A case report of a lung cancer patient with two uncommon EGFR mutations and a review of the literature: two sides of the same coin.

Lung cancer is the malignancy with the highest morbidity and mortality worldwide. Approximately 60% of non-small cell lung cancer (NSCLC) presents driver alterations most of which are targetable. Nowadays, limited clinical data are available regarding the efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with NSCLC harboring uncommon EGFR mutations, considering their heterogeneity. Herein, we report a rare case of EGFR-mutated lung adenocarcinoma which has developed into squamous cell carcinoma with uncommon EGFR (Ex18) compound mutations and phosphatidylinositol 3-kinase mutation receiving afatinib at the forefront.

Is multidisciplinary management possible in the treatment of lung cancer? A report from three Italian meetings.

PURPOSE: To report criticisms and barriers to the "real-life" application of international guidelines and recent developments in the management of locally advanced non-small cell lung cancer (NSCLC) in Italy. METHODS: Three 2-day courses were organized. During the first day, experts in different fields of thoracic oncology gave their lecture on diagnosis and therapy for locally advanced NSCLC. During the second day, all participants were divided into four groups to discuss on a clinical case as a multidisciplinary team (MDT). The aim was to stimulate the discussion on practical issues in the management of NSCLC patients in the real-life practice. RESULTS: A total of 196 physicians were involved in the courses as learners. Invasive diagnosis of nodal disease for staging purposes, a priori definition of "surgical resectability" and a regular MDT with all crucial participants available were the three main key points identified for a good management of these patients. The main barriers to the clinical application of a good diagnostic and therapeutic approach to the patient were the absence of a regular and complete MDT in the South and Centre of Italy, while in the North of Italy, time for discussion of clinical cases in the MDT and waiting lists for staging and therapeutic interventions were deemed as the major concerns. CONCLUSION: The meetings showed that diagnosis and treatment of locally advanced NSCLC are still extremely variable between different Italian regions. Logistic issues, waiting lists, paucity of well-trained staff and expertise seem to be the main barriers to international guidelines application.

Fibrotic lung toxicity induced by cytotoxic drugs, radiation and immunotherapy in patients treated for lung cancer.

Patients treated for lung cancer may develop lung toxicity induced by chemotherapy (DILD), radiation or combined radiation recall pneumonitis. In the literature, some cases of immune-mediated pneumonitis have been reported associated with immunotherapy. The clinical and radiologic features of interstitial lung toxicity are unspecific, dyspnoea and dry cough are the most common symptoms while the most frequent radiological pattern is the cryptogenic organizing pneumonia (COP). Why only some individuals treated with these drugs develop interstitial lung toxicity is unclear.In the last few years some studies have reported the utility of KL 6 for the evaluation of DILD. The treatment is based on high doses of systemic steroids or immune suppressor. In this study we report severe interstitial lung damage in patients treated with different anti-blastic, immune and radiation therapies. Treated with surgery, chemotherapy, immuno and radiotherapy for lung cancer, they unfortunately died of severe DILD.

Neoadjuvant approach for nonsmall cell lung cancer: overview of the current issues.

PURPOSE OF REVIEW: Despite the large numbers of studies, role of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy is debated. This approach would increase resectability in locally advanced patients, and improve surgical outcome in resectable patients. Thus, an overview of recent literature is relevant to highlight the current issues. RECENT FINDINGS: Literature in the previous year mainly focused on overall treatment strategy, radiotherapy technique, role of radiological response and metabolic imaging, and biological agents in this setting. SUMMARY: Current data suggest that neoadjuvant chemotherapy is beneficial if compared with surgery alone or definitive chemoradiotherapy. Benefit of radiotherapy addition in this setting is not clear, especially in patients undergoing pneumonectomy. Hypofractionated regimens and dose escalation protocols should be considered for further investigation. Response evaluation with radiologic and metabolic assessment is prognostic for survival outcome; its usefulness as a selection tool for adaptive strategies has been investigated recently. More robust data on biological agents and immunological agents in this setting are needed; further investigation on predictive biomarker is suggested.

The "ZEEP-PEEP test" to evaluate the response to positive end-expiratory pressure delivered by helmet: A prospective physiologic study.

