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1.
Artigo em Inglês | MEDLINE | ID: mdl-32201002

RESUMO

OBJECTIVE: Improvement in ex vivo lung perfusion protocols could increase the number of donors available for transplantation and protect the lungs from primary graft dysfunction. We hypothesize that perfusate adsorption during ex vivo lung perfusion reconditions the allograft to ischemia-reperfusion injury after lung transplantation. METHODS: Donor pig lungs were preserved for 24 hours at 4°C, followed by 6 hours of ex vivo lung perfusion according to the Toronto protocol. The perfusate was additionally adsorbed through a CytoSorb adsorber (CytoSorbents, Berlin, Germany) in the treatment group, whereas control lungs were perfused according to the standard protocol (n = 5, each). Ex vivo lung perfusion physiology and biochemistry were monitored. Upon completion of ex vivo lung perfusion, a left single lung transplantation was performed. Oxygenation function and lung mechanics were assessed during a 4-hour reperfusion period. The inflammatory response was determined during ex vivo lung perfusion and reperfusion. RESULTS: The cytokine concentrations in the perfusate were markedly lower with the adsorber, resulting in improved ex vivo lung perfusion physiology and biochemistry during the 6-hour perfusion period. Post-transplant dynamic lung compliance was markedly better during the 4-hour reperfusion period in the treatment group. Isolated allograft oxygenation function and dynamic compliance continued to be superior in the adsorber group at the end of reperfusion, accompanied by a markedly decreased local inflammatory response. CONCLUSIONS: Implementation of an additional cytokine adsorber has refined the standard ex vivo lung perfusion protocol. Furthermore, cytokine removal during ex vivo lung perfusion improved immediate post-transplant graft function together with a less intense inflammatory response to reperfusion in pigs. Further studies are warranted to understand the beneficial effects of perfusate adsorption during ex vivo lung perfusion in the clinical setting.

2.
J Thorac Oncol ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004713

RESUMO

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32011665

RESUMO

OBJECTIVES: Patients with oligometastatic non-small-cell lung cancer (NSCLC) may benefit from therapy with curative intent. Our goal was to identify prognostic factors related to better prognosis in a multicentre analysis of patients who underwent surgery of primary tumours in combination with radical treatment of all metastatic sites. METHODS: We retrospectively reviewed the records of oligometastatic patients who underwent resection of primary tumours at 4 centres (August 2001-February 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery, radiotherapy or a combination. The Cox proportional hazards model was used for identification of prognostic factors on overall survival. RESULTS: We treated 124 patients; 72 (58%) were men, mean age 60 ± 9.8 years, with 87 (70%) adenocarcinoma. Sixty-seven (54%) patients had positive pathologic-N stage (pN). Brain metastases were most common (n = 76; 61%) followed by adrenal (n = 13; 10%) and bone (n = 12; 10%). Systemic therapy was administered in 101 (82%) patients. Median follow-up was 60 months [95% confidence interval (CI) 41-86]. Thirty- and 90-day mortality rates were 0 and 2.4%, respectively. One-, 2-, and 5-year overall survival were 80%, 58% and 36%, respectively. Cox regression analysis showed that patients ≤60 years [hazard ratio (HR) 0.41, 95% CI 0.24, 0.69; P = 0.001] and patients with pN0 (HR 0.38, 95% CI 0.21-0.69; P = 0.002) had a significant survival benefit. The presence of bone metastases negatively affected survival (HR 2.53, 95% CI 1.05-6.09; P = 0.04). CONCLUSIONS: Treatment with curative intent of selected oligometastatic NSCLC, including resection of the primary tumour, can be performed safely and with excellent 5-year survival rates, especially in younger patients with pN0 disease.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31919516

