C-MET inhibitors in the treatment of lung cancer.

OPINION STATEMENT: Lung cancer is the most common malignant neoplasm and constitutes the most common neoplastic cause of death globally. The results of therapies employing standard chemotherapy are unsatisfactory. Currently, efforts are being made to personalize the therapy; numerous clinical studies are being conducted around the world to assess the efficacy and safety of agents directed at molecular targets. One of these molecular targets is the c-MET proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF). C-MET hyperactivity has been observed in numerous neoplasms, including non-small-cell lung carcinoma. Prolonged or continuous activity of the receptor leads to excessive cell proliferation and is related to the development or progression of neoplastic disease. C-MET inhibitors can be classified into three groups: small-molecule tyrosine kinase inhibitors of the c-MET receptor (crizotinib, tivantinib, cabozantinib, foretinib), as well as monoclonal antibodies against c-MET (onartuzumab) and against the HGF ligand (ficlatuzumab, rilotumumab). The efficacy and safety of these agents is assessed both in monotherapy and in combination with other molecularly targeted agents. Furthermore, the toxicity profile of c-MET inhibitors is completely different from that of standard chemotherapy. The best understood c-MET inhibitor used in the treatment of non-small-cell lung carcinoma patients is crizotinib. It is registered for patients with the presence of ALK gene rearrangements after the failure of the first line of treatment based on platinum derivatives. The purpose of this present paper is to present clinical studies that assessed the efficacy and safety of c-MET inhibitors for the treatment of non-small-cell lung carcinoma, as well as current indications for the use of these molecules.

Natriuretic peptides in the evaluation of syncope in children and adolescents.

INTRODUCTION: Natriuretic peptides have an increasing role in assessing cardiovascular conditions. The number of papers addressing their role in the evaluation of children with syncope of unclear etiology is sparse. The aim of this study was to determine whether measuring atrial natriuretic peptide (ANP) and the inactive form, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration in children admitted due to differential diagnosis of syncope can be helpful in establishing the most probable cause of this condition. METHODS: The study included 88 patients between 9 and 18 years of age hospitalized due to syncope. The control group comprised 25 healthy children. In order to identify the cause of syncope, children with this condition were subjected to cardiologic and neurologic evaluation, and ANP and NT-proBNP concentrations were determined. RESULTS: The syncope group and the controls did not differ significantly in terms of natriuretic peptides concentrations. Similarly, no significant intergroup differences in natriuretic peptide concentrations were documented between children representing various types of response to the tilt test, and between the subgroups of patients with syncope of various origins. CONCLUSION: Analysis of natriuretic peptides concentrations in children with syncope does not result in unambiguous findings that would enable establishing accurate diagnosis.

Plasma levels of IL-17, VEGF, and adrenomedullin and S-cone dysfunction of the retina in children and adolescents without signs of retinopathy and with varied duration of diabetes.

The study objective was to assess chosen biochemical parameters of blood and bioelectric function of the retina in patients with T1DM. The study group consisted of 41 patients with T1DM with no signs of diabetic retinopathy. The control group included 21 pediatric patients. We performed (1) S-cone ERG testing with retina response stimulation in both eyes at the luminance of 0.1, 0.2, and 0.5 (cd × s/m(2)) with the 440 nm blue flash and light application of the amber background (300 ph cd/m(2), 495 nm wavelength), (2) anthropometric measurements, (3) biochemical investigations: IL-17, VEGF, and ADM by the ELISA method. A comparison of the ERG results with biochemical investigations indicates a likely correlation between the worsening of retinal bioelectric function and VEGF levels growing with diabetes duration. We showed a negative correlation between ADM and HbA1c and described possible causes of ADM reduction observed in subgroup I. We demonstrated the presence of bioelectric retinal dysfunction already before the diagnosis of diabetic retinopathy, which provides new possibilities in the diagnosis of preclinical chronic complications of diabetes. The changes observed in the levels of IL-17, ADM, and VEGF suggest their involvement in the diabetic pathogenesis of eye diseases.