Introduction: The improvement in oxygenation after helmet application in hypoxemic patients may be explained by the alveolar recruitment obtained with positive end expiratory pressure (PEEP) or by the administration of a more accurate inspiratory fraction of oxygen (FiO2). We have designed the "ZEEP-PEEP test", capable to distinguish between the FiO2-related or PEEP-related oxygenation improvement. Our primary aim was to describe the use of this test during helmet CPAP to assess the oxygenation improvement attributable to PEEP application. Material and methods: We performed a prospective physiological study including adult critically ill patients. Respiratory and hemodynamic parameters were recorded before helmet application (PRE step), after helmet application without PEEP (ZEEP step) and after the application of the PEEP valve (PEEP step), while maintaining a constant FiO2. We defined as "PEEP responders" patients showing a PaO2/FiO2 ratio improvement ≥10% after PEEP application. Results: 93 patients were enrolled. Compared to the PRE step, PaO2/FiO2 ratio was significantly improved during helmet CPAP both at ZEEP and PEEP step (189 ± 55, 219 ± 74 and 241 ± 82 mmHg, respectively, p < 0.01). Both PEEP responders (41%) and non-responders showed a significant improvement of PaO2/FiO2 ratio after the application of helmet at ZEEP, PEEP responders also showed a significant improvement of oxygenation after PEEP application (208 ± 70 vs 267 ± 85, p < 0.01). Conclusions: Helmet CPAP improved oxygenation. This improvement was not only due to the PEEP effect, but also to the increase of the effective inspired FiO2. Performing the ZEEP-PEEP test may help to identify patients who benefit from PEEP.

Sound and Light Levels in a General Intensive Care Unit Without Windows to Provide Natural Light.

BACKGROUND: Appropriate levels and patterns of sound and light in an intensive care room help to maintain the patient's normal physiological functions. High sound levels can disrupt the patient's normal sleep architecture, cause hearing deficits, and induce the onset of delirium. Intensive care unit patients frequently report poor sleep, partly due to the environment. OBJECTIVES: An observational pilot prospective study was designed to record sound pressure and light pollution levels in an Italian intensive care unit, without windows to provide natural light. METHOD: Sound levels were measured in decibel A (dBA) every 10 seconds. Sound data were analyzed for sound peak, defined as the number of times sound levels exceeded 45, 50, 60, 65, 70, 75, 80, and 85 dBA. Light measures were taken every 10 seconds on a continuous basis. Light data were analyzed for light "peaks," defined as the number of times light levels exceeded 100, 200, 300, 400, and 500 lux. RESULTS: The overall median sound level during the study period was equal to 54.60 (interquartile range [IQR], 51.70-57.70) dBA. The daytime median sound level was 56.00 (IQR, 53.00-59.50) dBA, and the nighttime median was 53.00 (IQR, 49.50-55.20) dBA (P < .001). The overall median light level was equal to 114 (IQR, 0-225) lux. The daytime median light level was 184 (IQR, 114-293) lux, and the nighttime median was 0 (IQR, 0-50) lux (P < .001). With respect to room lighting, rooms were observed to have "no lights on" 12.6% of daytime and 41% of nighttime. DISCUSSION: The sound levels recorded in our sample demonstrated that peaks >45 dBA during daytime and nighttime are, respectively, equal to 99.9% and 98.6% of all readings. The Environmental Protection Agency/World Health Organization recommended thresholds for both day (45 dBA) and night (35 dBA). Sound levels reached "toxic levels" when sound-generating activities were performed by nurses and physicians.

Gastric and colonic metastasis from NSCLC: A very unusual case report.

RATIONALE: Lung cancer is the most common cause of cancer-related deaths worldwide. Approximately 50% of patients is metastatic at diagnosis and the most common metastatic sites are bone, lungs, brain, adrenal glands, liver, and extra thoracic lymph nodes. The occurrence of gastrointestinal metastasis from lung carcinoma is rare and seems more commonly related to small cell lung cancer compared to non-small cell lung cancer (NSCLC). PATIENT INFORMATION AND DIAGNOSIS: A 78-year-old man with completely surgically resected NSCLC and no initial evidence of distant metastases developed colon and gastric metastases 7 months after diagnosis, confirmed by serial radiological examinations and endoscopic biopsies. INTERVENTIONS: The patient was subjected to total gastrectomy with D2 lymph node dissection plus partial colectomy for intraoperative detection of a transverse colon neoformation. Subsequent instrumental imaging showed bilateral lung tumor recurrence, treated with gemcitabine monotherapy for 8 months as first line chemotherapy for lung adenocarcinoma. RESULTS: The patient presented complete response to therapy and was disease-free for 4 years. LESSONS: Colonic and gastric metastasis are very infrequent in NSCLC. The resection of gastrointestinal metastasis may provide benefits in terms of both symptom control and survival in patients properly selected.

