight/non-neuroendocrine cell fate. LCNECs are divided into two subgroups according to genomic alterations: type I LCNECs exhibit a neuroendocrine profile characterized by achaete-scute homolog 1 (ASCL1)high/delta-like protein 3 (DLL3)high/NOTCHlow and type II LCNECs show the pattern ASCL1low/DLL3low/NOTCHhigh. Here, we used immunohistochemistry, transmission electron microscopy, and digital analysis to examine the role of the Notch ligand DLL3 as an immunomarker of the neuroendocrine state and ASCL1 as a regulator of cell-cell interactions in SCLCs and LCNECs. High DLL3 and ASCL1 expression was associated with atypical submicroscopic characteristics involving nuclear size, chromatin arrangement, Golgi apparatus, and endoplasmic reticulum, and was characteristic of type I LCNECs with similarity to SCLCs, whereas low DLL3 and ASCL1 expression was found in both SCLCs and type II LCNECs. In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.

Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins

Abstract Intratumoral similarities and differences between large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) are determined partially by the Notch signaling pathway, which controls the switch from neuroendocrine to slight/non-neuroendocrine cell fate. LCNECs are divided into two subgroups according to genomic alterations: type I LCNECs exhibit a neuroendocrine profile characterized by achaete‐scute homolog 1 (ASCL1)high/delta-like protein 3 (DLL3)high/NOTCHlow and type II LCNECs show the pattern ASCL1low/DLL3low/NOTCHhigh. Here, we used immunohistochemistry, transmission electron microscopy, and digital analysis to examine the role of the Notch ligand DLL3 as an immunomarker of the neuroendocrine state and ASCL1 as a regulator of cell-cell interactions in SCLCs and LCNECs. High DLL3 and ASCL1 expression was associated with atypical submicroscopic characteristics involving nuclear size, chromatin arrangement, Golgi apparatus, and endoplasmic reticulum, and was characteristic of type I LCNECs with similarity to SCLCs, whereas low DLL3 and ASCL1 expression was found in both SCLCs and type II LCNECs. In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs.

A novel cause of invasive pulmonary infection in an immunocompetent patient: Aspergillus candidus.

Aspergillus candidus, a common contaminant of grain dust, may represent an important respiratory hazard to grain workers, considering its immunomodulating capability by producing p-terphenyl metabolites and terprenins, potent cytotoxic substances. However, there are only three cases of A. candidus infection in the English literature, one fatal solitary brain mass and two onychomycosis. We describe the first case of invasive pulmonary infection and skin abscesses due to A. candidus, determination of minimal inhibitory concentration for anti-fungals, and the successful treatment with liposomal amphotericin B and itraconazole. Possible mechanisms involved in the dissemination of infection in an immunocompetent host are discussed.

Prognostic values of stromal proportion and PCNA, Ki-67, and p53 proteins in patients with resected adenocarcinoma of the lung.

Data from 64 patients who underwent surgical resection of lung adenocarcinomas were studied to identify clinicopathologic markers that might provide prognostic information on the clinical behavior of this neoplasia Patient staging was performed in accordance with the tumor-node-metastasis system as follows: Stage I (n = 29), Stage II (n = 11), Stage IIIA (n = 21), and Stage IIIB (n = 3). Overall follow-up time corresponded to the follow-up time for patients who were alive and to the survival time for patients who had died, all of them expressed in months. Data included age, staging, histologic type, morphometric assessment of histologic features related to tumor (stroma and vascularization), and immunohistochemical detection of proliferation cell markers (Ki-67 protein and proliferating cell nuclear antigen) and p53 protein. The morphometric assessment was made by the point-counting procedure. Data analysis included Life Tables for Survival and Cox Regression models. Overall follow-up analysis showed that significant univariate predictors (P < .05) were T stage; N stage; tumor stromal proportion; and immunohistochemical indexes of proliferating cell nuclear antigen, Ki-67, and p53 proteins. Variables that presented independent predictive value for overall follow-up with the multivariate model (P < .05) were sex, T stage, N stage, tumor stromal proportion, and immunohistochemical detection of p53 protein. We conclude that tumor stromal proportion and immunohistochemical detection of p53 protein, controlled for sex, T stage, and N stage, may be of critical value in the evaluation of recurrence of lung adenocarcinoma, serving as indicators for a more accurate prognosis.

