Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite i... more Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite its prevalence, especially among patients with chronic obstructive pulmonary disease, AATD is still underdiagnosed. The aim of this study is to identify individuals with lung disease and severe AATD in central-eastern Europe. Subjects with respiratory symptoms that could be indicative of AATD provided blood samples as dried blood spot. The alpha1 -antitrypsin (AAT) concentration was determined by nephelometry and, if lower than 1.70 mg/dL in dried blood spot (equivalent to 1.04 g/L in serum), polymerase chain reaction was used to detect the PiS and PiZ alleles. Isoelectric focusing was used for confirmation of doubtful genotype results. From 13 countries, 11 648 subjects were included. Genotyping of 1404 samples with AAT levels <1.70 mg/dL revealed 71 (5.06%) PiS, 151 (10.8%) PiZ, 1 (0.071%) PiSS, 8 (0.57%) PiSZ and 32 (2.28%) PiZZ. Phenotyping of 1363 samples negative for the S and Z alleles or with PiS and PiZ genotype showed two (0.147%) PiZ(rare) and two (0.147%) Pi(null)(null). The countries with the highest rate of severe AATD were Croatia, Russia and Slovakia. By regions, the Baltic countries area showed the highest rate of both PiZ and severe AATD (2.45% and 1.20%, respectively) while the lowest rates were observed in the Balkan Peninsula (0.48% and 0.31%, respectively). This study confirms the need for targeted testing of symptomatic patients and provides AATD genotype data from countries for which only some estimates of prevalence were available until now.
Purpose Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung can... more Purpose Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV topotecan in patients with SCLC sensitive to initial chemotherapy. Patients and Methods Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status ≤ 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of ≥ 90 days were assigned to treatment with either oral topotecan 2.3 mg/m2/d on days 1 through 5 or IV topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. Results A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral topotecan (n = 153) and 21.9% with IV topotecan (n = 151), with ...
Purpose This open-label, randomized, multicenter phase III study compared oral topotecan/intraven... more Purpose This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d × 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d × 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. Results Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of −0.03 (95% CI, −6.53 to 6.47) met the predefined criteria of ≤ 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks...
Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary... more Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary Brandt, MD; Jay Pinsky, BA; Lyssa Ochoa, BS; Leland Fan, MD. Texas Children's Hospital/Baylor College of ...
Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary... more Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary Brandt, MD; Jay Pinsky, BA; Lyssa Ochoa, BS; Leland Fan, MD. Texas Children's Hospital/Baylor College of ...
The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at inte... more The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at intensive care units and demonstrate its' main indications, results and influences on the patients' condition. In 35.4% of cases immediate improvement was observed, in 31.6% the examination contributed to choose the proper treatment. Due to the safe method only one serious complication occurred because of bronchoscopy. The results justify-according to the literature-that fiberoptic bronchoscopy is an indispensable method to check airways and for diagnostical and therapeutic interventions of critically ill patients.
Congenital bronchoesophageal fistula manifesting in adulthood is an infrequent disorder. Presenti... more Congenital bronchoesophageal fistula manifesting in adulthood is an infrequent disorder. Presenting a successfully treated case, the authors review the clinicopathological features of the disease regarding the data of literature. The long-standing, non-specific respiratory symptoms recurring in the same pulmonary location call the attention to the fistula, which should be verified by esophagography and endoscopy. The adequate treatment consisting of fistulectomy and resection of the destroyed lung parenchyma lead to prompt recovery.
Multiple duct anastomoses during LLS transplantation increase the incidence of biliary complicati... more Multiple duct anastomoses during LLS transplantation increase the incidence of biliary complications. The optimal plane of hepatotomy that results in the least number of bile ducts at the surface was investigated according to LHD variations. Ducts of 30 human livers were injected with resin and LHD branching on 3D-CT reconstructions were analyzed. Ducts on the virtual hepatotomy surface were estimated in three splitting lines. Variations with subtypes were described. Ia (66.7%): ducts from segments (S.) II-III form a common trunk and S.IV duct joins it. Ib (10%): common trunk formed by ducts from S.II-S.III while S.IV duct joins the common hepatic duct. IIa (16.67%): S.IV duct drains into S.III duct. IIc (3.33%): S.IV duct drains into both S.II and S.III ducts. III (3.33%): trifurcation of S.II, S.III and S.IV ducts. When the virtual hepatotomy line was on the FL, there was a single duct for the anastomosis in 30% of cases but two, three, or four ducts in 53.3%, 10%, and 3.3%, respe...