RESUMO

OBJECTIVES: No significant data are available to assess whether complex sleeve lobectomy (complex-SL) can be considered comparable to conventional lobectomy (CL) in terms of surgical outcome. The purpose of this study was to compare surgical and oncological outcomes of complex-SL with CL in patients with lung cancer. METHODS: Between 2000 and 2015, a total of 568 patients who underwent open CL (defined as resection of only 1 lobe) and 187 patients who underwent SL were analysed. The SL group was divided into 2 subgroups: standard-SL (bronchial SL, n = 106) and complex-SL (n = 81) (defined as bronchial sleeve resection together with another surgical intervention: bronchovascular SL, n = 40; vascular SL, n = 26; atypical bronchoplasty with resection of more than 1 lobe, n = 12; bronchial SL + chest wall resection, n = 3). RESULTS: The complex-SL group had more patients with chronic obstructive pulmonary disease (COPD) (25.9% vs 12.5%, P = 0.001), neoadjuvant treatment (39.5% vs 12.0%, P < 0.001), advanced-stage non-small-cell lung cancer (53.2% vs 33.1%, P = 0.001) and low preoperative forced expiratory volume in 1 s (77.2% vs 84.3%, P = 0.004) than the CL group. The overall surgical mortality (in-hospital or 30-day) was 2.6% (n = 20); it was 2.8% for CL and 2.8% for complex-SL. Postoperative complications occurred in 34.9% of the CL group and 39.5% of the complex-SL group (P = 0.413). The pulmonary complication rate was similar between the groups (24.1% for CL, 27.2% for complex-SL, P = 0.552). The 5-year survival in the CL group was 57.1%, and in the complex-SL group it was 56.2% (P = 0.888). Multivariate analysis showed that TNM stage (P < 0.001) and N status (P < 0.001) were significant and independent negative prognostic factors for survival. CONCLUSIONS: Complex-SL had a comparable outcome to CL, although the complex-SL group had more patients with advanced-stage NSCLC, low preoperative forced expiratory volume in 1 s and COPD.

5.
Mol Cancer Ther ; 19(2): 552-563, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31619462

RESUMO

Loss of function of BRCA1-associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. A genetically engineered model was established expressing either functional or nonfunctional BAP1, and whole-genome siRNA synthetic lethality screens were performed assessing differentially impaired survival between the two cell lines. The whole-genome siRNA screen unexpectedly revealed 11 hits (FDR < 0.05) that were more cytotoxic to BAP1-proficient cells. Two actionable targets, ribonucleotide reductase (RNR) catalytic subunit M1 (RRM1) and RNR regulatory subunit M2 (RRM2), were validated. In line with the screen results, primary mesothelioma (BAP1 +/-) overexpressing BAP1 C91A (catalytically dead mutant) was more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in BAP1-proficient cell line-derived spheroids compared with BAP1 deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in BAP1 mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with BAP1-WT but not with BAP1 C91A. Upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared with control or C91A mutant. Together, we found that BAP1 is involved in the regulation of RNR levels during replication stress. Our observations reveal a potential clinical application where BAP1 status could serve as predictive or stratification biomarker for RNR inhibition-based therapy in MPM.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31590949

RESUMO

OBJECTIVES: Intracavitary chemotherapy is a promising concept to improve local tumor control for malignant pleural mesothelioma with reported high morbidity rates. We have demonstrated that administration of cisplatin loaded to fibrin increased local drug concentration and reduced systemic toxicity in preclinical models. We present a phase I trial of intracavitary cisplatin-fibrin after surgical tumor resection. METHODS: A total of 12 patients (75% International Mesothelioma Interest Group stage III-IV) were treated with 4 dose levels of intracavitary cisplatin-fibrin (11-44 mg/m2 body surface area) in a dose-escalating design. Cisplatin-fibrin was sprayed on the resected surfaces after pleurectomy/decortication. Blood and tissue samples were taken to assess toxicity and pharmacokinetics. Patients were regularly followed up. RESULTS: No dose-limiting toxicity was observed. Major morbidity occurred in 4 patients (33%). The 30-day and 90-day mortality were both 0%. Of 80 adverse events, 9 were classified serious, but none of these were related to study treatment. Local cisplatin concentration in the chest wall tissue was high at all dose levels (median, 46.3 µg/g [12-133 µg/g]). In serum, median cisplatin area under the concentration time curve values were always below renal toxicity levels. The median overall survival with 95% confidence interval was 21 months (10-31 months). In 1 patient with epithelioid malignant pleural mesothelioma (International Mesothelioma Interest Group stage I), there was no sign of relapse 48 months after treatment (44 mg/m2 body surface area). CONCLUSIONS: The administration of intracavitary cisplatin-fibrin is safe with favorable pharmacokinetics. Although most patients had advanced disease, long-term outcomes are comparable to other multimodal concepts. A confirmation phase II trial is ongoing.