Head and neck squamous carcinomas with exophytic and endophytic type of growth have the same prognosis after surgery and adjuvant radiotherapy.

Head and neck squamous cell carcinomas (HNSCC) are characterized by exophytic or endophytic growth. We hypothesized that the growth pattern predicts outcome and associates with distinct clinical and immunological profiles. Tumors obtained from 60 HNSCC patients treated with surgery and adjuvant radiotherapy were identified as exophytic or endophytic. Recurrence-free survival (RFS) at 42 months was determined. In a subsets of 30 patients (22 exophytic and 8 endophytic) tumor stroma and parenchyma were evaluated for infiltrating CD4(+) and CD8(+) T, dendritic, myeloid and FOXP3(+) regulatory T cells (Treg) and expression of immunosuppressive cytokines by immunohistochemistry. The localization and frequency of positive cells were determined microscopically and analyzed by hierarchical clustering to distinguish exophytic versus endophytic tumors. 34/60 patients had exophytic and 26/60 endophytic tumors. No differences in clinicopathologic data, disease progression or RFS were seen between the two cohorts. Infiltrates of CD3(+)CD8(+) T cells were larger in endophytic than exophytic tumors, while FOXP3(+) Treg, TGF-ß(+), IL-10(+), Arg-1(+), CD11b(+) cells were equally prominent in both. FOXP3(+) Treg accumulated in endophytic tumor nests, while the exophytic tumor stroma was enriched in IL-10(+) cells (both at p < 0.05). Hierarchical clustering based on immunophenotyping failed to identify different clusters in these two tumor types. However, CD68(+) macrophages and FOXP3(+) Treg showed a distinct distribution. The HNSCC growth pattern did not predict RFS. Although higher numbers and differences in localization of immunosuppressive cells in endophytic versus exophytic tumors were observed, no significant relationship was established between the growth pattern and the immune profile of infiltrating lymphocytes.

Possible role of α-mannosidase and ß-galactosidase in larynx cancer.

BACKGROUND: Lysosomal exoglycosidases, such as α-mannosidases (MAN) and ß-galactosidases (GAL), are found in different glycoside hydrolase sequence-based families. Considerable research has proved plays the role of MAN, which play a key role in the modification and diversification of hybrid N-glycans, processes with strong cellular links to cancer. Therefore the study aim was to investigate the activities of MAN and GAL in larynx cancer compared to controls. MATERIAL AND METHODS: Larynx cancer (n = 21) and normal healthy tissue (n = 21) were collected from patients during total laryngectomy. A biopsy of macroscopically healthy tissue in the area of the lower 1/3 of omohyoid muscle was taken for frozen sections in each case and these served as controls. The release of p-nitrophenol from p-nitrophenol derivatives of MAN and GAL was used. RESULTS: In all specimens we observed significantly higher activity of investigated enzymes in larynx cancer compared with controls. The mean release of MAN from activated cells was 3.702 ±1.3245 nkat/g wet tissue compared to controls (1.614 ±0.8220 nkat/g wet tissue). The mean release of GAL from the activated cells was 3.383 ±2.1980 nkat/g wet tissue compared to controls (2.137 ±1.3685 nkat/g wet tissue). Differences in observed activity were statistically significant. CONCLUSION: The present data indicate that MAN and GAL are significantly and consistently elevated in larynx cancer growth. It also means that catabolic reactions involving glycoproteins, glycolipids and proteoglycans may play a role in larynx cancer. Further research should also evaluate the relative importance of these particular exoglycosidases in indicating the progress of the disease in considering the spectrum of identified marker mediators.

[Propranolol for treatment of subglottic hemangioma]. / Zastosowanie propranololu w leczeniu naczyniaka podglosniowego.

Subglottic hemangiomas are extremely dangerous due to its location and rapid growth during the proliferative phase. Many different treatments are described but these methods are still not satisfactory. Recently propranolol has been used as a new option in hemangioma therapy. We describe a case of 6-week infant with subglottic hemangioma discovered direct laryngoscopy, presented with dyspnoea and inspiratory stridor. After oral propranolol administration all baseline airway symptoms had resolved and endoscopic examination demonstrated significant regression of the hemangioma. We suggest that the propranolol should be used as a first-line treatment in subglottic hemangiomas in children.

