Target therapy of lung cancer

Rak pluća vodeći je uzrok smrti među karcinomima, kako u Hrvatskoj tako i u svijetu. Najčešća je zloćudna novotvorina u muškaraca, a treća po učestalosti u žena u Republici Hrvatskoj. Razvoj terapije raka pluća tekao je sporo do posljednjih desetak godina. Napretkom molekularno genetičkih istraživanja došlo je do otkrića pogonskih mutacija i lijekova koji ciljano inhibiraju iste. Ove spoznaje primjenjuju se diljem svijeta u terapiji adenokarcinoma pluća kod kojeg se svi bolesnici rutinski testiraju na EGFR i ALK mutacije te liječe inhibitorima tirozin kinaza EGFR i ALK poput erlotiniba, gefitiniba i crizotiniba. Inhibitori tirozin kinaze EGFR i ALK značajno su poboljšali kvalitetu života i duljinu preživljenja bolesnika oboljelih od adenokarcinoma pluća, međutim pojavio se problem razvoja rezistencije na te lijekove te potreba za novim ciljanim lijekovima za bolesnike sa razvijenom rezistencijom. Kod ostalih histoloških tipova još nisu otkrivene pogonske mutacije koje bi bile pogodne za razvoj učinkovitih ciljanih lijekova. Postoje pretkliničke i kliničke studije koje ukazuju na moguće molekularne ciljeve kod sitnostaničnog i karcinoma pluća pločastih stanica. Kroz ovaj pregledni rad prikazat će se trenutačno stanje primjene ciljane terapije u liječenju bolesnika oboljelih od karcinoma pluća, razvoj ciljanih lijekova za liječenje karcinoma pluća, studije kojima je dokazana njihova učinkovitost te mogući ciljevi za ciljanu terapiju budućnosti.Lung cancer is the leading cause of cancer related death in the world. It is the most common malignant disease in the Republic of Croatia among men and third most common among women. Lung cancer therapy evolved slowly until the last decade, when advances in molecular science and genetics led to the discovery of driver mutations and the development of target drugs to inhibit those mutations. Target therapy of lung adenocarcinoma became the standard of care for patients harbouring EGFR and ALK mutations. Lung adenocarcinoma patients are routinely screened for EGFR and ALK mutations and treated with tyrosine kinase inhibitors like erlotinib, gefitinib and crizotinib which increased the survival and provided better quality of life for those patients. Unfortunately, resistance to these drugs is becoming a bigger issue and the development of new target drugs to overcome it is a priority. Driver mutations in small cell lung cancer and squamous cell lung cancer are being studied intensively, but no effective target drugs have been developed yet. However, several promising potentialy druggable mutations have been discovered in preclinical and clinical studies. In this review, we will address the current status of clinically relevant driver mutations, drugs that are currently being used in lung cancer target therapy and their development through recent years, studies that have proven their effectiveness and potential driver mutations that could be the target for future drug development

Target therapy of lung cancer

Rak pluća vodeći je uzrok smrti među karcinomima, kako u Hrvatskoj tako i u svijetu. Najčešća je zloćudna novotvorina u muškaraca, a treća po učestalosti u žena u Republici Hrvatskoj. Razvoj terapije raka pluća tekao je sporo do posljednjih desetak godina. Napretkom molekularno genetičkih istraživanja došlo je do otkrića pogonskih mutacija i lijekova koji ciljano inhibiraju iste. Ove spoznaje primjenjuju se diljem svijeta u terapiji adenokarcinoma pluća kod kojeg se svi bolesnici rutinski testiraju na EGFR i ALK mutacije te liječe inhibitorima tirozin kinaza EGFR i ALK poput erlotiniba, gefitiniba i crizotiniba. Inhibitori tirozin kinaze EGFR i ALK značajno su poboljšali kvalitetu života i duljinu preživljenja bolesnika oboljelih od adenokarcinoma pluća, međutim pojavio se problem razvoja rezistencije na te lijekove te potreba za novim ciljanim lijekovima za bolesnike sa razvijenom rezistencijom. Kod ostalih histoloških tipova još nisu otkrivene pogonske mutacije koje bi bile pogodne za razvoj učinkovitih ciljanih lijekova. Postoje pretkliničke i kliničke studije koje ukazuju na moguće molekularne ciljeve kod sitnostaničnog i karcinoma pluća pločastih stanica. Kroz ovaj pregledni rad prikazat će se trenutačno stanje primjene ciljane terapije u liječenju bolesnika oboljelih od karcinoma pluća, razvoj ciljanih lijekova za liječenje karcinoma pluća, studije kojima je dokazana njihova učinkovitost te mogući ciljevi za ciljanu terapiju budućnosti.Lung cancer is the leading cause of cancer related death in the world. It is the most common malignant disease in the Republic of Croatia among men and third most common among women. Lung cancer therapy evolved slowly until the last decade, when advances in molecular science and genetics led to the discovery of driver mutations and the development of target drugs to inhibit those mutations. Target therapy of lung adenocarcinoma became the standard of care for patients harbouring EGFR and ALK mutations. Lung adenocarcinoma patients are routinely screened for EGFR and ALK mutations and treated with tyrosine kinase inhibitors like erlotinib, gefitinib and crizotinib which increased the survival and provided better quality of life for those patients. Unfortunately, resistance to these drugs is becoming a bigger issue and the development of new target drugs to overcome it is a priority. Driver mutations in small cell lung cancer and squamous cell lung cancer are being studied intensively, but no effective target drugs have been developed yet. However, several promising potentialy druggable mutations have been discovered in preclinical and clinical studies. In this review, we will address the current status of clinically relevant driver mutations, drugs that are currently being used in lung cancer target therapy and their development through recent years, studies that have proven their effectiveness and potential driver mutations that could be the target for future drug development