7.
Lung Cancer ; 138: 19-26, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31606521

RESUMO

OBJECTIVES: For early stage non-small cell lung cancer (NSCLC) retrospective data of functionally compromised patients undergoing segmentectomy showed equal outcomes for perioperative complications and quality of life (QoL) compared with lobectomy patients. However no prospectively randomized data comparing patients eligible for both procedures are available. MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial and investigated perioperative complications and QoL in patients with NSCLC stage IA (7th edition) undergoing segmentectomy versus lobectomy. The EORTC Questionnaire Core-30 (QLQ C-30) supplemented by thirteen-item lung cancer-specific module (LC13) was assessed before surgery, at discharge, 6 weeks, 3, 6 and 12 months post-surgery. RESULTS: 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled, whereby 54 were assigned to lobectomy and 54 to segmentectomy. Due to nodal disease, tumor size and surgical reasons estimated during the operation, eight patients of the segmentectomy group received a lobectomy. In hospital and 90 days mortality was 0% in both groups. Perioperative complications were observed in 6 (11.3%) patients after segmentectomy and in 8 patients (14.8%) after lobectomy (p = 0.563), while the 90-day morbidity were 17% and 25.9% (9 and 14 patients), respectively (p = 0.452). Twelve months after surgery, there was a significant deterioration to the baselines of physical (p < 0.001) and cognitive functioning (p = 0.025), dyspnea (p < 0.001) and fatigue (p = 0.003) in the lobectomy group. Dyspnea showed a faster recovery in the segmentectomy compared to lobectomy group with statistical significance (p = 0.016 after 12 months). CONCLUSION: In patients with early-stage NSCLC, segmentectomy is associated with a statistically not significant lower perioperative morbidity and appears to provide a superior recovery in QoL compared with lobectomy patients.

8.
Front Oncol ; 9: 961, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616640

RESUMO

Introduction: Therapy options for patients with oligoprogressive malignant pleural mesothelioma (MPM) are limited. Stereotactic Body Radiotherapy (SBRT) may be a promising therapeutic option, as it delivers a localized ablative dose of radiation and therefore balances efficacy and treatment related toxicities. The intent of this retrospective analysis was to evaluate the feasibility of SBRT for limited pleural recurrences. Methods and Materials: This retrospective single-institution study is based on the 21 consecutive patients treated with hypofractionated radiotherapy for oligoprogressive MPM. Clinical and radiological data was collected at regular follow-up visits including toxicity, local control and survival. Results: At primary diagnosis, 57% of the patients presented with stage III disease. Initial treatment of MPM consisted of induction chemotherapy (n = 12) prior to a macroscopic complete resection (n = 18). Three patients received additional intracavitary chemotherapy and another three patients were treated with chemotherapy alone without another treatment at the time of first diagnosis. A total of 50 lesions in recurrent MPM were treated with SBRT. The median number of radiotherapy fractions was 5 (range 3-20) with a median dose per fraction of 5 Gy (range 2.5-12.5 Gy). The median total treatment dose was 30 Gy (20-50 Gy) with a median prescription isodose line (IDL) of 65% (65-100%). Median follow-up of all patients from diagnosis was 28 months (range 7-152 months). Analyzing all lesions separately, the 12-months-local control from SBRT was 73.5%. The median progression free survival (PFS) after SBRT was 6 months (range 0-21 months) and the median OS from first first SBRT was 29 months (range 0-61 months). Only one patients experienced above Grade 3 toxicities. Conclusion: This analysis demonstrates the feasibility of a SBRT approach for oligorecurrent MPM. SBRT was well-tolerated even after multiple repetitions and local control was high with a promising median OS.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31499540