[Paranasal sinuses melanoma--a case report]. / Czerniak zlosliwy zatok przynosowych--opis przypadku.

The malignant melanoma has been presented in majority in the skin location. The mucosal form of melanoma is extremely rare, the localisation involving the structures of paranasal sinuses is the most frequent location according to head and neck region. The authors present the patients case with that location of illness.

Case report: a 10-year-old girl with primary hypoparathyroidism and systemic lupus erythematosus.

Objectives Hypoparathyroidism is a rare disease in children that occurs as a result of autoimmune destruction of the parathyroid glands, a defect in parathyroid gland development or secondary to physical parathyroid gland disturbance. Typical symptoms of hypoparathyroidism present as hypocalcaemia and hyperphosphatemia due to decreased parathyroid hormone secretion and may lead to nerve and muscles disturbances resulting in clinical manifestation of tetany, arrhythmias and epilepsy. Currently, there is no conventional hormone replacement treatment for hypoparathyroidism and therapeutic approaches include normalising mineral levels using an oral calcium supplement and active forms of vitamin D. Case presentation We present the case of a 10-year-old girl with primary hypoparathyroidism who had no prior history of autoimmune disorders, but who subsequently developed systemic lupus erythematosus.

[Early glottic cancer--treatment results]. / Wyniki leczenia wczesnych raków glosni.

INTRODUCTION: Early glottic cancer (stage T1, T2) is connected with very good prognosis as well as organ and function preservation. The aim of the study was the assessment of early glottic treatment results. MATERIAL AND METHODS: Between 1999-2005 1007 patients with larynx cancer were treated in Dept. of Otolaryngology Head Neck Oncological Surgery Poznan University of Medical Sciences. The majority constitute the patients with II and III stage of clinical advancement of the disease. Early glottic cancer was diagnosed in 43 patients (4.3%). The diagnose of the larynx cancer was set upon indirect and direct laryngoscopy, histological examination of larynx samples and neck ultrasonography. In all 43 patients CO2 laser surgery in Klein1 sasser microlaryngoscopy set was performed. RESULTS: In all cases, confirmed in histological examination the resection was radical. Follow-up was conducted every month in the first year of observation, then every 2-3 months. The time of follow-up ranged from 40 to 64 month, mean 51 month. In 4 patients (9.3%) treated for early glottic cancer with CO2 laser surgery the local relapse occurred after 10, 15, 19 and 28 month respectively. In two patients total laryngectomy, in one reconstructive partial laryngectomy and in one radiotherapy was performed. The mean time of observation after salvage treatment is 29 months. All patients are alive and free of disease. CONCLUSION: The laser surgery is an effective and non-invasive treatment of early glottic cancer but the strict follow-up regimen is demanded.

[Scared atrophy of the cervical part of trachea as an effect of prolongated intubation]. / Bliznowaty zanik odcinka szyjnego tchawicy w nastepstwie przedluzonej intubacji.

Tracheal intubation is presently one of the basic medical procedures. It is connected with many different complications. One of them is tracheal stenosis, which occurs in 6-21 percent of patients after intubation of the trachea. In contrast to this high frequency of tracheal stenosis we didn't find any publications about complete atrophy of a big part of trachea after prolongated intubation and we describe a first case of such complication. The reasons and the possibilities of treatment in such situation are discussed.

Central aortic pressure, arterial stiffness and echocardiographic parameters of children with overweight/obesity and arterial hypertension.