The Survival Rate of Lung Transplant Patients in Croatia

INTRODUCTION AND OBJECTIVE Nowadays, lung transplantation is accepted modality of treatment for well-selected patients suffering from terminal, non-malignant respiratory disease. The aim of this study was to determine post-transplant survival rate and to give general overview of lung transplant patients in Croatia. Patients studied in this research were transplanted through the lung transplantation programme at Clinical Centre for Pulmonary Diseases Jordanovac, University Hospital Centre Zagreb. METHODS The research is retrospective analysis of prospectively collected data on 71 patients from year 2001 until February 2019. Descriptive statistics were calculated and survival outcomes were analysed by the Kaplan-Meier method. RESULTS Since the first transplantation in February 2001 to February 2019 all transplantations through lung transplantation programme in Croatia were performed in AKH Vienna. Total number of transplanted patients, was 71 (33 male (46,48%) and 38 female (53,52%)) with median of age 52. Survival rate after the 1 st post-transplant year was 79,1% after 3 rd year 69,8% and after 5 th year 63,0% with mean survival rate of 78,96 months. The time on the waiting list increased from median of 61,5 days (in years 2010-2015) to 138,5 days (in years 2015-2018). Clinically significant graft rejection experienced 39,4% of patients after median time of 61,56 months. CONCLUSION Survival rate of lung transplanted patient in Croatia is comparable to other European countries. Analysing such a type of data is crucial in addressing possible improvement measures and broadening general knowledge in the field. In the aim to improve patient outcomes excellent teamwork among all involved specialists and strict patient follow-up are of utmost importance

WEIGHT GAIN IN LUNG TRANSPLANTATION PATIENTS DURING THE COVID-19 PANDEMIC IN CROATIA

Background: To determine the effect of lockdown measures on lung transplant patients during the COVID-19 pandemic. Subjects and methods: We collected data from Croatian lung transplant patients before and after the lockdown and analyzed changes in weight, BMI, lung function and blood lipid status. Results: An average increase of 3.74 kg (+4.92%) body weight during the 4 month lockdown period was observed. Lung function values and blood lipid status remained stable. Conclusion: Such weight gain could have detrimental effects on the morbidity and mortality of lung transplant patients. Further follow up is needed to determine the long term impacts of this observation

WEIGHT GAIN IN LUNG TRANSPLANTATION PATIENTS DURING THE COVID-19 PANDEMIC IN CROATIA

Background: To determine the effect of lockdown measures on lung transplant patients during the COVID-19 pandemic. Subjects and methods: We collected data from Croatian lung transplant patients before and after the lockdown and analyzed changes in weight, BMI, lung function and blood lipid status. Results: An average increase of 3.74 kg (+4.92%) body weight during the 4 month lockdown period was observed. Lung function values and blood lipid status remained stable. Conclusion: Such weight gain could have detrimental effects on the morbidity and mortality of lung transplant patients. Further follow up is needed to determine the long term impacts of this observation

Klinička obilježja i preživljenje bolesnika s malignim mezoteliomom pleure – iskustvo jednog centra

