Publications by authors named "Walter Weder"

315 Publications

Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma.

Cancer Imaging 2021 Aug 3;21(1):48. Epub 2021 Aug 3.

Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Objectives: Tumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients' survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS).

Methods: Between 09/2013-08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median.

Results: Median pathological tumor volume (pTV) and pTW were 530 ml [130 ml - 1000 ml] and 485 mg [95 g - 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0-238.0), median cTT was 9.0 mm (6.2-13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS.

Conclusion: Preoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.
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http://dx.doi.org/10.1186/s40644-021-00415-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330125PMC
August 2021

Two centres experience of lung cancer resection in patients with advanced non-small cell lung cancer upon treatment with immune checkpoint inhibitors: safety and clinical outcomes.

Eur J Cardiothorac Surg 2021 Jul 31. Epub 2021 Jul 31.

Department of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA, USA.

Objectives: Recent trials have begun to explore immune checkpoint inhibitors for non-small cell lung cancer in the neoadjuvant setting, but data on tumour response and surgical outcome remain limited.

Methods: Retrospective evaluation of clinical data from patients with non-small cell lung cancer treated with immune checkpoint inhibitors followed by lung resection was performed at 2 large volume institutions (1 North American, 1 European). Data were analysed using Chi-squared, Fisher's and Wilcoxon rank-sum tests where appropriate.

Results: Thirty-seven patients were identified from 2017 to 2019. Forty-nine per cent were Stage IIIB and IV. Forty-six per cent received immunotherapy alone and 54% in combination with chemo- and/or radiotherapy. Sixteen per cent of cases were successfully performed minimally invasively. Twenty patients were operated with lobectomy (6 of these with wedges or segments of a neighbouring lobe, 2 with sleeve resections and 1 with a chest wall resection), 4 with bilobectomies, 11 with pneumonectomy (including 5 extrapleural pneumonectomies and 1 atrial resection) and 1 with a wedge resection. Overall, 10 patients (27%) developed postoperative complications and the 90-day mortality was zero. One-year recurrence-free survival was 73% for stage II/IIIA and 55% for stage IIIB/stage IV. The major pathologic response rate was 34%.

Conclusion: In this retrospective study, lung resection after immunotherapy (alone or in combination) is safe, although often requires complex surgery. Due to increasing number of clinical trials adopting immunotherapy in the neoadjuvant setting, it is likely that this therapy will become part of standard of care. Immunotherapy may also allow surgery to have a role for selected patients with advanced disease.
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http://dx.doi.org/10.1093/ejcts/ezab340DOI Listing
July 2021

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for -mutated resectable non-small-cell lung cancer: NeoADAURA.

Future Oncol 2021 Jul 19. Epub 2021 Jul 19.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center & Weill Cornell Medical College, New York, NY 10021, USA.

Osimertinib is a third-generation, irreversible oral EGFR-tyrosine kinase inhibitor), that potently inhibits EGFR-tyrosine kinase inhibitor-sensitizing mutations and T790M resistance mutations together with efficacy in CNS metastases in patients with non-small-cell lung cancer (NSCLC). Here we describe the rationale and design for the Phase III NeoADAURA study (NCT04351555), which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery, in patients with resectable stage II-IIIB N2 mutation-positive NSCLC. The primary end point is centrally assessed major pathological response at the time of resection. Secondary end points include event-free survival, pathological complete response, nodal downstaging at the time of surgery, disease-free survival, overall survival and health-related quality of life. Safety and tolerability will also be assessed. Trial Registration number: NCT04351555 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2021-0549DOI Listing
July 2021

SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial.

J Clin Oncol 2021 Sep 12;39(26):2872-2880. Epub 2021 Jul 12.

Department of Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland.

Purpose: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab.

Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m and docetaxel 85 mg/m once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%.

Results: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related.