RESUMO

BACKGROUND: Primary pulmonary sarcoma (PPS) is a rare malignant lung neoplasm, and there is very little medical evidence about treatment of PPS. The aim of this study is to clarify the clinical characteristics and therapeutic outcome of patients who underwent surgical resection for PPS. METHODS: We retrospectively reviewed the records of patients who underwent surgical resection for PPS in our institution between 1995 and 2014. Cases who only underwent biopsy were excluded. RESULTS: A total of 24 patients (18 males, 6 females), with a median age of 60 (interquartile range: 44-67) years, were analyzed. The surgical procedures performed in these patients were pneumonectomy (n = 10), lobectomy (n = 11), and wedge resection (n = 3). Complete resection was achieved in 16 patients. The pathological stages (tumor, node, metastases lung cancer classification, 8th edition) of the patients were I (n = 4), II (n = 12), III (n = 2), and IV (n = 5), and there were four cases of lymph node metastasis. The 5-year overall survival rate of the patients was 50% (95% confidence interval [CI]: 29-72). Adverse prognostic factors for overall survival were incomplete resection (hazard ratio [HR]: 4.4, 95% CI: 2.1-42), advanced pathological stage (HR 14, 95% CI: 2.8-66), higher pathological grade (HR 4.5, 95% CI: 1.2-17), and tumor size ≥ 7 cm (HR 4.7, 95% CI: 1.1-21). CONCLUSIONS: Our series of PPS revealed that incomplete resection, advanced pathological stage, higher pathological grade, and tumor size were unfavorable factors for long-term survival.

10.
Clin Lung Cancer ; 20(5): 391-396, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31262689

RESUMO

BACKGROUND: Despite recent studies, the effect of chemotherapy on programmed death-ligand 1 (PD-L1) expression remains controversial. In this study, we investigated whether PD-L1 expression is affected by platinum-based chemotherapy. Furthermore, we evaluated correlation of PD-L1 expression with oncogenic driver alterations. MATERIALS AND METHODS: We retrospectively evaluated changes in PD-L1 expression by immunohistochemical (IHC) analysis in resected specimens and in biopsies at non-small cell lung cancer recurrence in patients receiving or not adjuvant chemotherapy after surgical resection. Four IHC score groups were defined: TC0 < 1%, T ≥ 1% and < 5%, TC2 ≥ 5% and < 50%, and TC3 ≥ 50%. RESULTS: Thirty-six patients with adenocarcinoma were included. Twenty (56%) patients underwent adjuvant chemotherapy, and 16 (44%) patients did not receive adjuvant chemotherapy. PD-L1 expression was present in 10 (28%) of 36 initial tumor specimens. From patients receiving adjuvant chemotherapy, 7 (35%) of 20 tumor biopsies showed significant upregulation in PD-L1 expression at recurrence. In contrast, from patients with no adjuvant therapy, only 2 (12.5%) of 16 showed a change in PD-L1 expression. Six (17%) of 36 patients were PD-L1-negative in the primary tumor and turned positive at recurrence. KRAS mutation was present in 70% of patients expressing PD-L1. CONCLUSION: PD-L1 expression in non-small cell lung cancer can change from primary to recurrence, implicating the need for re-biopsy at recurrence. Moreover, chemotherapy might increase expression of PD-L1, supporting a combinatorial therapy with chemotherapy and anti-PD(L)1 treatment.