Maligni pleuralni mezoteliom rijetka je i agresivna primarna novotvorina mezotelnih stanica pleure. Glavni rizični čimbenik je izloženost azbestu, najčešće uz latenciju od 30–50 godina. Unatoč terapiji medijan preživljenja je od 4 do 18 mjeseci, ovisno o izvoru. Cilj istraživanja bio je odrediti karakteristike bolesnika oboljelih od malignoga pleuralnog mezotelioma te ishode njihova liječenja na KBC Zagreb u razdoblju od 1999. do 2012. godine. Ispitane su karakteristike 101 bolesnika dijagnosticiranog i liječenog na KBC Zagreb u razdoblju od rujna 1999. do rujna 2012. Analizirali smo ukupno preživljenje (OS), preživljenje bez progresije bolesti (PFS) te preživljenje ovisno o histološkom podtipu tumora, dobi, kliničkom stadiju, pleurodezi talkom i modalitetu liječenja. Koristili smo Kaplan-Meierovu metodu za izradu krivulje preživljenja. 89 bolesnika bilo je muškog, 12 ženskog spola, a medijan dobi 62 godine. Prema TNM klasifikaciji stadij IV je utvrđen kod 69,3%, stadij III kod 26,73%, te stadij II kod samo 3,96% bolesnika. 73,26% bolesnika imalo je epiteloidni, 4,95% sarkomatoidni, 1% mješoviti te 20,79% NOS (nespecifirani) histološki podtip bolesti. Kirurški je liječeno 14,85% bolesnika, kemoterapijom 55,44%, dok je radioterapija primijenjena kod 9,9% bolesnika. Medijan OS iznosi 11 mjeseci, dok je PFS 10 mjeseci. Prema histološkom podtipu medijan OS iznosio je 11 mjeseci za epiteloidni, 12,5 za NOS te 5,5 za sarkomatoidni, a prema kliničkom stadiju 7 mjeseci za stadij II, 17,5 mjeseci za stadij III te 11 mjeseci za stadij IV. Medijan OS bio je dulji u skupini bolesnika mlađoj od 65 godina (12 naspram 8,5 mjeseci, p=0.28), skupini sa učinjenom pleurodezom (13 naspram 7,5 mjeseci, p=0.06) te u skupini liječenoj kemoterapijom (12,5 naspram 7,5 mjeseci, p=0.10). Očekivano preživljenje bolesnika oboljelih od malignoga pleuralnog mezotelioma u Republici Hrvatskoj u skladu je s podatcima iz literature. Ispitane metode liječenja relativno skromno utječu na preživljenje bolesnika

Target therapy of lung cancer

Rak pluća vodeći je uzrok smrti među karcinomima, kako u Hrvatskoj tako i u svijetu. Najčešća je zloćudna novotvorina u muškaraca, a treća po učestalosti u žena u Republici Hrvatskoj. Razvoj terapije raka pluća tekao je sporo do posljednjih desetak godina. Napretkom molekularno genetičkih istraživanja došlo je do otkrića pogonskih mutacija i lijekova koji ciljano inhibiraju iste. Ove spoznaje primjenjuju se diljem svijeta u terapiji adenokarcinoma pluća kod kojeg se svi bolesnici rutinski testiraju na EGFR i ALK mutacije te liječe inhibitorima tirozin kinaza EGFR i ALK poput erlotiniba, gefitiniba i crizotiniba. Inhibitori tirozin kinaze EGFR i ALK značajno su poboljšali kvalitetu života i duljinu preživljenja bolesnika oboljelih od adenokarcinoma pluća, međutim pojavio se problem razvoja rezistencije na te lijekove te potreba za novim ciljanim lijekovima za bolesnike sa razvijenom rezistencijom. Kod ostalih histoloških tipova još nisu otkrivene pogonske mutacije koje bi bile pogodne za razvoj učinkovitih ciljanih lijekova. Postoje pretkliničke i kliničke studije koje ukazuju na moguće molekularne ciljeve kod sitnostaničnog i karcinoma pluća pločastih stanica. Kroz ovaj pregledni rad prikazat će se trenutačno stanje primjene ciljane terapije u liječenju bolesnika oboljelih od karcinoma pluća, razvoj ciljanih lijekova za liječenje karcinoma pluća, studije kojima je dokazana njihova učinkovitost te mogući ciljevi za ciljanu terapiju budućnosti.Lung cancer is the leading cause of cancer related death in the world. It is the most common malignant disease in the Republic of Croatia among men and third most common among women. Lung cancer therapy evolved slowly until the last decade, when advances in molecular science and genetics led to the discovery of driver mutations and the development of target drugs to inhibit those mutations. Target therapy of lung adenocarcinoma became the standard of care for patients harbouring EGFR and ALK mutations. Lung adenocarcinoma patients are routinely screened for EGFR and ALK mutations and treated with tyrosine kinase inhibitors like erlotinib, gefitinib and crizotinib which increased the survival and provided better quality of life for those patients. Unfortunately, resistance to these drugs is becoming a bigger issue and the development of new target drugs to overcome it is a priority. Driver mutations in small cell lung cancer and squamous cell lung cancer are being studied intensively, but no effective target drugs have been developed yet. However, several promising potentialy druggable mutations have been discovered in preclinical and clinical studies. In this review, we will address the current status of clinically relevant driver mutations, drugs that are currently being used in lung cancer target therapy and their development through recent years, studies that have proven their effectiveness and potential driver mutations that could be the target for future drug development

Tracheal complications of mechanical ventilation for COVID-19: a plot twist for survivors

Tracheal complications should be suspected in mechanically ventilated COVID-19 survivors with respiratory symptoms. Treatment requires a multimodal approach of interventional bronchoscopy and surgery with tight follow-up due to a high rate of restenosis