Stereological estimates of nuclear star volume and vessels as predictors of chemotherapy response in small cell carcinoma of the lung: a preliminary report.

AIMS: This study was designed to evaluate the role of morphometric and clinical parameters in predicting chemotherapy responder patients with small cell carcinoma of the lung. METHODS AND RESULTS: Morphometric studies were performed by means of point counting techniques. Forty-six patients were included in this study. Group 1 patients (n = 19) were those without response to chemotherapy; Group 2 (n = 27) was composed by patients with partial or complete response to chemotherapy. Logistic regression analysis was used to attain the best separation of non-responder from responder patients. Star volume of the nuclei and vessel were selected during the backward procedure as relevant variables to characterize the two groups of patients. The overall sensitivity of the model was 80.43%. CONCLUSIONS: Our results indicate that histopathological data may help to predict the chemotherapy response in patients with small cell lung carcinoma, and encourage the use of morphometric procedures in histopathological analysis of this type of lung tumours.

Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.

BACKGROUND: In patients with the acute respiratory distress syndrome, massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury. We determined whether a ventilatory strategy designed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome. METHODS: We randomly assigned 53 patients with early acute respiratory distress syndrome (including 28 described previously), all of whom were receiving identical hemodynamic and general support, to conventional or protective mechanical ventilation. Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure (PEEP) for acceptable oxygenation, with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels (35 to 38 mm Hg). Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve, a tidal volume of less than 6 ml per kilogram, driving pressures of less than 20 cm of water above the PEEP value, permissive hypercapnia, and preferential use of pressure-limited ventilatory modes. RESULTS: After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P<0.001). The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group (P=0.005): the rates of clinical barotrauma were 7 percent and 42 percent, respectively (P=0.02), despite the use of higher PEEP and mean airway pressures in the protective-ventilation group. The difference in survival to hospital discharge was not significant; 13 of 29 patients (45 percent) in the protective-ventilation group died in the hospital, as compared with 17 of 24 in the conventional-ventilation group (71 percent, P=0.37). CONCLUSIONS: As compared with conventional ventilation, the protective strategy was associated with improved survival at 28 days, a higher rate of weaning from mechanical ventilation, and a lower rate of barotrauma in patients with the acute respiratory distress syndrome. Protective ventilation was not associated with a higher rate of survival to hospital discharge.

Temporal hemodynamic effects of permissive hypercapnia associated with ideal PEEP in ARDS.

The associated use of permissive hypercapnia (PHY) and high PEEP levels (PEEP(IDEAL)) has been recently indicated as part of a lung-protective-approach (LPA) in acute respiratory distress syndrome (ARDS). However, the net hemodynamic effect produced by this association is not known. We analyzed the temporal hemodynamic effects of this combined strategy in 48 patients (mean age 34 +/- 13 yr) with ARDS, focusing on its immediate (after 1 h), early (first 36 h), and late (2nd-7th d) consequences. Twenty-five patients were submitted to LPA--with the combined use of permissive hypercapnia (PHY), VT < 6 ml/kg, distending pressures above PEEP < 20 cm H2O, and PEEP 2 cm H2O above the lower inflection point on the static inspiratory P-V curve (P(FLEX))- and 23 control patients were submitted to conventional mechanical ventilation. LPA was initiated at once, resulting in an immediate increase in heart rate (p = 0.0002), cardiac output (p = 0.0002), oxygen delivery (DO2l, p = 0.0003), and mixed venous Po2 (p = 0.0006), with a maintained systemic oxygen consumption (p = 0.52). The mean pulmonary arterial pressure markedly increased (mean increment 8.8 mm Hg; p < 0.0001), but the pulmonary vascular resistance did not change (p = 0.32). Cardiac filling pressures increased (p < 0.001) and the systemic vascular resistance fell (p = 0.003). All these alterations were progressively attenuated in the course of the first 36 h, despite persisting hypercapnia. Plasma lactate suffered a progressive decrement along the early period in LPA but not in control patients (p < 0.0001). No hemodynamic consequences of LPA were noticed in the late period and renal function was preserved. A multivariate analysis suggested that these acute hyperdynamic effects were related to respiratory acidosis, with no depressant effects ascribed to high PEEP levels. In contrast, high plateau pressures were associated with cardiovascular depression. Thus, as long as sufficiently low distending pressures are concomitantly applied, the sudden installation of PHY plus PEEP(IDEAL) induces a transitory hyperdynamic state and pulmonary hypertension without harmful consequences to this young ARDS population.