11.
Sci Rep ; 9(1): 10910, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358841

RESUMO

Surgery of the chest wall is potentially required to cover large defects after  removal of malignant tumours. Usually, inert and non-degradable Gore-Tex serves to replace the missing tissue. However, novel biodegradable materials combined with stem cells are available that stimulate the healing. Based on poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) and pure PLGA, a dual layer biodegradable hybrid nanocomposite was generated. Mouse adipose-derived stem cells were cultered on electrospun disks (ASCs of C57BL/6), and biomechanical tests were performed. The cell-seeded scaffolds were engrafted in C57BL/LY5.1 mice to serve as a chest wall substitute. Cell invasion into the bi-layered material, extent of CD45+ cells, inflammatory response, neo-vascularization and ECM composition were determined at 1 and 2 months post-surgery, respectively. The bi-layered hybrid nanocomposite was stable after a 2-week in vitro culture, in contrast to PLGA/aCaP without a PLGA layer. There was a complete biointegration and good vascularization in vivo. The presence of ASCs attracted more CD45+ cells (hematopoietic origin) compared to cell-free scaffolds. Inflammatory reaction was similar for both groups (±ASCs) at 8 weeks. A bi-layered hybrid nanocomposite fabricated of electrospun PLGA/aCaP and a reinforcing layer of pristine PLGA is an ideal scaffold for chest wall reconstruction. It is stable and allows a proper host tissue integration. If ASCs are seeded, they attract more CD45+ cells, supporting the regeneration process.

12.
Noncoding RNA ; 5(2)2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31212997

RESUMO

Combining neo-adjuvant chemotherapy and surgery is part of multimodality treatment of malignant pleural mesothelioma (MPM), but not all patients benefit from this approach. In this exploratory analysis, we investigated the prognostic value of circulating miR-625-3p and lncRNA GAS5 after neo-adjuvant chemotherapy. 36 MPM patients from the SAKK 17/04 trial (NCT00334594), whose blood was available before and after chemotherapy were investigated. RNA was isolated from plasma and reverse transcribed into cDNA. miR-16-5p and ß-actin were used as a reference gene for miR-625-3p and GAS5, respectively. After exclusion of samples due to hemolysis or RNA degradation, paired plasma samples from 32 patients before and after chemotherapy were further analyzed. Quantification of miR-625-3p levels in all 64 samples revealed a bimodal distribution and cloning and sequencing of miR-625-3p qPCR product revealed the presence of miR-625-3p isomiRs. Relative change of the circulating miR-625-3p and GAS5 levels after chemotherapy showed that increased circulating miR-625-3p and decreased GAS5 was significantly associated with disease progression (Fisher's test, p = 0.0393). In addition, decreased levels of circulating GAS5 were significantly associated with shorter overall and progression-free survival. Our exploratory analysis revealed a potential value of circulating non-coding RNA for selection of patients likely to benefit from surgery after platinum-based adjuvant chemotherapy.

13.
Radiother Oncol ; 138: 121-125, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31252293

RESUMO

Postoperative radiotherapy after extrapleural pneumonectomy of malignant pleural mesothelioma was investigated in the randomized phase II trial SAKK17/04. The relapse rate within the high and/or low-dose PTV without previous distant failure was 24%, the isolated in-field-relapse rate within the PTVs was 5% and the distant relapse rate outside of the PTVs was 81%. Clinical outcome was mainly determined by distant disease progression outside of the radiation field.