Conclusion: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.
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http://dx.doi.org/10.1200/JCO.21.00276DOI Listing
September 2021

Thymomectomy plus total thymectomy versus simple thymomectomy for early-stage thymoma without myasthenia gravis: a European Society of Thoracic Surgeons Thymic Working Group Study.

Eur J Cardiothorac Surg 2021 May 23. Epub 2021 May 23.

Department of Thoracic Surgery, Zurich University Hospital, Zurich, Switzerland.

Objectives: Resection of thymic tumours including the removal of both the tumour and the thymus gland (thymothymectomy; TT) is the procedure of choice and is recommended in most relevant articles in the literature. Nevertheless, in recent years, some authors have suggested that resection of the tumour (simple thymomectomy; ST) may suffice from an oncological standpoint in patients with early-stage thymoma who do not have myasthenia gravis (MG) (non-MG). The goal of our study was to compare the short- and long-term outcomes of ST versus TT in non-MG early-stage thymomas using the European Society of Thoracic Surgeons thymic database.

Methods: A total of 498 non-MG patients with pathological stage I thymoma were included in the study. TT was performed in 466 (93.6%) of 498 patients who had surgery with curative intent; ST was done in 32 (6.4%). The completeness of resection, the rate of complications, the 30-day mortality, the overall recurrence and the freedom from recurrence were compared. We performed crude and propensity score-adjusted comparisons by surgical approach (ST vs TT).

Results: TT showed the same rate of postoperative complications, 30-day mortality and postoperative length of stay as ST. The 5-year overall survival rate was 89% in the TT group and 55% in the ST group. The 5-year freedom from recurrence was 96% in the TT group and 79% in the ST group.

Conclusion: Patients with early-stage thymoma without MG who have a TT show significantly better freedom from recurrence than those who have an ST, without an increase in postoperative morbidity rate.
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http://dx.doi.org/10.1093/ejcts/ezab224DOI Listing
May 2021

Lung Volume Reduction Surgery in Patients with Homogeneous Emphysema.

Thorac Surg Clin 2021 May;31(2):203-209

Department of Thoracic Surgery, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.

Randomized controlled trials have demonstrated that lung volume reduction surgery (LVRS) improves exercise capacity, lung function, and quality of life in patients with heterogenous emphysema on computed tomographic and perfusion scan. However, most patients have a nonheterogenous type of destruction. These patients, summarized under "homogeneous emphysema," may also benefit from LVRS as long they are severely hyperinflated, and adequate function is remaining with a diffusing capacity of the lungs for carbon monoxide greater than 20% and no pulmonary hypertension. Surgical mortality is low when patients are well selected.
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http://dx.doi.org/10.1016/j.thorsurg.2021.02.007DOI Listing
May 2021

Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer.

Nat Rev Clin Oncol 2021 09 28;18(9):547-557. Epub 2021 Apr 28.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.
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http://dx.doi.org/10.1038/s41571-021-00501-4DOI Listing
September 2021

CD26 as a target against fibrous formation in chronic airway rejection lesions.

Life Sci 2021 Aug 21;278:119496. Epub 2021 Apr 21.

Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Aims: Chronic lung allograft dysfunction (CLAD) after lung transplantation (Tx) is the clinical result of chronic airway rejection lesions (CARL), histomorphologically described as either obliterative remodeling of small airways or alveolar fibroelastosis, or as a combination of both. We here investigated the CD26-inhibitory effect on CD26-expressing CARL.

Main Methods: CARL were induced by BALB/c → C57BL/6 mouse Tx under mild immunosuppression. CARL-related pro-fibrotic mediators were determined by RT-qPCR and western blotting (WB), EMT and ERK markers by WB. CD26 co-expression by immunofluorescence. CD26 was inhibited by Vildagliptin, gene depleted by CD26 mice. Primary lung fibroblasts were employed for ex vivo analyses. Samples from lung transplant patients with CLAD were analyzed by immunohistochemistry.