Primary malignant fibrous histiocytoma of the lung. Report of a case with bronchial brushing cytologic features.

BACKGROUND: Malignant fibrous histiocytoma (MFH) arising primarily in the lungs is rare, and a preoperative diagnosis, as well as a surgical planning, is very important because of the tumor's propensity for vascular invasion and its low incidence of lymph node metastasis. The correct preoperative diagnosis of thoracic MFH is not easy to establish because the small fragments from needle and transbronchial biopsies are often inadequate for a conclusive histologic analysis. A preoperative bronchial brushing cytology suggestion of the diagnosis of primary MFH of the lungs may be helpful in such cases. CASE: A 37-year-old male presented with a large, irregular mass in the inferior and middle lobes on chest roentgenography as well as on computed tomography. Two bronchoscopies were performed, with the diagnosis of undifferentiated large cell carcinoma. After surgical resection a more sophisticated pathologic analysis, including immunohistochemical and ultrastructural studies, revealed a primary MFH of the lungs. Revision of the bronchial brushing cytology disclosed many spindle-shaped cells with a "comet" configuration, strongly suggestive of MFH. CONCLUSION: The bronchial brushing cytology features of spindle-shaped and bizarre, multinucleated giant cells with a comet appearance may be the key to the cytomorphologic diagnosis of MFH.

Morphometric evaluation of argyrophilic nucleolar organizer region is useful in predicting long-term survival in squamous cell carcinoma of the lung.

Nucleolar organizer regions identified by means of an argyrophilic technique (AgNOR) were quantified by digital image analysis in 81 patients with squamous cell carcinoma of the lung. Survival rate was modeled as function of AgNOR expression by Cox regression models controlled for staging, histologic grade, age, and sex. Our results indicate that AgNOR expression has a significant prognostic role. Tumors at lower stages have a lower expression of AgNOR than those with more advanced disease. Tumors with high histopathologic grade have a higher expression of AgNOR. Patients with low AgNOR expression presented a higher survival rate than those with higher amounts of AgNOR. The foregoing results strongly encourage the development of prospective trials to assess the real role of AgNOR in determining prognosis in squamous cell carcinoma of the lung.

Stereological estimates of the nuclear/cytoplasmic ratio and star volume on fibreoptic biopsies are of prognostic value for survival in a preliminary study of advanced squamous cell carcinoma of the lung.

AIMS: This study evaluated the role of morphometric and clinical parameters in establishing the prognosis of patients submitted to radiotherapy for advanced squamous cell carcinoma of the lung. METHODS AND RESULTS: Morphometric studies were performed by point counting techniques. Forty patients were included in this study. Group 1 patients (n = 22) were those with survival equal to or less than 6 months; group 2 (n = 10) patients had a survival of 7 to 12 months; and group 3 (n = 8) included patients with survival greater than 12 months. To characterize these three groups of patients, models combining categorical and continuous variables were constructed by means of discriminant analysis. Weight loss, histological grade, nuclear/cytoplasmic ratio and star volume of the nuclei were selected during the backward procedure as relevant variables to characterize the three groups of patients. The overall sensitivity of the model was 90%. CONCLUSIONS: Our results indicate that histopathological data may help to predict prognosis in patients with advanced squamous cell lung carcinoma, and encourage the use of morphometric procedures in histopathological analysis of this type of lung tumour.

[Predictive factors of abandoning treatment in tuberculosis patients]. / Fatores preditivos de abandono de tratamento por pacientes com tuberculose.