The histological results of transbronchial lung biopsies have been analysed in 109 patients with ... more The histological results of transbronchial lung biopsies have been analysed in 109 patients with diffuse or localised lung diseases. This diagnostic procedure is relatively safe, well tolerable and can be carried out in outpatients. In diffuse lung diseases its use can replace the open lung biopsy. The efficacy of this method depends on the availability of biplanar fluoroscopy, the quality of the excisors, the quantity and size of the biopsy material and the technique of the histological handling.
122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endob... more 122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endobronchial laser treatment was performed either with flexible bronchoscope (64%), or with rigid instrument (36%). This method can result a final recovery of the patients with benign tumors, or inflammatory processes, at the patients with malignant tumors can be achieved an effective palliation. Taking account the generally accepted indications and contraindications of the endobronchial laser phototherapy the number of the complications can be reduced.
Magyar Sebészet (Hungarian Journal of Surgery), 2011
ABSTRACT Pulmonary fibrosis and impeding gangrene as complications of radiotherapy and chemothera... more ABSTRACT Pulmonary fibrosis and impeding gangrene as complications of radiotherapy and chemotherapy developed in a patient who previously underwent right upper lobectomy. Following completion pneumonectomy, bronchopleural fistula and consecutive thoracic empyema formed. This case presentation is to demonstrate the vicious circle of severe complications following oncological treatment. The role of vacuum assisted closure and other management options are discussed which resulted in full recovery of the patient after three years finally.
Abstract Important in the endoscopic management of the main airway stenosis is the implantation o... more Abstract Important in the endoscopic management of the main airway stenosis is the implantation of a tracheobronchial stent. We modified the original insertion technique for a silicone stent, replacing the rigid bronchoscope with the flexible bronchoscope. Thirty-...
PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral ang... more PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.
MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lun... more MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 10(8) plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148. Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4-6·7) in the TG4010 group and 5·1 months (4·2-5·9) in the placebo group (HR 0·74 [95% CI 0·55-0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54-1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42-1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1-2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events). TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.
Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite i... more Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite its prevalence, especially among patients with chronic obstructive pulmonary disease, AATD is still underdiagnosed. The aim of this study is to identify individuals with lung disease and severe AATD in central-eastern Europe. Subjects with respiratory symptoms that could be indicative of AATD provided blood samples as dried blood spot. The alpha1 -antitrypsin (AAT) concentration was determined by nephelometry and, if lower than 1.70 mg/dL in dried blood spot (equivalent to 1.04 g/L in serum), polymerase chain reaction was used to detect the PiS and PiZ alleles. Isoelectric focusing was used for confirmation of doubtful genotype results. From 13 countries, 11 648 subjects were included. Genotyping of 1404 samples with AAT levels <1.70 mg/dL revealed 71 (5.06%) PiS, 151 (10.8%) PiZ, 1 (0.071%) PiSS, 8 (0.57%) PiSZ and 32 (2.28%) PiZZ. Phenotyping of 1363 samples negative for the S and Z alleles or with PiS and PiZ genotype showed two (0.147%) PiZ(rare) and two (0.147%) Pi(null)(null). The countries with the highest rate of severe AATD were Croatia, Russia and Slovakia. By regions, the Baltic countries area showed the highest rate of both PiZ and severe AATD (2.45% and 1.20%, respectively) while the lowest rates were observed in the Balkan Peninsula (0.48% and 0.31%, respectively). This study confirms the need for targeted testing of symptomatic patients and provides AATD genotype data from countries for which only some estimates of prevalence were available until now.
Purpose Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung can... more Purpose Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV topotecan in patients with SCLC sensitive to initial chemotherapy. Patients and Methods Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status ≤ 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of ≥ 90 days were assigned to treatment with either oral topotecan 2.3 mg/m2/d on days 1 through 5 or IV topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. Results A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral topotecan (n = 153) and 21.9% with IV topotecan (n = 151), with ...
Purpose This open-label, randomized, multicenter phase III study compared oral topotecan/intraven... more Purpose This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d × 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d × 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. Results Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of −0.03 (95% CI, −6.53 to 6.47) met the predefined criteria of ≤ 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks...
Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary... more Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary Brandt, MD; Jay Pinsky, BA; Lyssa Ochoa, BS; Leland Fan, MD. Texas Children's Hospital/Baylor College of ...
Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary... more Page 1. THE CHANGING FACE OF EMPYEMAS IN CHILDREN Karen D. Schultz, MD*; Sheldon Kaplan, MD; Mary Brandt, MD; Jay Pinsky, BA; Lyssa Ochoa, BS; Leland Fan, MD. Texas Children's Hospital/Baylor College of ...
The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at inte... more The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at intensive care units and demonstrate its' main indications, results and influences on the patients' condition. In 35.4% of cases immediate improvement was observed, in 31.6% the examination contributed to choose the proper treatment. Due to the safe method only one serious complication occurred because of bronchoscopy. The results justify-according to the literature-that fiberoptic bronchoscopy is an indispensable method to check airways and for diagnostical and therapeutic interventions of critically ill patients.
Congenital bronchoesophageal fistula manifesting in adulthood is an infrequent disorder. Presenti... more Congenital bronchoesophageal fistula manifesting in adulthood is an infrequent disorder. Presenting a successfully treated case, the authors review the clinicopathological features of the disease regarding the data of literature. The long-standing, non-specific respiratory symptoms recurring in the same pulmonary location call the attention to the fistula, which should be verified by esophagography and endoscopy. The adequate treatment consisting of fistulectomy and resection of the destroyed lung parenchyma lead to prompt recovery.
Multiple duct anastomoses during LLS transplantation increase the incidence of biliary complicati... more Multiple duct anastomoses during LLS transplantation increase the incidence of biliary complications. The optimal plane of hepatotomy that results in the least number of bile ducts at the surface was investigated according to LHD variations. Ducts of 30 human livers were injected with resin and LHD branching on 3D-CT reconstructions were analyzed. Ducts on the virtual hepatotomy surface were estimated in three splitting lines. Variations with subtypes were described. Ia (66.7%): ducts from segments (S.) II-III form a common trunk and S.IV duct joins it. Ib (10%): common trunk formed by ducts from S.II-S.III while S.IV duct joins the common hepatic duct. IIa (16.67%): S.IV duct drains into S.III duct. IIc (3.33%): S.IV duct drains into both S.II and S.III ducts. III (3.33%): trifurcation of S.II, S.III and S.IV ducts. When the virtual hepatotomy line was on the FL, there was a single duct for the anastomosis in 30% of cases but two, three, or four ducts in 53.3%, 10%, and 3.3%, respe...
The histological results of transbronchial lung biopsies have been analysed in 109 patients with ... more The histological results of transbronchial lung biopsies have been analysed in 109 patients with diffuse or localised lung diseases. This diagnostic procedure is relatively safe, well tolerable and can be carried out in outpatients. In diffuse lung diseases its use can replace the open lung biopsy. The efficacy of this method depends on the availability of biplanar fluoroscopy, the quality of the excisors, the quantity and size of the biopsy material and the technique of the histological handling.
122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endob... more 122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endobronchial laser treatment was performed either with flexible bronchoscope (64%), or with rigid instrument (36%). This method can result a final recovery of the patients with benign tumors, or inflammatory processes, at the patients with malignant tumors can be achieved an effective palliation. Taking account the generally accepted indications and contraindications of the endobronchial laser phototherapy the number of the complications can be reduced.
Magyar Sebészet (Hungarian Journal of Surgery), 2011
ABSTRACT Pulmonary fibrosis and impeding gangrene as complications of radiotherapy and chemothera... more ABSTRACT Pulmonary fibrosis and impeding gangrene as complications of radiotherapy and chemotherapy developed in a patient who previously underwent right upper lobectomy. Following completion pneumonectomy, bronchopleural fistula and consecutive thoracic empyema formed. This case presentation is to demonstrate the vicious circle of severe complications following oncological treatment. The role of vacuum assisted closure and other management options are discussed which resulted in full recovery of the patient after three years finally.
Abstract Important in the endoscopic management of the main airway stenosis is the implantation o... more Abstract Important in the endoscopic management of the main airway stenosis is the implantation of a tracheobronchial stent. We modified the original insertion technique for a silicone stent, replacing the rigid bronchoscope with the flexible bronchoscope. Thirty-...
PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral ang... more PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.
MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lun... more MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 10(8) plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148. Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4-6·7) in the TG4010 group and 5·1 months (4·2-5·9) in the placebo group (HR 0·74 [95% CI 0·55-0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54-1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42-1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1-2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events). TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.
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