Diffuse Pulmonary Meningotheliomatosis: Clinic-Pathologic Entity or Indolent Metastasis from Meningioma (or Both)?

Pulmonary minute meningothelial-like nodules (MMNs) are common incidental findings in surgical specimens, consisting of tiny proliferation (usually no larger than 5-6 mm) of bland-looking meningothelial cells showing a perivenular and interstitial distribution, sharing morphologic, ultrastructural, and immunohistochemical profiles with meningiomas. The identification of multiple bilateral MMNs leading to an interstitial lung disease characterized by diffuse and micronodular/miliariform patterns radiologically allows the diagnosis of diffuse pulmonary meningotheliomatosis (DPM). Nevertheless, the lung is the most common site of metastatic primary intracranial meningioma, and differential diagnosis with DPM may be impossible without clinic-radiologic integration. Herein, we report four cases (three females; mean age, 57.5 years) fitting the criteria of DPM, all incidentally discovered and histologically evidenced on transbronchial biopsy (2) and surgical resection (2). All cases showed immunohistochemical expression of epithelial membrane antigen (EMA), progesterone receptor, and CD56. Notably, three of these patients had a proven or radiologically suspected intracranial meningioma; in two cases, it was discovered before, and in one case, after the diagnosis of DPM. An extensive literature review (44 patients with DPM) revealed similar cases with imaging studies excluding intracranial meningioma in only 9% (4 of 44 cases studied). The diagnosis of DPM requires close correlation with the clinic-radiologic data since a subset of cases coexist with or follow a previously diagnosed intracranial meningioma and, thus, may represent incidental and indolent metastatic deposits of meningioma.

Pathologic comparison of conventional video-assisted thoracic surgical (VATS) biopsy versus non-intubated/"awake" biopsy in fibrosing interstitial lung diseases.

Surgical lung biopsy remains the standard procedure for the subset of patients with fibrosing interstitial lung disease (F-ILD) who require a lung biopsy to secure a confident diagnosis. Little is known about the pathologic features of samples obtained via non-intubated/"awake" surgical lung biopsy and the diagnostic accuracy of awake biopsy in patients with F-ILD. Two expert thoracic pathologists blinded to the type of lung biopsy compared the clinical-pathologic features of 120 conventional VATS biopsies with those of 21 consecutive non-intubated/"awake" VATS biopsies. No statistically significant differences between the two procedures were observed with regard to identification of histopathological features. Biopsy length, average of sampled lobes and mean number of slides were similar with the two procedures, while the width of the biopsies was significantly deeper with conventional VATS (31.5 mm versus 25.6 mm; p = 0.01). By contrast, the mean age of patients (69.5 versus 64.5 years; p = 0.02) and the level of diagnostic confidence (100% versus 75%; p = 0.007) were significantly higher among patients undergoing the "awake" procedure. Diagnostic yield was 100% in both groups, with a similar distribution of ILD diagnoses. Non-intubated/"awake" biopsy has the potential to become the standard surgical procedure in patients with F-ILD requiring a histological confirmation of their diagnosis. However, larger prospective studies are needed to validate the safety and diagnostic yield of "awake" compared to conventional VATS.

Blockage of interleukin-1ß with canakinumab in patients with Covid-19.

There is the urgent need to study the effects of immunomodulating agents as therapy for Covid-19. An observational, cohort, prospective study with 30 days of observation was carried out to assess clinical outcomes in 88 patients hospitalized for Covid-19 pneumonia and treated with canakinumab (300 mg sc). Median time from diagnosis of Covid-19 by viral swab to administration of canakinumab was 7.5 days (range 0-30, IQR 4-11). Median PaO2/FiO2 increased from 160 (range 53-409, IQR 122-210) at baseline to 237 (range 72-533, IQR 158-331) at day 7 after treatment with canakinumab (p < 0.0001). Improvement of oxygen support category was observed in 61.4% of cases. Median duration of hospitalization following administration of canakinumab was 6 days (range 0-30, IQR 4-11). At 7 days, 58% of patients had been discharged and 12 (13.6%) had died. Significant differences between baseline and 7 days were observed for absolute lymphocyte counts (mean 0.60 vs 1.11 × 109/L, respectively, p < 0.0001) and C-reactive protein (mean 31.5 vs 5.8 mg/L, respectively, p < 0.0001).Overall survival at 1 month was 79.5% (95% CI 68.7-90.3). Oxygen-support requirements improved and overall mortality was 13.6%. Confirmation of the efficacy of canakinumab for Covid-19 warrants further study in randomized controlled trials.