BACKGROUND: A non-invasive estimation of central aortic pressure and echocardiographic parameters, and appropriate interpretation thereof make it possible to determine the status of the vascular wall and myocardium. These parameters are early markers of unfavorable remodeling of the cardiovascular system. OBJECTIVES: The aim of this study was to analyze the central aortic pressure and echocardiographic parameters of overweight/obese children (with or without concomitant arterial hypertension). MATERIAL AND METHODS: The study included 84 children (mean age: 15 years) - 45 with primary arterial hypertension, 39 normotensive, and 38 controls. Central aortic systolic (cSys) and diastolic (cDia) pressures, pulse wave augmentation index (Aix@75), peripheral resistance, pulse wave reflection and pulse wave velocity (PWV) were determined by means of brachial oscillometry. A number of echocardiographic parameters were recorded. RESULTS: Obese children with arterial hypertension showed the highest values of cSys, cDia and PWV, as well as interventricular septal end-diastolic thickness (IVS), left atrial diameter (LAD), left ventricular mass index (LVMI), elongation index and cardiac output (CO). Patient age, cSYS, cDIA and LAD were identified as significant predictors of PWV. The groups did not differ in terms of Aix@75, peripheral resistance and pulse wave reflection values. CONCLUSIONS: Children with overweight/obesity present with elevated values of cSys, PWV, LVMI, LAD and CO. The risk of these abnormalities is further increased due to concomitant arterial hypertension.

[The sentinel node in cancer of the oral cavity, pharynx and larynx]. / Wezel wartowniczy w nowotworach jamy ustnej, gardla i krtani.

AIM OF THE STUDY: The evaluation of the importance of the prognostic of sentinel node biopsy in head and neck cancer with N0 neck. MATERIAL AND METHODS: Prospective study included 19 patients with squamous cell carcinoma of the oral cavity, pharynx and larynx without enlarged lymph nodes in ultrasound examination (N0). The study was carried out in ENT Department of Medical University in Poznan between 2001-2004. Each patient underwent lymphoscintigraphy after administration of radionuclide Technetium 99m (Nanocol). In case of detection of sentinel node, blue dye was injected into the tumour bed and dyed lymph nodes were removed. The specimens were evaluated histologically and immunohistochemically. The patients are still followed up. RESULTS: So far 19 patients were included in our study. The tumours were classified from T1 to T4. In each case sentinel nodes were located. Metastases in removed lymphnodes were found in 5 patients. In one of them regional recidive was observed after 5 month. In the other patients no changes were found in follow up examination. In 14 cases in histological examination no metastases were found in sentinel nodes. In this group in one case local recurrence was observed and in another two lymph nodes metastases were confirmed. In patients with positive sentinel node elective neck dissection was performed. So far immunohistochemical examination has not provided us with any vital information. In no case with negative sentinel node we found micrometastases with the use of cytokeratin. CONCLUSIONS: Based on our preliminary observation of the patients we have found that there is certain correlation confirming the fact that sentinel node may be reliable for the whole neck lymphatic system. Further clinical observation are needed based on a larger number of patients and longer observation period.

[Importance and usefulness of laryngological screening of the preschool children population in conductive hypoacusis diagnostics]. / Znaczenie i przydatnosc przesiewowych badan laryngologicznych populacji dziecihcej w wieku wczesnoszkolnym w wykrywaniu niedosluchu przewodzeniowego.

INTRODUCTION: Incidence of upper respiratory tract ailments among children between 2 and 9 years old is very common. Discreet symptoms, like low grade conductive hypoaccusis or articulation's disorders are ignore or imperceptible by parents. The survive of these disorders in the child's development stage has a direct influence on cognitive functions, speech and social development and progress in learning. The aim of the work was to prove the efficiency of laryngological screening among asymptomatic population of preschool children on the basis of comparison of two difference populations: for the first time examined (Szczecinek) and at regular intervals of one year (Wolsztyn). MATERIAL AND METHODS: In the town Szczecinek and in the town Wolsztyn laryngological screening among 1172 (762 and 410 respectively) children was carried out. All the participating individuals were fully laryngological examined and tested with tympanometric audiometry. RESULTS: On the base of these examinations in the town Wolsztyn the following was to state: 46 (11.2%) children were refered to surgical treatment. In this group in 31 (67.4%) pathological tympanometric curve b- and c- type were affirmed. 42 (10.2%) children were refered to conservative treatment. In the town Szczecinek 142 (18.6%) children were refered to surgical treatment. In this group in 81 (57%) pathological tympanometric curve b- and c- type were affirmed. 110 (14.4%) children were refered to conservative treatment. CONCLUSIONS: (1) Usefulness of laryngological screening was confirm of the proportion of laryngological findings in the population of healthy seeming children refered to treatment. (2) The screening role is higher at rural area by low acsses to ENT consultants. Every year repeated screening influence population health, conscious approaching the ENT healthcare.

