Which Tyrosine Kinase Inhibitor Must We Apply Before? A Case Report of Crizotinib-resistant Patient with Concomitant EGFR and EML4-ALK Gene Mutations

ABSTRACT The concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocations in lung adenocancers are very rare scenarios. Until now, 42 cases described in the literature have all been treated by different drugs. There is no overall consensus regarding the treatment for this adenocarcinoma subgroup. We report here a case of lung adenocarcinoma with concomitant EGFR mutation in exon 21 (L858R) and ALK rearrangement in primary tumour, EGFR mutation in exon 21 (L858R) and no ALK rearrangement in its synchronous metastasis. We treated this patient with crizotinib as the second-line therapy (after the first line docetaxel-cisplatin chemotherapy), but no response was obtained. The therapeutic choice for the lung adenocancer patients with concomitant EGFR mutation and ALK rearrangement is unclear. Examination of c-ros oncogene 1 mutation can be used as an indicator in the prediction of the crizotinib treatment success. The ALK mutation may not responsible for the resistance to EGFR-tyrosine kinase inhibitors (TKI), and EGFR-TKI can be initiated to EGFR and ALK dual mutant patients as the first treatment.

The diagnostic value of cell blocks in Liquid-Based Cytology of bronchial aspiration and bronchial brushing materials.

INTRODUCTION: Fibreoptic bronchoscopy is used for the diagnosis and treatment of several pulmonary diseases. Conventional smear and Liquid-based cytology (LBC) methods are applied to cytology samples of various bronchoscopic techniques. If the cytology sample is sufficient for evaluation, a cell block (CB) can be prepared from the remaining material. The aim of this study is to identify the diagnostic value of conventional smear, LBC and CB methods in bronchial cytological specimens. METHODS: A retrospective review of 329 samples from 240 patients was made and, of these, 144 patients were found to have neoplasia. A blind review of the specimens was performed and all were reclassified individually. The endoscopic findings of the 144 patients with neoplasia were analysed retrospectively. The cytological diagnoses were then compared with the final diagnosis or the endoscopic findings of patients with neoplasia. The sensitivity was calculated for each method, both separately and together. RESULTS: It was determined that CB led to a 10.1% increase in the diagnostic sensitivity for bronchial aspiration (BA) specimens, while no significant increase was seen in bronchial brush specimens. In BA specimens of neoplasia patients with normal bronchoscopic findings, while three methods were applied together with an increase in the number of cases diagnosed as malignant cytology, there was no significant increase in bronchial brush specimens. CONCLUSION: This study demonstrated that adding cell block to CB and LBC seemed to contribute the cytological diagnosis in BA materials significantly. Another advantage of CB is the opportunity of applying advanced methods such as immunocytochemical and molecular techniques.

Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: an in vivo animal study.

The aim of this study was to investigate the effect of benzydamine hydrochloride bioadhesive gel on healing of oral mucosal ulceration in an animal model. For in vivo determination of the effects of the bioadhesive gel, 36 rabbits were separated into three groups: the first group was treated with the gel formulation without active agent, the second group with the gel formulation containing benzydamine, and the third group received no treatment. Clinical healing was established by measuring the area of the ulcer in each test group on days 3, 6, 9 and 12. Histological healing was determined on the same days. Benzydamine containing gel applications resulted in a decrease in the ulcer area in 12 days (p=0.000). Histological evaluation showed that the benzydamine group had a higher mean histological score than the base and the control groups during the whole test period, and the difference between the benzydamine group and the control group was significant (p=0.04). The bioadhesive gel formulation of benzydamine hydrochloride showed a statistically significant increased rate of mucosal repair in this experimental standard mucosal wound animal study. It is a candidate for the topical treatment of oral mucosal ulcerative lesions.

The utility of toluidine blue staining and brush cytology as adjuncts in clinical examination of suspicious oral mucosal lesions.