Immune-Checkpoint-Inhibitor-Related Lung Toxicity: A Multicentre Real-Life Retrospective Portrait from Six Italian Centres.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. METHODS: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. RESULTS: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). CONCLUSIONS: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management.

Beyond Conventional: The New Horizon of Targeted Therapy for the Treatment of Advanced Non Small Cell Lung Cancer.

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.

Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies.

The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.

Short and mid-term outcomes of multimodal treatment for locally-advanced non-small cell lung cancer in elderly patients.

OBJECTIVE: Multimodality treatments are effective for locally advanced non-small cell lung cancer (LA-NSCLC) showing benefits in overall (OS) and disease-free survival (DFS), but these options are frequently denied to elderly patients. METHODS: The objectives of this retrospective study were: to investigate mortality, morbidity and oncological outcomes of pulmonary resection after induction therapy (IT) for NSCLC in elderly patients. We divided the cohort into two: patients < 70 years (group A) and patients ≥70 years (group B). A multivariable logistic regression was built to identify factors associated with morbidity. RESULTS: 77 patients underwent pulmonary resection after IT, 27 were aged ≥70 years. Type of chemotherapy, surgical procedures, pathological stages were comparable between the two groups, while the preoperative use of chemo-radiation therapy regimen was more frequent in group A (p = 0.027). In-hospital mortality was similar, while the percentage of patients with complications (38% vs 48.1%, p = 0.47) and the complication rate (50% vs 77%, p = 0.01) were higher in group B, but the severity of complications was comparable. The multivariable analysis did not identify any risk factors associated with morbidity. OS at 3 years and DFS at 2 years were not different (61% vs 48.5%, p = 0.64; 61.7% vs 44%, p = 0.393). CONCLUSIONS: Lung resection for LA-NSCLC after IT can be performed safely in selected elderly patients with favourable postoperative and mid-term oncological results.

Management of locally advanced non-small cell lung cancer in the modern era: A national Italian survey on diagnosis, treatment and multidisciplinary approach.

Concurrent chemotherapy and radiotherapy (cCRT) is considered the standard treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Unfortunately, management is still heterogeneous across different specialists. A multidisciplinary approach is needed in this setting due to recent, promising results obtained by consolidative immunotherapy. The aim of this survey is to assess current LA-NSCLC management in Italy. From January to April 2018, a 15-question survey focusing on diagnostic/therapeutic LA-NSCLC management was sent to 1,478 e-mail addresses that belonged to pneumologists, thoracic surgeons, and radiation and medical oncologists. 421 answers were analyzed: 176 radiation oncologists, 86 medical oncologists, 92 pneumologists, 64 thoracic surgeons and 3 other specialists. More than a half of the respondents had been practicing for >10 years after completing residency training. Some discrepancies were observed in clinical LA-NSCLC management: the lack of a regularly planned multidisciplinary tumor board, the use of upfront surgery in multistation stage IIIA, and territorial diffusion of cCRT in unresectable LA-NSCLC. Our analysis demonstrated good compliance with international guidelines in the diagnostic workup of LA-NSCLC. We observed a relationship between high clinical experience and good clinical practice. A multidisciplinary approach is mandatory for managing LA-NSCLC.

Stereotactic Ablative Radiotherapy as an Alternative to Lobectomy in Patients With Medically Operable Stage I NSCLC: A Retrospective, Multicenter Analysis.

BACKGROUND: Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non-small-cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well-controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT. MATERIALS AND METHODS: One hundred eighty-seven patients with clinical-stage T1a-T2bNoMO NSCLC were treated in 2 academic hospitals between August 2008 and May 2015. Patients underwent LOB or SBRT; those undergoing SBRT were sub-classified as surgical candidates and nonsurgical candidates, according to the presence of surgical contraindications or comorbidities. RESULTS: In univariate analysis, no significant difference was found in local control between patients who underwent SBRT and LOB, with a trend in favor of surgery (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.07-1.01; P < .053). Univariate analysis showed that overall survival (OS) was significantly better in patients who underwent LOB (HR, 0.44; 95% CI, 0.23-0.85) with a 3-year OS of 73.4% versus 65.2% for surgery and radiation therapy patients, respectively (P < .01). However, no difference in OS was observed between operable patients undergoing SBRT and patients who underwent LOB (HR, 1.68; 95% CI, 0.72-3.90). Progression-free survival was comparable between patients who underwent LOB and SBRT (HR, 0.61; P = .09). CONCLUSION: SBRT is a valid therapeutic approach in early-stage NSCLC. Furthermore, SBRT seems to be very well-tolerated and might lead to the same optimal locoregional control provided by surgery for patients with either operable or inoperable early-stage NSCLC.