Key Findings: CARL revealed a significantly higher expression of profibrotic proteins vs. normal lungs (p < 0.05). CD26 and EMT co-expressed in CARL with significantly higher Vimentin, Slug, Hif-1α, α-SMA expression vs. normal lungs (p < 0.05). Vildagliptin decreased the expression of α-SMA and N-cadherin in wild type (WT) lung fibroblasts (p < 0.05). Primary lung fibroblasts from WT and CD26 mice treated with TGF-β1, IFN-γ, and FGF showed a reduction of EMT protein expression, proliferation, and reduced activation of ERK in CD26 mice vs. WT mice. CD26-positive cells were found in patient samples with CLAD in areas of loose fibrosis, but not in areas of dense fibrosis.

Significance: CD26 is expressed in CARL-developing lung transplants and CD26-inhibition downregulates fibrosis-forming mediators and fibroblast proliferation. CD26 thus qualifies as a target to attenuate the development of CARL mainly via modulation of ERK and the EMT pathway.
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http://dx.doi.org/10.1016/j.lfs.2021.119496DOI Listing
August 2021

Lymphovascular invasion is an independent prognostic factor for survival in pathologically proven N2 non-small cell lung cancer.

Swiss Med Wkly 2021 Feb 4;151:w20385. Epub 2021 Feb 4.

Department of Thoracic Surgery, University Hospital of Zurich, Switzerland.

Background: We aimed to analyse the nodal spread of our non-small cell lung cancer pN2 cohort according to tumour location, the possible implications of an unusual spreading pattern, and other factors influencing postoperative survival after anatomical lung resection.

Methods: In this retrospective observational study, clinical data was collected for 124 consecutive non-small cell lung cancer (NSCLC) patients with a pathological N2 (stage IIIA or B) undergoing anatomical lung resection at our institution between 2001 and 2010. Cox regression was used to analyse independent predictors of 5-year overall survival and recurrence-free survival.

Results: A total of 105 patients were included in the final analysis. Tumour location in the right upper lobe and middle lobe  was significantly more often associated with involvement of lymph node stations 2 and 4 than NSCLC in the right lower lobe (station 2: right upper vs right lower lobe, p = 0.001 and middle vs right lower lobe, p = 0.038; station 4: right upper vs right lower lobe, p<0.001 and middle vs right lower lobe, p = 0.056), while tumours in the right upper lobe showed significantly less involvement of stations 7 and 8 compared with right lower lobe tumours (station 7 p <0.001, station 8 p = 0.004). Left sided tumours in the upper lobe had significantly more involvement of station 5 compared to lower lobe tumours (p = 0.009). However, atypical lymphatic nodal zone involvement did not emerge as a significant predictor of survival. Lymphovascular invasion was the only independent prognostic factor for 5-year overall survival (hazard ratio [HR] 2.10, p = 0.015) and recurrence-free survival (HR 1.68, p = 0.049) when controlled for adjuvant therapy.

Conclusion: Lymphovascular invasion was identified as the only independent prognostic factor for 5-year overall survival and recurrence-free survival in our pathologically proven N2 NSCLC cohort when controlled for adjuvant therapy. This study extends the current evidence of an adverse prognostic effect of lymphovascular invasion on a stage III population, confirms the adverse prognostic effect of lymphovascular invasion detected by immunohistochemistry, and thereby reveals another subgroup within the pN2 population with worse prognosis regarding 5-year overall survival and recurrence-free survival.  .
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http://dx.doi.org/10.4414/smw.2021.20385DOI Listing
February 2021

Robotic-assisted thoracoscopic surgery for clinically stage IIIA (c-N2) NSCLC-is it justified?

Transl Lung Cancer Res 2021 Jan;10(1):1-4

Department of Thoracic Surgery, University Hospital Zurich, Zürich, Switzerland.

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http://dx.doi.org/10.21037/tlcr-20-647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867792PMC
January 2021

Alterations in Are Associated with Cisplatin Resistance through Inhibition of Apoptosis in Malignant Pleural Mesothelioma.