The objective of this study was to investigate the utility of toluidine blue and brush cytology in patients with clinically detected oral mucosal lesions. Clinical examination of 35 patients was completed before toluidine blue application, oral brush cytology and scalpel biopsy. Lesions were photographed before and after stain application; followed by brush cytology. All findings were compared with histopathologic results. Severe dysplasia and carcinoma-in-situ were determined as 'positive'; no dysplasia and mild to moderate dysplasia were defined as 'negative'. The sensitivity, specificity, positive and negative predictive values of clinical examination and toluidine blue were the same: 0.923, 0.433, 0.414, and 0.929, respectively. Those of brush cytology were 0.923, 0.517, 0.462, and 0.938. The concordance of all methods was 30% for benign and 61% for malignant lesions. Adjuncts identified 92% of carcinoma-in-situ and squamous cell carcinoma as confirmed by histopathology, in contrast to clinical findings alone in which 62% of these lesions were identified (p=0.046). In conclusion, adjunct diagnostic methods decreased the level of uncertainty for the diagnosis of oral malignancies and lichenoid dysplasias when applied as adjuncts to clinical examination.

Ligasure vessel sealing system versus harmonic scalpel for sutureless nonanatomical pulmonary resections in a rabbit model. Which one is safer?

BACKGROUND: The safety and efficacy of the ligasure vessel sealing system (LVSS) and harmonic scalpel (HS) in sutureless nonanatomical lung resections were evaluated. METHODS: On twenty adult rabbit lungs, 1 x 1 cm wedge resections were performed under one-lung ventilation with both LVSS and HS. The air tightness and tissue damage caused by these different techniques were measured and compared. RESULTS: No statistically significant differences were found when the air tightness for both devices was compared after resection (p = 0.37). Tissue damage was obtained for LVSS, and the difference was statistically significant (p < 0.001). discussion: LVSS and HS can both be used for peripheral lung resections without any need of further intervention for securing the air tightness. LVSS was found safer by means of tissue damage when compared with HS in this experimental study.

Comparison of the harmonic scalpel and the ultrasonic surgical aspirator in subsegmental lung resections: an experimental study.

BACKGROUND: In this study, we evaluated the effectiveness of two devices using ultrasonic energy for dissection of lung parenchyma in an experimental animal model by comparing the two methods with each other. METHODS: Twenty New Zealand rabbits were used. One-lung ventilation was obtained under direct vision and the left lung was collapsed. The rabbits were ventilated with pressure-controlled ventilation during the experiment, beginning with a pressure level of 10 cmH(2)O. After a 1 x 1-cm pulmonary wedge resection of part of the collapsed left lung using a harmonic scalpel (group A) or an ultrasonic surgical aspirator (group B), the left lung was inflated and the pressure level was increased by 5 cmH(2)O every five minutes. The pressure level which caused an air leak from the resection surface was recorded. The morphological damage to the lung parenchyma was evaluated under light microscopy. RESULTS: The mean value of airway pressure levels that resulted in an air leak from the resection surface was 32.5 +/- 9.2 cmH(2)O for group A and 24.5 +/- 2.9 cmH(2)O for group B, and the difference between the two groups was statistically significant. The mean level of coagulation necrosis was 558.6 +/- 380.8 microns (133 - 1064 microns) for group A. No tissue damage to pulmonary parenchyma was observed in group B. CONCLUSION: The harmonic scalpel can be safely used in peripheral lung resections without needing any other method to ensure hemostasis and air tightness. The ultrasonic surgical aspirator can be used for the dissection and resection of deeper lesions and preserves more lung tissue but requires additional interventions for control of the air leak from the resection surface.

Experimental use of N-butyl cyanoacrylate tissue adhesive on lung parenchyma after pulmonary resection.