14.
Lung Cancer ; 131: 95-103, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31027705

RESUMO

INTRODUCTION: The PD-L1 biomarker is an important factor in selecting patients with non-small cell lung cancer for immunotherapy. While several reports suggest that PD-L1 positivity is linked to a poor prognosis, others suggest that PD-L1 positive status portends a good prognosis. METHODS: PD-L1 positivity prevalence, assessed via immunohistochemistry (IHC) on tissue microarrays (TMAs), and its association with clinicopathological characteristics, molecular profiles and patient outcome- Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS)- is explored in the ETOP Lungscape cohort of stage I-III non-small cell lung cancer (NSCLC). Tumors are considered positive if they have ≥1/5/25/50% neoplastic cell membrane staining. RESULTS: PD-L1 expression was assessed in 2182 NSCLC cases (2008 evaluable, median follow-up 4.8 years, 54.6% still alive), from 15 ETOP centers. Adenocarcinomas represent 50.9% of the cohort (squamous cell: 42.4%). Former smokers are 53.7% (current: 31.6%, never: 10.5%). PD-L1 positivity prevalence is present in more than one third of the Lungscape cohort (1%/5% cut-offs). It doesn't differ between adenocarcinomas and squamous cell histologies, but is more frequently detected in higher stages, never smokers, larger tumors (1/5/25% cut-offs). With ≥1% cut-off it is significantly associated with IHC MET overexpression, expression of PTEN, EGFR and KRAS mutation (only for adenocarcinoma). Results for 5%, 25% and 50% cut-offs were similar, with MET being significantly associated with PD-L1 positivity both for AC (p < 0.001, 5%/25%/50% cut-offs) and SCC (p < 0.001, 5% & 50% cut-offs and p = 0.0017 for 25%). When adjusting for clinicopathological characteristics, a significant prognostic effect was identified in adenocarcinomas (adjusted p-values: 0.024/0.064/0.063 for RFS/TTR/OS 1% cut-off, analogous for 5%/25%, but not for 50%). Similar results obtained for the model including all histologies, but no effect was found for the squamous cell carcinomas. CONCLUSION: PD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Imunoterapia/métodos , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Europa (Continente) , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-met/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
15.
Swiss Med Wkly ; 149: w20064, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30994925

RESUMO

AIM OF THE STUDY: Non-intubated, video-assisted thoracoscopic surgery (NiVATS) has been successfully developed in several centres worldwide. Local anaesthesia techniques and techniques to perform thoracoscopic surgery on a spontaneously breathing lung are the two key elements which must be adopted to establish a NiVATS programme. We established NiVATS by performing bilateral, uniportal sympathectomies, and compared it to classical video-assisted thoracoscopic surgery (VATS) under general anaesthesia with double-lumen intubation. METHODS: Ten consecutive bilateral VATS sympathectomies were compared with ten consecutive NiVATS procedures. Nineteen of the procedures were for palmar hyperhidrosis and one was for facial blushing. Duration of anaesthesia, surgery and hospitalisation, perioperative complications, side effects and quality of life before and after sympathectomy were analysed. RESULTS: Median age was 26.5 years (range 17–55) and mean BMI in the NiVATS group was 21.8 (range 19.1–26.3). NiVATS sympathectomies were performed as outpatient procedures significantly more often (9/10 vs 3/10, p = 0.008). Quality of life was significantly increased after sympathectomy in all patients, with no significant differences between the NiVATS and the VATS groups. There were no differences between the two groups regarding compensatory sweating (40 vs 50%, p = 0.66). The duration of anaesthesia, not including the time required for the surgery, was significantly shorter in the NiVATS group (p <0.001). The duration of surgery, from the first local anaesthesia until the last skin suture, was significantly longer in the NiVATS group (p = 0.04), but showed a constant decline during the learning curve, from 95 minutes initially to 48 minutes for the last procedure. Costs were significantly lower in the NiVATS group (p = 0.04). CONCLUSION: Thoracoscopic sympathectomy is a suitable procedure with which to establish a NiVATS programme. Patients are usually young and of healthy weight, facilitating the learning curve for the local anaesthesia techniques and the surgery. Compared to VATS, sympathectomy is more likely to be performed as an outpatient procedure and has a lower cost, while safety and efficacy are maintained.