Sixty-Day Mortality Among 520 Italian Hospitalized COVID-19 Patients According to the Adopted Ventilatory Strategy in the Context of an Integrated Multidisciplinary Clinical Organization: A Population-Based Cohort Study.

PURPOSE: Although the decision of which ventilation strategy to adopt in COVID-19 patients is crucial, yet the most appropriate means of carrying out this undertaking is not supported by strong evidence. We therefore described the organization of a province-level healthcare system during the occurrence of the COVID-19 epidemic and the 60-day outcomes of the hospitalized COVID-19 patients according to the respiratory strategy adopted given the limited available resources. PATIENTS AND METHODS: All COVID-19 patients (26/02/2020-18/04/2020) in the Rimini Province of Italy were included in this population-based cohort study. The hospitalized patients were classified according to the maximum level of respiratory support: oxygen supplementation (Oxygen group), non-invasive ventilation (NIV-only group), invasive mechanical ventilation (IMV-only group), and IMV after an NIV trial (IMV-after-NIV group). Sixty-day mortality risk was estimated with a Cox proportional hazard analysis adjusted by age, sex, and administration of steroids, canakinumab, and tocilizumab. RESULTS: We identified a total of 1,424 symptomatic patients: 520 (36.5%) were hospitalized, while 904 (63.5%) were treated at home with no 60-day deaths. Based on the respiratory support, 408 (78.5%) were assigned to the Oxygen group, 46 (8.8%) to the NIV-only group, 25 (4.8%) to the IMV-after-NIV group, and 41 (7.9%) to the IMV-only group. There was no significant difference in the PaO2/FiO2 at IMV inception in the IMV-after-NIV and IMV-only groups (p=0.9). Overall 60-day mortality was 24.2% (Oxygen: 23.0%; NIV-only: 19.6%; IMV-after-NIV: 32.0%; IMV-only: 36.6%; p=0.165). Compared with the Oxygen group, the adjusted 60-day mortality risk significantly increased in the IMV-after-NIV (HR 2.776; p=0.024) and IMV-only groups (HR 2.966; p=0.001). CONCLUSION: This study provided a population-based estimate of the impact of the COVID-19 outbreak in a severely affected Italian province. A similar 60-day mortality risk was found for patients undergoing immediate IMV and those intubated after an NIV trial with favorable outcomes after prolonged IMV.

Competence in flexible bronchoscopy and basic biopsy technique.

Diagnostic bronchoscopy and tissue sampling techniques using forceps (endobronchial biopsy [EBB] and transbronchial biopsies [TBB]) or needle aspiration (transbronchial needle aspiration-TBNA), all performed with a flexible bronchoscope, are the basic elements of any interventional procedure. The flexible fibrobronchoscopy allows the visualization of the airways and is used both for diagnostic and therapeutic purposes. The working channel of both fibrobronchoscopes with optical fibers and videobronchoscopes, even if of relatively small diameter, allows the insertion of various diagnostic and therapeutic accessories. Fiber optic systems have been widely replaced by video cameras using a miniaturized charge-coupled device camera positioned at the end of the scope that provides electronic transmission of images to a monitor. The indications for both diagnostic and therapeutic fibrobronchoscopy derive from a correct evaluation of symptoms and objective signs of the patient and from the correct interpretation of imaging methods. Although bronchoscopy techniques keep evolving at a rapid pace, basic procedures such as bronchoalveolar lavage, transbronchial lung biopsy, and transbronchial needle aspiration still play a key role in pulmonary disease diagnostics, and therefore, these methods must still be part of the training of interventional pulmonologists. Trainees will acquire a thorough knowledge of thoracic anatomy and become skilled in the interpretation of thoracic imaging, after which they will be given a theoretical and practical training course on virtual reality simulators, on animal or cadaver models, the effectiveness of which has been fully demonstrated by scientific studies. Specific DOPS tests have been developed for a qualitative evaluation of procedures on simulators, on animal models and on the patient.