BACKGROUND: The aim of this study was to investigate the effectiveness of N-butyl cyanoacrylate tissue adhesive for the prevention of air leak together with the morphological changes to lung parenchyma. METHODS: Twelve New Zealand rabbits were used. The rabbits were ventilated with pressure-controlled ventilation during the experiment, beginning with a pressure level of 10 cm H (2)O. After a 2 x 2-cm pulmonary wedge resection, the resection surface was sealed with N-butyl cyanoacrylate and the pressure level was increased every five minutes in 5-cm H (2)O increments. The pressure level which caused an air leak from the resection surface was recorded. The morphological damage to the lung parenchyma was evaluated under light microscopy. RESULTS: The mean value of the pressure levels that caused air leak was 43.3 +/- 8.8 cm H (2)O. No tissue damage to lung parenchyma was recorded after histopathological examination. CONCLUSION: N-butyl cyanoacrylate was effective in preventing air leak from the pulmonary resection surface even with high airway pressure levels. It could be used as an aid for pulmonary resection lines or to control the air leak from pulmonary parenchyma.

Therapy, outcome and analysis of c-kit expression in patients with extrapulmonary small cell carcinoma.

In this study, we aimed to investigate the clinicopathological characteristics with special emphasis on c-kit expression and the treatment results of patients with extrapulmonary small cell carcinoma (EPSCC). The medical records of the patients with EPSCC were reviewed, and the data regarding patient and tumour characteristics, treatment and clinical outcome were retrieved and analysed. A total of 28 patients with the diagnosis of EPSCC were identified. There were 19 males and 9 females, with a mean age of 56.5 years. Patients with limited disease (LD) (n = 13) were treated with surgery, chemotherapy (CT) and radiotherapy with different sequences. Patients with extensive disease (ED) (n = 15) were mainly treated with combination CT. The median overall survival was 14.5 months in patients with LD compared to 11 months in those with ED (p = 0.029). Ten patients (36%) showed c-kit overexpression. There was no significant difference between the survival of c-kit-positive and c-kit-negative patients (p = 0.367). In conclusion, our study demonstrates that the prognosis of EPSCC is poor despite currently available treatments. C-kit may be considered as a potential target for novel therapeutical approaches.

The histological effect of harmonic scalpel and electrocautery in lung resections. An experimental study in a rat model.

AIM: In the last decade, ultrasonically activated scalpels (the Harmonic Scalpel, HS) have been developed and used for both open and endoscopic surgical procedures. The present study compares the deepness of lung tissue damage caused by HS and unipolar electrocautery (EC) in rats. METHODS: Ten rats were used for the study. Morphological damage on lung parenchyma of the rats was measured with the ocular micrometer in light microscopy. RESULTS: The mean depth of the tissue damage was 0.23+/-0.08 mm in the HS group, and 0.33+/-0.10 mm in the EC group. The difference was statistically significant between the 2 groups (p=0.028). CONCLUSION: HS induces significantly less tissue damage than EC in rat lungs.

Eosinophilic bronchitis as a cause of chronic cough.

Eosinophilic bronchitis is a recently described condition in patients with chronic cough, sputum eosinophilia, normal spirometry and no evidence of bronchial hyperreactivity. The aim of the study was to assess the causes of chronic cough and to identify the prevalence of eosinophilic bronchitis as a cause of chronic cough. Thirty-six patients [mean age 45.4 +/- 14.3 years (range 16-69 years), M/F: 4/32] with an isolated chronic cough lasting for more than 4 weeks were recruited from the outpatient clinic. In all patients, after a full history and physical examination, blood eosinophil count, eosinophilic cationic protein (ECP), serum total and specific IgE levels were measured. Spirometry, methacholine provocation test, skin prick tests, ear, nose and throat examination, induction of sputum and esophageal pH testing were performed. The mean duration of cough was 31.3 +/- 52.3 months. Sputum eosinophilia greater than 3% was present in 12 (33.3%) patients and they were diagnosed as eosinophilic bronchitis. Their induced sputum had a mean eosinophil count of 8.3% and a mean ECP level of 98.5 mg x l(-1), which were higher than the others (P=0.003, both). The diagnosis of the remaining patients were postnasal drip syndrome in eight, gastroesophageal reflux disease in eight, post-infectious cough in two and cough-variant asthma in one patient. In conclusion, eosinophilic bronchitis is an important cause of chronic cough and should be considered in the assessment of patients before regarding them as having idiopathic chronic cough.