16.
Br J Cancer ; 120(10): 968-974, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988393

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (CT) followed by radiotherapy (RT) and surgery showed a median survival of 28.7 months in resectable stage IIIB non-small-cell lung cancer (NSCLC) patients (pts). Here, we evaluate the impact of concomitant cetuximab to the same neoadjuvant chemo-radiotherapy (CRT) in selected patients (pts) with NSCLC, stage IIIB. METHODS: Resectable stage IIIB NSCLC received three cycles of CT (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3w) followed by RT (44 Gy in 22 fractions) with concomitant cetuximab (250 mg/m2, q1w) and subsequent surgery. The primary endpoint was 1-year progression-free survival (PFS). RESULTS: Sixty-nine pts were included in the trial. Fifty-seven (83%) pts underwent surgery, with complete resection (R0) in 42 (74%) and postoperative 30 day mortality of 3.5%. Responses were: 57% after CT-cetuximab and 64% after CRT-cetuximab. One-year PFS was 50%. Median PFS was 12.0 months (95% CI: 9.0-15.6), median OS was 21.3 months, with a 2- and 3-yr survival of 41% and 30%, respectively. CONCLUSIONS: This is one of the largest prospective phase 2 trial to investigate the role of induction CRT and surgery in resectable stage IIIB disease, and the first adding cetuximab to the neoadjuvant strategy. This trial treatment is feasible with promising response and OS rates, supporting an aggressive approach in selected pts.

17.
J Thorac Dis ; 11(3): 766-776, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31019764

RESUMO

Background: Adequate patient selection is the key to successful lung volume reduction in patients with pulmonary emphysema. Computed tomography (CT) enables a reliable detection of pulmonary emphysema and allows an accurate quantification of the severity. Our goal was to investigate the usefulness and reliability of color-coded (CC) CT images in classification of emphysema and preoperative lung volume reduction planning. Methods: Fifty patients undergoing lung volume reduction surgery at our institution between September 2015 and February 2016 were retrospectively investigated. Three readers visually assessed the amount and distribution patterns of pulmonary emphysema on axial, multi-planar and CC CT images using the Goddard scoring system and a surgically oriented grading system (bilateral markedly heterogenous, bilateral intermediately heterogenous, bilateral homogenous and unilateral heterogenous emphysema). Observer dependency was investigated by using Fleiss' kappa (κ) and the intraclass correlation coefficient (ICC). Results were compared to quantitative results from densitometry measurements and lung perfusion scintigraphy by using Spearman correlation. Recommendations for lung volume reduction sites based on emphysema amount and distribution of all readers were compared to removal sites from the surgical reports. Results: Inter-rater agreement for emphysema distribution rating was substantial for CC images (κ=0.70; 95% CI, 0.64-0.80) and significantly better compared to axial and multiplanar images (P≤0.001). The inter-rater agreement for recommended segment removal was moderate for CC images (κ=0.56; 95% CI, 0.49-0.63) and significantly better compared to axial and multiplanar images (P<0.001). Visual emphysema rating correlated significantly with measurements from densitometry and perfusion scintigraphy in the upper and lower lung zones in all image types. Conclusions: CC CT images allow a precise, less observer-dependent evaluation of distribution of pulmonary emphysema and resection recommendation compared to axial and multiplanar CT images and might therefore be useful in lung volume resection surgery planning.

18.
Lung ; 197(2): 217-226, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30739218

RESUMO

PURPOSE: Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation. METHODS: Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins - 6 and - 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1). RESULTS: Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin - 6 (p = 0.008) and - 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004). CONCLUSIONS: Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.


Assuntos
Anestésicos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Pulmão/efeitos adversos , Pulmão/efeitos dos fármacos , Ropivacaina/farmacologia , Doença Aguda , Aloenxertos , Animais , Caveolina 1/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Mediadores da Inflamação/sangue , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
19.
Lancet Respir Med ; 7(4): 313-324, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30744937