Lung Cancer in Patients with Severe Idiopathic Pulmonary Fibrosis: Critical Aspects.

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis is conditioned by comorbidities such as gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and lung cancer. At 5 years follow-up, 15% of IPF patients develop lung cancer, which can significantly reduce their survival. Because diagnostic or therapeutic procedures such as surgical, radiation or pharmacological treatments may induce acute exacerbations and increase mortality, the management of lung cancer in IPF patients is a very difficult task. This study discusses advantages and disadvantages of lung cancer treatments in patients with severe IPF, highlighting several controversial aspects on this topic, including potential nintedanib treatment.

Radiotherapy timing in the treatment of limited-stage small cell lung cancer: the impact of thoracic and brain irradiation on survival.

AIMS AND BACKGROUND: Small cell lung cancer is an aggressive histologic subtype of lung cancer in which the role of chemotherapy and radiotherapy has been well established in limited-stage disease. We retrospectively reviewed a series of limited-stage small cell lung cancers treated with chemotherapy and thoracic and brain radiotherapy. METHODS AND STUDY DESIGN: A total of 124 patients affected by limited-stage small cell lung cancer has been treated over 10 years in our Institute. Fifty-three patients (42.8%) had concomitant radio-chemotherapy treatment and 71 patients (57.2%) a sequential treatment. Eighty-eight patients (70.9%) underwent an association of a platinum-derived drug (cisplatinum or carboplatinum) and etoposide. Prophylactic cranial irradiation was planned in all patients with histologically proven complete response to primary radio-chemotherapy. RESULTS: With a mean follow-up of 2.2 years, complete response was obtained in 50.8% of cases. We found a significant difference between different radio-chemotherapy association approaches (P = 0.007): percentages of overall survival were respectively 10.0%, 12.9% and 5.6% in early, late concomitant and sequential radio-chemotherapy timing. Cranial prophylaxis did not seem to influence overall survival (P = 0.21) or disease-free survival for local relapse (P = 0.34). CONCLUSIONS: Concomitant radio-chemotherapy is the best approach according to our experience. Our results show a benefit of prophylactic cranial irradiation in distant metastasis-free survival.

Aspectos ambientais do processo de fabricação de placas de revestimentos cerâmicos (via úmida), com ênfase nos efluentes líquidos / Environmental aspects of the process of production of ceramic tiles (wet process), with emphasis in liquid effluents

No presente estudo buscou-se desenvolver uma metodologia simplificada para avaliar o impacto ambiental do processo de fabricação de placas de revestimentos cerâmicos – via úmida. Para dar subsídios ao desenvolvimento do modelo de avaliação ambiental e para obter um maior conhecimento do processo produtivo, foram elaboradas planilhas que correlacionavam as etapas do sistema produtivo com os tipos e volumes de resíduos nele gerados. Relacionaram-se a estas planilhas, as normas técnicas da Associação Brasileira de Normas Técnicas (ABNT), as quais determinam as metodologias de amostragem, caracterizações, monitoramento, tratamento dos resíduos sólidos e efluentes líquidos e gasosos; as Legislações Federal e Estadual pertinentes, as quais dispõem sobre o controle da poluição ambiental. A validação destes resultados foi obtida pela realização de ensaios analíticos nas matérias-primas utilizadas e nos resíduos gerados no processo produtivo. Os resultados das análises químicas reforçam que a toxicidade positiva nos efluentes líquidos está relacionada com a composição química dos insumos utilizados na decoração. Os resíduos sólidos que mais comprometem o meio ambiente são aqueles provenientes dos setores de preparação e aplicação de tintas e vidrados. Também realizou-se um estudo de caracterização das matérias-primas naturais e no produto, utilizando as técnicas de fluorescência de raio X, análise termodiferencial e termogravimétrica, microscopia eletrônica de varredura e difração de raio X, buscando compreender as interações dos componentes da massa do corpo cerâmico, durante a etapa de queima, e sua influência na qualidade do produto final. Essas informações são úteis, tanto do ponto de vista da caracterização cristaloquímica das matérias-primas que compõem o corpo cerâmico, identificando sua evolução quando submetidos a processos de queima, quanto do ponto de vista ambiental, servindo de base para estudos futuros que promovam o estabelecimento de especificações de controle de massa, e melhor aproveitamento dos recursos minerais, evitando eventuais desperdícios durante o processo. Com a consolidação de todos os dados foi possível indicar, em cada etapa do processo produtivo, as não conformidades existentes com relação às especificações legais, bem como sugestões para sua adequação ambiental.