Competence in pulmonary endoscopy emergencies.

In clinical practice, interventional pulmonologists face several situations which can lead to dramatic consequences especially regarding ventilation and require immediate intervention. We describe the main pathological conditions where an urgent bronchoscopy is crucial because they act through mechanisms such as airway obstructions or alteration of the anatomic integrity of the tracheobronchial tree. We point out the problems resulting from inhalation of foreign bodies, one of the most dramatic respiratory emergencies typical in childhood which needs not only the appropriate endoscopic equipment suitable for the age, but also great experience in the management of the possible related complications. Massive hemoptysis is then discussed in order to help to choose the right endoscope and to clarify the steps requested to face this dramatic event. Lastly, iatrogenic tracheal injuries are described, in spite of their low occurrence. The correct endoscopic assessment of the lesions enables to select the proper multidisciplinary therapeutic approach together with surgeons and anesthetists. Due to their peculiarities, emergencies do not allow classic training so it is difficult to estimate the procedure volume necessary to achieve an adequate endoscopic experience. We think, in this field, it is advisable to refer to numbers proposed for elections endoscopic procedures. For these reasons, we consider desirable the use of simulators and clinic case discussions during interventional pulmonologist's training.

Antimetabolites in the treatment of advanced pleural mesothelioma: a network meta-analysis of randomized clinical trials.

An indirect comparison of cisplatin-pemetrexed (CP) and cisplatin-raltitrexed (CR) was performed. The Odds Ratios of 10, 15 and 20 month survival rate and response rate were assumed as indexes of efficacy; the Odds Ratio of grade III-IV side effects, and the absolute risk of overall, hematologic and non-hematologic toxicity, were assumed as indexes of safety. The outcomes of 352 patients were analysed. The Odds Ratios and 95% Confidence Interval (95% CI) of 10, 15 and 20 months survival rate and response rate were 1.2 (95% CI 0.65-2.24, p = 0.559), 1.02 (95% CI 0.49-2.12, p = 0.953), 1.13 (95% CI 0.44-2.91, p = 0.805) and 0.56 (95% CI 0.26-1.21, p = 0.141), respectively. An absolute increased risk of grade III-IV side effects was observed for CP: 6% (95% CI 3-9%, p < 0.001), 9% (95% CI 2-16%, p = 0.008) and 3% (95% CI 0-5%, p = 0.035) for overall, hematological and non-hematological toxicity. CP and CR can be considered comparable in terms of efficacy in the treatment of metastatic pleural mesothelioma, with a modest increased risk of grade III-IV side effects for CP.

A commentary on interstitial pneumonitis induced by docetaxel: clinical cases and systematic review of the literature.

BACKGROUND: Pulmonary toxicity is a well-known complication observed with several anticancer drugs. Docetaxel, a taxane chemotherapy drug widely used in the treatment of many types of solid tumors including non-small cell lung cancer (NSCLC), rarely causes infiltrative pneumonitis. The exact mechanism by which docetaxel develops this side effect is not well understood; probably it is produced by type I and IV hypersensitivity responses. Here we describe 2 cases of infiltrative pneumonitis induced by docetaxel as second-line chemotherapy in advanced NSCLC. MATERIALS AND METHODS: Two patients with advanced NSCLC were treated with weekly docetaxel as second-line chemotherapy. After 3 courses of chemotherapy, restaging computed tomography (CT) of the chest revealed bilateral diffuse ground-glass opacities with a peribronchial distribution possibly indicative of hypersensitivity pneumonitis. No evidence of pulmonary embolus or pleural effusion was found. Fiberoptic bronchoscopy showed normal bronchi without lymphangitis; biopsies showed interstitial fibrosis without tumor cells. Bronchial tissue laboratory tests for fungi or bacilli were negative. No malignant cells were found at bronchoalveolar lavage. The patients were given high-dose corticosteroid therapy with prednisone 0.7 mg per kilogram per day. RESULTS: After 1 month of therapy, contrast-enhanced chest CT showed complete disappearance of the pulmonary changes in both patients. Spirometry and blood gas analysis revealed complete recovery of pulmonary function. The patients continued their oncological follow-up program. CONCLUSIONS: Pulmonary injury is a rare adverse event during docetaxel chemotherapy. Prompt treatment with high-dose corticosteroids is needed to avoid worsening of respiratory performance.

Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosis of sarcoidosis in clinically unselected study populations.

Literature suggests that ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has excellent performance characteristics for diagnosis of sarcoidosis. However, many authors challenge the external validity of EBUS-TBNA results, as most studies were performed in referral centres by highly experienced investigators, and included populations with very high sarcoidosis prevalence. We performed a systematic review and meta-analysis to estimate the role of EBUS-TBNA for diagnosis of sarcoidosis in studies enrolling consecutive patients with lymphadenopathy detected at imaging studies, regardless of the suspected underlying clinical aetiology. The Pubmed, Embase, Cinahl, Web of Science and Cochrane Library databases were screened to identify the pertinent literature. Quality of eligible studies was assessed by Quality Assessment, Data Abstraction and Synthesis-2 criteria. Pooled diagnostic yield, sensitivity and specificity were calculated, and a summary receiver operating characteristic curve was constructed. Subgroup analysis was planned to identify possible sources of study heterogeneity. Fourteen studies, collectively involving 2097 patients, fulfilled eligibility criteria. The median prevalence of sarcoidosis was 15%. EBUS-TBNA had a pooled diagnostic yield of 0.79 (standard deviation, 0.24), a pooled sensitivity of 0.84 (95% confidence interval (CI), 0.79-0.88) and a pooled specificity of 1.00 (95% CI, 0.99-1.00). Only subgroup analysis exploring the influence of study design seemed to influence the observed inter-study heterogeneity for sensitivity, retrospective studies showing worst sensitivity than prospective ones. The results of EBUS-TBNA for diagnosis of sarcoidosis in clinically unselected populations are excellent and compare favourably with published results from studies conducted in selected populations. High-quality trials would be needed to evaluate factors possibly explaining the observed heterogeneity in sensitivity.

Noninferiority trials in second-line treatments of nonsmall cell lung cancer: a systematic review of literature with meta-analysis of phase III randomized clinical trials.

BACKGROUND: To assess the role of the novel second-line treatments in nonsmall cell lung cancer (NSCLC). METHODS: A systematic review of the literature with meta-analysis of phase III randomized clinical trials (RCTs) was independently performed by 3 authors. All the trials comparing any novel treatment with every-3-weeks docetaxel (3WD) and designed as noninferiority trial were included in the analysis. One-year survival rate (SR) was the primary end point, and quality of life and safety represented the secondary end points. RESULTS: Four RCTs met the selection criteria. The outcomes of 3355 patients were analyzed in the pooled analysis. No heterogeneity was documented in the primary analysis either including all the trials or analyzing separately gefitinib and the chemotherapeutic alternatives to 3WD. The cumulative odds ratio was 0.927 (P=0.313) for 1-year SR, 0.889 (P=0.323) for the chemotherapeutic alternatives to 3WD and 0.953 (P=0.616) for gefitinib. The experimental arms showed a significant advantage in quality of life in the cumulative analysis (odds ratio=1.623, P=0.01) and in the subgroup of patients treated with gefitinib (odds ratio=1.962, P<0.001); a better safety profile for the experimental arm was observed in the cumulative analysis and in the subgroups of alternative chemotherapies or gefitinib. CONCLUSION: All the noninferiority trials demonstrated the noninferiority of pemetrexed, oral topotecan, or gefitinib in 1-year SR (primary end point), but the improvement in overall survival remains modest. The improvement in quality of life and safety (secondary end points) represents the main value of these treatments, whose aim is mainly palliative.

Diffuse lung disease in neurofibromatosis.

Prevalence, characteristics and the very existence of neurofibromatosis-associated diffuse lung disease remain unclear, mostly because the few studies that looked at pulmonary involvement in such patients used chest X-ray as diagnostic mean. We report on the clinical, functional and HRCT findings in a patient with neurofibromatosis-associated diffuse lung disease and provide a short literature review.