Clin Cancer Res 2021 Apr 5;27(8):2277-2291. Epub 2021 Feb 5.

Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.

Purpose: The clinical standard treatment for patients with malignant pleural mesothelioma (MPM) includes a cisplatin-based chemotherapy, leading to reduction of tumor size in only a minority of patients. Predicting response to chemotherapy in patients with MPM by using a genetic marker would, therefore, enable patient stratification.

Experimental Design: In this retrospective biomarker study, eligible patients had resectable MPM, measurable disease, and available primary MPM tissue. All patients underwent first-line treatment with cisplatin and pemetrexed, followed by surgery. Thorough molecular analysis was performed (whole-exome and targeted deep sequencing, and copy-number analyses), and also mechanistic data (viability assays, Western blots, and immunoprecipitation) using mesothelioma cell lines with and without siRNA-mediated BRCA1-associated protein 1 (BAP1) knockdown were provided.

Results: In a training cohort of patients with MPM ( = 28), mutations or deletions of each predicted resistance to chemotherapy in patients with primary MPM. The negative predictive value of loss in patients with MPM was confirmed by amplicon sequencing and copy-number array technology in an independent test cohort ( = 39). Preliminary mechanistic studies using siRNA-based knockdown of BAP1 in MPM cell culture models along with immunoprecipitation assays confirmed chemoresistance , possibly through inhibition of apoptosis and transcriptional regulation of the BAP1/HCF1/E2F1 axis.

Conclusions: Alterations in in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4037DOI Listing
April 2021

Long-Term Outcomes of Cadaveric Lobar Lung Transplantation: An Important Surgical Option.

Ann Thorac Cardiovasc Surg 2021 Aug 20;27(4):244-250. Epub 2021 Jan 20.

Department of Thoracic Surgery, Zurich University Hospital, University of Zurich, Zurich, Switzerland.

Background: Cadaveric lobar lung transplantation (L-LTx) is developed to overcome donor-recipient size mismatch. Controversial short- and long-term outcomes following L-LTx have been reported compared to full-sized lung transplantation (F-LTx). This study reports long-term outcomes after L-LTx.

Methods: We reviewed patients undergoing lung transplantation (LTx) between 2000 and 2016. The decision to perform L-LTx was made based mainly on donor-recipient height discrepancy and visual assessment of donor lungs. Predicted donor-recipient total lung capacity (TLC) ratio was calculated more recently. Primary outcome was overall survival.

Results: In all, 370 bilateral LTx were performed during the study period, among those 250 (67%) underwent F-LTx and 120 (32%) underwent L-LTx, respectively. One- and 5-year survival rates were 85% vs. 90% and 53% vs. 63% for L-LTx and F-LTx, respectively (p = 0.16). Chronic lung allograft dysfunction (CLAD)-free survival at 5 years was 48% in L-LTx vs. 51% in F-LTx recipients (p = 0.89), respectively. Age, intraoperative extracorporeal membrane oxygenation (ECMO) use, intensive care unit (ICU) stay, and postoperative renal replacement therapy (RRT) were significant prognostic factors for survival using multivariate analysis.

Conclusions: Overall survival and CLAD-free survival following L-LTx were comparable to F-LTx. Given the ongoing donor organ shortage, cadaveric L-LTx remains as an important resource in LTx.
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http://dx.doi.org/10.5761/atcs.oa.20-00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374092PMC
August 2021

Postoperative outcome of tracheal resection in benign and malignant tracheal stenosis.

Swiss Med Wkly 2020 Dec 30;150:w20383. Epub 2020 Dec 30.

Department of Thoracic Surgery, University Hospital of Zürich, Switzerland.

Background: Tracheal or cricotracheal resection is the standard of care for definitive treatment of tracheal stenosis. However, the incidence is low, the management is complex, and only a few centres have reported their experience. Therefore, more clinical reports on this topic are needed.