In spite of the efforts to control the spread of tuberculosis worldwide this disease remains one of the biggest problems in public health. Multiresistance has a dramatic effect in this scenario. Non compliance with treatment is directly related to disease spread and the appearance of multiresistance bacilli. Aiming to verify if it is possible to identify patients prone to non compliance from data obtained in the first visit we have studied a population enrolled in a prospective study. Among 257 consecutive patients evaluated between january 1991 and january 1994, we compared 87 patients that abandoned treatment before six months (group A) with 97 that completed six months of treatment (group C). The abandon rate in this group as 33.85% which is larger than 12.9% rate reported by the Health Ministry. Comparing A to C, only the prevalence of alcoholism (A 33.3% x C 22.5%, p = 0.015) and risk behavior for HIV infection (A 27.6% x C 10.2%, p = 0.046), as well as the frequency of non pulmonary disease (A 38.0% x C 24.5%, p = 0.034) were significantly different between both groups. Regarding the moment of abandon (0, 1st or 3rd month) there was no difference in the A group. We conclude that patients at high risk of abandoning tuberculosis treatment can be identified with data obtained at the first visit, allowing to establish a different policy such as supervised treatment for this population.

Beneficial effects of the "open lung approach" with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation.

Alveolar overdistention and cyclic reopening of collapsed alveoli have been implicated in the lung damage found in animals submitted to artificial ventilation. To test whether these phenomena are impairing the recovery of patients with acute respiratory distress syndrome (ARDS) submitted to conventional mechanical ventilation (MV), we evaluated the impact of a new ventilatory strategy directed at minimizing "cyclic parenchymal stretch." After receiving pre-established levels of hemodynamic, infectious, and general care, 28 patients with early ARDS were randomly assigned to receive either MV based on a new approach (NA, consisting of maintenance of end-expiratory pressures above the lower inflection point of the P x V curve, VT < 6 ml/kg, peak pressures < 40 cm H2O, permissive hypercapnia, and stepwise utilization of pressure-limited modes) or a conventional approach (C = conventional volume-cycled ventilation, VT = 12 ml/kg, minimum PEEP guided by FIO2 and hemodynamics and normal PaCO2 levels). Fifteen patients were selected to receive NA, exhibiting a better evolution of the PaO2/FIO2 ratio (p < 0.0001) and of compliance (p = 0.0018), requiring shorter periods under FIO2 > 50% (p = 0.001) and a lower FIO2 at the day of death (p = 0.0002). After correcting for baseline imbalances in APACHE II, we observed a higher weaning rate in NA (p = 0.014) but not a significantly improved survival (overall mortality: 5/15 in NA versus 7/13 in C, p = 0.45). We concluded that the NA ventilatory strategy can markedly improve the lung function in patients with ARDS, increasing the chances of early weaning and lung recovery during mechanical ventilation.

Usefulness of morphometric evaluation of histopathologic slides in predicting long-term outcome of patients with squamous cell carcinoma of the lung. A preliminary report.

The present work was designed to evaluate the role of morphometric parameters in contributing to establish prognosis in 35 patients who underwent surgical resection of squamous cell carcinoma (SCC) of the lung. Morphometric studies were performed by means of point counting techniques. Patients considered as disease-free survivors, ie, those without tumor recurrence for more than 60 months (n = 6), were designated as DOWELL, whereas the remaining 29 patients comprised the DOBAD group. In order to characterize DOWELL patients, multivariate models combining numeric and categoric variables were constructed considering numeric variables (age and morphometric parameters) or indexes for categoric data such as stage, and presence of residual tumor. Staging, incomplete tumor resection, and nucleus-cytoplasm ratio were selected by the model as significantly associated with survival. In addition, nuclear volume contributed (although nonsignificantly per se) to further refine the model by increasing its r value. Our results indicate that histopathologic data, when evaluated quantitatively, could predict prognosis in patients with SCC, together with staging and clinical data and encourage the use of morphometric procedures in the histopathologic analysis of SCC.

Nuclear/cytoplasmic ratio correlates strongly with survival in non-disseminated neuroendocrine carcinoma of the lung.

In order to verify whether quantitative morphological indices of neuroendocrine carcinoma of the lung may help to predict survival, 47 biopsies (from 37 males and 10 females; 16-82 years of age) were studied by light microscopy. Areal fractions of nuclei, cytoplasm, stroma, and blood vessels were determined using a standard point counting method. The counts were made in six non-coincident microscopic fields in each case, and the areal fractions of nuclei, of the entire tumour cell, stroma, blood vessels and the nuclear/cytoplasmic ratio were computed. In a multivariate linear regression analysis, survival in months after biopsy was considered the dependent variable of age and of all morphometric parameters listed above. The significance level was set at 5%. For all patients (disregarding staging) survival was negatively correlated (P < 0.001, multiple r = 0.5435) with age and nuclear/cytoplasmic ratio. When only patients with disease confined to the thorax (stages I, II and III) were taken into account, the accuracy of the function predicting survival increased considerably (P = 0.004, multiple r = 0.7957). The use of simple stereological methods, therefore, proved to be of value in predicting survival in patients with neuroendocrine carcinomas of the lung.