Bevacizumab in the treatment of advanced, non-squamous non-small cell lung cancer: an evidence-based approach.

BACKGROUND: To assess the efficacy and safety of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous non-small cell lung cancer (NSCLC) on the basis of the two registrative trials [ECOG E4599 trial and BO17704 (AVAiL) trial]. METHODS: A pooled analysis of the two trials was performed using a random effect model, and the results were summarized as number-needed-to-treat (NNT) and number-needed-to-harm (NNH). A 2-step analysis was performed. The primary analysis included only the patients treated with bevacizumab 15 mg/kg in the experimental arm, whereas the secondary analysis (with descriptive aim) included the patients treated with bevacizumab 15 mg/kg or those treated with bevacizumab 7.5 mg/kg in the experimental arm. The 1-year survival and 6-month progression-free rates were assumed as indexes of efficacy, and grade III-IV side effects were assumed as index of safety in both analyses. RESULTS: 1,921 patients were potentially eligible for the pooled analysis and were included in the secondary analysis, whereas 1,576 patients were included in the primary analysis. A large heterogeneity was documented for both 6-month progression-free interval (I(2) = 88.164%, p = 0.004) and overall survival (I(2) = 73.541, p = 0.052). The absolute risk reduction of 1-year death and 6-month progression were 3.3% (95% CI = -6.5 to 13.2%, p = 0.507), with a NNT = 30; and 15.2% (95% CI = 0.07-29.6%, p = 0.04), with a NNT = 6 (both in favor of the bevacizumab-containing regimens), respectively. The absolute risk of treatment-related death was 2.4% (95% CI = 0.8-3.9%, p = 0.003), with a NNH = 41 against the bevacizumab-containing regimens; that of bleeding was 3.3% (95% CI = 1.6-4.9%, p < 0.001), with a NNH = 30; that of hypertension was 6.6% (95% CI = 4.6-8.6%, p < 0.001), with a NNH = 15; that of proteinuria was 2.1% (95% CI = 0.3-3.8%, p = 0.024), with a NNH = 47; that of neutropenia was 7.3% (95% CI = 3.2-11.4%, p < 0.001), with a NNH = 13; that of thrombocytopenia was 1.5% (95% CI = 0.2-2.7%, p = 0.021), with a NNH = 66. No significant differences were observed in the efficacy and the safety analysis when all the patients treated with bevacizumab 7.5 mg/kg and 15 mg/kg were included into the pooled analysis. CONCLUSION: Adding bevacizumab to standard chemotherapy in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC seems to favor a modest improvement in the main outcomes, with a significant worsening of the safety profile. These data suggest caution in the generalized use of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC.

Second-line treatments in non-small cell lung cancer. A systematic review of literature and metaanalysis of randomized clinical trials.

BACKGROUND: To assess the efficacy of second-line treatments in non-small cell lung cancer (NSCLC). METHODS: A systematic review of literature with metaanalysis of randomized clinical trials (RCTs) was independently performed by three authors. A primary analysis included all RCTs comparing any approach (chemotherapy or therapy with epidermal growth factor receptor [EGFR] inhibitors) with placebo; a secondary analysis included all RCTs comparing any treatment with docetaxel therapy every 3 weeks. The 1-year survival rate (SR) of the primary analysis was the primary outcome of the study; the 1-year SR of the secondary analysis, response rate (RR), and time to progression of primary and secondary analyses were the secondary end points. RESULTS: Fourteen RCTs met the selection criteria. The outcomes of 2,627 and 5,952 patients were analyzed in the primary and secondary analysis, respectively. A significant heterogeneity was documented in the primary analysis for 1-year SR with odd ratio [OR] = 0.763 (p = 0.029). No heterogeneity was documented for RR in the primary analysis, with OR = 0.165 (p < 0.001). A modest heterogeneity was documented in the secondary analysis for 1-year SR and RR, with 1-year SR OR = 0.924 (p = 0.122) and RR OR = 1.069 (p = 0.643). CONCLUSION: Second-line treatments in NSCLC seem to improve the main outcomes better than supportive care. Docetaxel administration every 3 weeks probably remains the "gold standard" because at present the data in literature are not enough to support a greater efficacy of other alternative options. Further trials are needed to identify a clinical and biological profile that could predict the response to treatments and a criterion to select the patients to be treated with chemotherapy or EGFR inhibitors.