[Use of the lymphoscintigraphy in detection of sentinel lymph nodes of the neck]. / Zastosowanie limfoscyntygrafii w wykrywaniu wartowniczych wezlów chlonnych w obrebie szyi.

Technique of the application of radioactive tracer to the primary tumor and lymphoscintigraphy with use of the stationary and handheld gamma probe was presented. Various types of the used radioactive tracers were characterized. Scintigraphical criteria for sentinel nodes recognition were discussed. Advantages and limitations of the use of lymphoscintigraphy for sentinel nodes detection were described. Necessity of further study to determine feasibility of sentinel nodes radiolocalization in stage N0 in head and neck cancer was pointed out.

[Laser surgery in the treatment of bilateral vocal cord paralysis]. / Zastosowanie lasera CO2 w chirurgicznym leczeniu porazenia obustronnego faldów glosowych.

The introduction of surgical lasers into microsurgery of the larynx has made the resection of the posterior vocal cord with or without the arytenoid cartilage possible. This method of surgical treatment allows one to carry out a fast, non-open larynx procedure and practically bloodless operation with minimal postoperative trauma and edema of the surrounding tissues. Since November 1990 at the Clinic of Otolaryngology of the University School of Medical Sciences 48 arytenoidectomies (40 on the right side, 8 on the left side), 19 partial chordectomies and 25 Kashima operations. All surgical treatment were performed by means of CO2 laser in patients with bilateral paralysis of the vocal cords. In all patients postoperative recovery was correct and breathing difficulties were not observed after extubation. Laryngoscopic control examinations were performed a day after operation and a wide lumen of air through the operative field was observed. At the control examination, narrowing of the lumen of the larynx was not observed, the healing process of the operation area was without granulation. Laser arytenoidectomy allows good results of the breathing and phonation function. No changes of granulation proliferation were observed at the side of the CO2 laser treatment. Lack of reaction to laser beam there was possibility to use endoscopic procedures in patients who did not undergo a tracheotomy.

Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection.

INTRODUCTION: Hydrogen breath test (BT) is commonly used as a diagnostic tool for the detection of small intestine bacterial overgrowth (SIBO). It was reported that colonic methane production is far more frequent in cystic fibrosis (CF) patients than in other subjects. Therefore, measuring exclusively hydrogen in the diagnostic breath test for diagnosing SIBO might be of limited value. We aimed to assess the usefulness of combined measurement of hydrogen and methane expiration for the diagnosis of SIBO in CF. MATERIAL AND METHODS: The study comprised 62 CF patients aged 5 to 18 years. Three-hundred-ninety subjects assessed due to gastrointestinal symptoms for the presence of SIBO served as a comparative group. In all subjects hydrogen/methane BT using glucose was performed. A positive BT was defined as fasting hydrogen > or = 20 ppm or fasting methane > or = 10 ppm or a rise of > or = 12 ppm hydrogen or > or = 6 ppm methane over baseline during the test. RESULTS: In 23 (37.1%) CF patients and in 52 (13.3%) subjects from the comparative group abnormal BT results were found. In seven (11.3%) CF patients and 29 (7.4%) of the other subjects studied methane measurement allowed diagnosis of SIBO. CONCLUSIONS: Small intestine bacterial overgrowth is frequent in cystic fibrosis. For its detection in cystic fibrosis and other gastrointestinal patients, combined hydrogen and methane measurement instead of hydrogen breath test should be applied. Without the additional measurement of methane a significant percentage of SIBO will be missed.