RESUMO

BACKGROUND: Severe emphysema is a debilitating condition with few treatment options. Lung volume reduction procedures in the treatment of severe emphysema have shown excellent results in selected patients but their exact role remains unclear with studies reporting a wide variation in outcomes. We therefore aimed to evaluate the effects of volume reduction. METHODS: We did a systematic review and meta-analysis. We searched MEDLINE on Sept 29, 2016, for trials of lung volume reduction in patients with emphysema, and we did an updated search on Embase and PubMed on June 18, 2018. We only included randomised controlled studies published in English evaluating the intervention with either sham or standard of care. Inclusion was limited to trials of techniques in which there was sustainable volume reduction. Primary outcomes were residual volume, FEV1, St George's Respiratory Questionnaire (SGRQ), and 6-min walk distance (6MWT). Secondary outcomes were severe adverse events (including mortality), short-term mortality, and overall mortality. We extracted summary level data from the trial publications and where necessary we obtained unpublished data. A random-effects model with the I2 statistic was used to determine heterogeneity and trial weight in each analysis. The study is registered with the PROSPERO database, number CRD42016045705. FINDINGS: We identified 4747 references in the search, and included 20 randomised controlled trials of lung volume reduction involving 2794 participants with emphysema. Following lung volume reduction from any of the interventions in pooled analyses (ie, surgery, endobronchial valve, endobronchial coil, or sclerosing agents), the mean differences compared with the control were reduction in residual volume of 0·58 L (95% CI -0·80 to -0·37), increase in FEV1 of 15·87% (95% CI 12·27 to 19·47), improvement in 6MWT of 43·28 m (31·36 to 55·21), and reduction in the SGRQ of 9·39 points (-10·92 to -7·86). The odds ratio for a severe adverse event, which included mortality, was 6·21 (95% CI 4·02 to 9·58) following intervention. Regression analysis showed improvements relative to the degree of volume reduction: FEV1 (r2=0·86; p<0·0001), 6MWT (r2=0·77; p<0·0001), and SGRQ (r2=0·70; p<0·0001). Most studies were at high risk of bias for lack of blinding, and heterogeneity was high for some outcomes when pooled across all interventions, but was generally lower in the subgroups by intervention type. INTERPRETATION: Despite limitations of high risk of bias and heterogeneity for some analyses, our results provide support that lung volume reduction in patients with severe emphysema on maximal medical treatment has clinically meaningful benefits. These benefits should be considered alongside potential adverse events. FUNDING: None.

20.
Eur J Cardiothorac Surg ; 55(4): 601-609, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649256

RESUMO

OBJECTIVES: We queried the European Society of Thoracic Surgeons (ESTS) prospective thymic database for descriptive analysis and for comparison with the ESTS retrospective thymic database (1990-2010). METHODS: Data were retrieved (January 2007-November 2017) for 1122 patients from 75 ESTS institutions. RESULTS: There were 484 (65%) thymomas, 207 (28%) thymic carcinomas and 49 (7%) neuroendocrine thymic tumours. Staging (Masaoka) included 483 (67%) stage I and II, 100 (14%) stage III and 70 (10%) stage IV tumours. The new International Association for the Study of Lung Cancer/International Thymic Malignancies Interest Group tumour, node and metastasis (TNM) classification was available for 224 patients and including 177 (85%) stage I-II, 37 (16%) stage IIIA and 10 (4%) stage IIIB tumours. Chemotherapy as induction and adjuvant treatment was used in 14% and 15% of the patients. Radiotherapy was almost exclusively used postoperatively (24%). A minimally invasive surgical approach (video-assisted thoracic surgery/robotic-assisted thoracic surgery) was used in 276 (33%) patients. The overall recurrence rate was 10.8% (N = 38). Compared to the ESTS retrospective database, the increased prevalence of thymic carcinomas (from 9% to 28%) and neuroendocrine thymic tumours (from 2% to 7%), an increase in the use of minimally invasive techniques (from 6% to 34%) and a wider use of chemotherapy as induction (from 9% to 15%) and adjuvant (from 2% to 16%) treatment were observed in the prospective database. The introduction of a set of variables considered essential for the data use ('minimum dataset') resulted in an increased average completeness rate. CONCLUSIONS: The reported data from the ESTS prospective thymic database confirm the recent trends in the management of thymic tumours. The ESTS prospective thymic database represents a powerful resource open to all ESTS members for the global effort to manage these rare tumours.

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