Second line treatments in advanced platinum-resistant non small cell lung cancer. A critical review of literature.

In the last 10 years the medical approach to platinum-resistant Non Small Cell Lung Cancer (NSCLC) has radically changed, passing from a lack of evidence of any primary treatment against the tumor, to the identification of chemotherapy or EGFR inhibitors as the gold standard for clinical practice. Eight randomized clinical trials support the evidence of efficacy of second-line treatments against NSCLC, and docetaxel, pemetrexed and erlotinib are the most effective options for clinical practice. However, many aspects remain still undefined: Can a treatment with docetaxel, pemetrexed or erlotinib be considered the gold standard for all patients with platinum-resistant NSCLC, and consequently should all patients be treated with at least one of these options? Are the benefits enough to justify the side effects observed with these chemotherapeutic options? Can a schedule be preferred to the others for either efficacy or safety profile? Can the new EGFR inhibitors be considered an innovation in the treatment of platinum-resistant NSCLC, and should they be used in all patients with platinum-resistant NSCLC? A systematic review of randomized clinical trials and a critical analysis of the results were performed with the aim to clarify the real meaning of medical treatments in advanced, platinum-resistant NSCLC.

Bronchoalveolar lavage findings in severe community-acquired pneumonia due to Legionella pneumophila serogroup 1.

BACKGROUND: No specific data are available in the literature on the bronchoalveolar Lavage (BAL) findings of Legionella pneumophila pneumonia. We report on the cytological and immunophenotypical BAL data of three immunocompetent patients with severe community-acquired pneumonia due to L. pneumophila serogroup 1. METHODS: Retrospective chart review. The microbiologial diagnosis was obtained by BAL culture or/and urinary antigen assay. RESULTS: All patients presented with high-grade fever, bilateral chest infiltrates and severe respiratory failure requiring ventilatory support. The cytological BAL pattern at presentation showed in all patients the association of a marked neutrophilia with a variable but remarkable percentage of lymphoblasts. Increased levels of activated T-Lymphocytes (both HLA-DR + and CD25 + cells) and, in 2 out of 3 patients, of T-cells bearing the gamma/delta T-cell receptor were the main immunophenotypical findings on flow cytometric analysis. CONCLUSIONS: We suggest that the association of lymphoblasts with a marked neutrophilia in BAL fluid of patients with a clinical-radiological setting compatible with acute pneumonia should suggest L. pneumophila as a possible etiologic agent.

Transbronchial needle aspiration improves the diagnostic yield of bronchoscopy in sarcoidosis.

BACKGROUND AND AIM: Transbronchial needle aspiration (TBNA) is a minimally invasive bronchoscopic procedure that allows sampling of hilar and mediastinal lymph nodes in close contact with the airways. We undertook this study to assess the value of TBNA in the diagnosis of sarcoidosis manifesting with intrathoracic lymphadenopathies (stages I and II), and to compare its yield with that of transbronchial lung biopsy (TBLB). METHODS: The results of bronchoscopy with combined TBNA and TBLB in 32 patients with stage I or II sarcoidosis were retrospectively analyzed. RESULTS: Sensitivity was 65.6% for TBNA (stage I, 82.3 %; stage II, 46.6%), and 62.5% for TBLB (stage 1, 52.9%; stage II, 73.3%). The combination of the two methods was associated with the highest diagnostic yield (93.7% overall sensitivity), and allowed significantly better results over both TBNA alone (93.7% vs 65.6%; p = 0.011) and TBLB alone (93.7% vs 62.5%; p = 0.005). CONCLUSIONS: The results of our study suggest that a diagnostic approach combining TBNA and TBLB is safe and effective in the setting of stage I and II sarcoidosis. It also confirmed the value of TBNA, with excellent diagnostic yields especially in stage I of the disease.