Derrame pleural tuberculoso: avaliacao clinica e laboratorial / Tuberculous pleural effusion: clinical and laboratory evaluation

Sao apresentados os resultados do estudo de 44 pacientes com diagnostico de derrame pleural tuberculoso. A idade media foi 35 anos. Houve predominio do sexo masculino e da raca branca. As queixas principais foram febre (41/44), dor toracica (41/44) e emagrecimento (34/44), com tempo medio de duracao de sintomas de seis semanas. Em 21 pacientes o derrame foi localizado do lado direito, em 23 no lado esquerdo e em um paciente em ambos os lados. Em 23 por cento dos pacientes foi observado acometimento do parenquima pulmonar ipsilateral. Destes, tres apresentavam cultura de escarro positiva. Foram realizadas 49 biopsias de pleura em 44 pacientes. A primeira biopsia foi diagnostica em 82,5 por cento dos pacientes. A cultura do fragmento de pleura foi positiva em 75,8 por cento e a cultura do liquido pleural em 22,5 por cento. O liquido pleural era um exsudato com uma relacao liquido pleural/sangue maior que 0,5 para proteinas e maior que 0,6 para DHL em todos os casos. O estudo citologico mostrou predominio de linfocitos e escassez de celulas mesoteliais. Os pacientes receberam esquema terapeutico adequado, apresentando boa evolucao. Houve apenas uma falha. Os pacientes apresentaram melhora significativa (p < 0,05) com relacao ao peso, hemoglobina e diminuicao de VHS. Dos 44 pacientes, 23 evoluriam...

Embolia septica pulmonar com foco primario em ouvido medio / Septic pulmonary embolism with primary focus in middle ear

Apresentamos o caso de um paciente com embolia septica de pulmao cujo foco primario era em ouvido medio. As bacterias implicadas foram aerobios Gram positivos, Gram negativos e anaerobios, sendo isolados oito diferentes agentes etiologicos em hemoculturas. As culturas de urina e escarro tambem se mostraram positivas. O tratamento consistiu em antibioticoterapia de amplo espectro e na exploracao cirurgica do foco inicial. A resposta foi favoravel apos 40 dias de antibioticoterapia.

[Tuberculous pleural effusion: clinical and laboratory evaluation]. / Derrame pleural, tuberculoso: avaliação clínca e laboratorial.

Clinical data concerning 44 patients with pleural tuberculosis are presented. The average age was 35 years. The main symptoms were fever (41/44), chest pain (41/44) and weight loss (34/44). In all but one case the pleural effusion was unilateral without preference for one or other hemithorax. In ten patients (23%) parenchymal lesions could be recognized on chest roentgenograms. Three patients had coexisting active pulmonary disease with positive sputum culture. Forty-nine pleural biopsies were performed in 44 patients. The culture of pleural tissue was positive in 75%, and culture of pleural fluid in 22.5%. The pleural fluid was exudative with fluid-to-serum ratios of protein and LDH exceeding 0.5 and 0.6 respectively. The cellular characterization of pleural fluid has demonstrated predominance of lymphocytes and scarcity of mesothelial cells. The patients received adequate treatment with excellent results, exhibiting an increased weight, increased hemoglobin and decreased ESR. The development of residual pleural thickening occurred in 23 out of 44 cases.

[Septic pulmonary embolism with primary focus in the middle ear]. / Embolia séptica pulmonar com foco primário em ouvido médio.

A case of septic pulmonary embolism is presented in which the primary site of infection was the middle ear. The implicated bacteria were aerobics both Gram positive and Gram negative and anaerobics. There were 8 different agents isolated from blood cultures. The cultures of urine and sputum were also positive. The patient received a broad spectrum antibiotic therapy and a surgical exploration of the initial site of infection was performed. A favorable response was observed after 40 days of treatment with antibiotics.