Methods: We performed a retrospective analysis of all patients who underwent tracheal or cricotracheal resection for malignant or benign tracheal stenosis in our institution between 2001 and 2016. Fisher’s exact test was used for analysis of complications and recurrence. P-value <0.05 was considered statistically significant.

Results: 37 patients, aged 19–74, underwent tracheal (n = 21, 56.8%) or cricotracheal (n = 16, 43.2%) resection for idiopathic (n = 15, 40.5%), neoplasm-related (n = 11, 29.7%), postintubation/-tracheotomy (n = 10, 27%), and congenital (n = 1, 2.7%) stenosis. Cervical incision was applied in 28 patients (75.7%), and an extended access (5 thoracotomy, 3 hemiclamshell, 1 partial-sternotomy) was required in 9 patients (24.3%). Mediastinal lymphadenectomy was done in 7 patients (18.9%), all with neoplasm-related stenosis. Median resection length was 2.8 cm (range 1.0–6.0), and longer than 4.0 cm in 6 cases (16.2%). Release manoeuvre was performed in 7 patients (18.9%). All patients were extubated immediately after surgery and median hospital stay was 5 days (range 3–15). Median follow-up was 6 months (range, 1-93). There was no 30-day mortality, and no dehiscence or fistula occurred at the suture line. Complications were seen in 11 patients (29.7%), significantly correlating to malignant stenosis (p = 0.011) and surgical procedure, meaning extended access (p = 0.011), mediastinal lymphadenectomy (p = 0.016), and release manoeuvres (p = 0.016). Temporary hoarseness was the most common complication (n = 5, 13.5%), but remained persistent in only one patient (n = 1, 2.7%). Recurrence was seen only in patients with idiopathic stenosis (n = 5, 13.5%).

Conclusions: Our results confirm good efficacy for surgical resection of tracheal stenosis. The complication rate is relatively low in comparison to the literature, suggesting the importance of managing tracheal stenosis in a tertiary referral centre.
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http://dx.doi.org/10.4414/smw.2020.20383DOI Listing
December 2020

The Impact on Outcome by Adding Bevacizumab to Standard Induction Chemotherapy Prior to Mesothelioma Surgery: A Retrospective Single Center Analysis.

Front Oncol 2020 13;10:588563. Epub 2020 Nov 13.

Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Objectives: Adding bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), to platinum-based chemotherapy/pemetrexed in 1 line treatment of advanced malignant pleural mesothelioma (MPM), significantly improved overall survival. However, increased high grade bleeding after operation was reported in patients with colorectal cancer who previously received bevacizumab. In the present analysis, we assessed for the first time the impact of adding bevacizumab to induction chemotherapy prior to surgery for mesothelioma patients.

Methods: Two hundred twenty-seven MPM patients, intended to be treated with induction chemotherapy followed by surgery at the University Hospital of Zurich between 2002 and December 2018, were included in the present analysis. After propensity score matching for gender, histology and age (1:3 ratio), data from 88 patients were analyzed. Sixty-six patients underwent induction chemotherapy (with cis-/carboplatin and pemetrexed: control group) alone and 22 patients underwent induction chemotherapy with the addition of bevacizumab (bevacizumab group) prior macroscopic complete resection (MCR). Perioperative and long-term outcome variables were analyzed.

Results: Patients undergoing combination treatment with bevacizumab had a significantly better response than with chemotherapy alone as assessed by modified RECIST (p=0.046). Intraoperative complications in the bevacizumab group (one patient), or in the control group (three patients) were not related to intraoperative bleeding. Postoperative transfusion of blood products occurred in a larger amount in the control group than in the bevacizumab group (p=0.047). Overall survival was not statistically different between both groups.

Conclusion: These initial data demonstrate that MCR can be performed safely after triple induction chemotherapy with bevacizumab without increased intra- and postoperative bleeding complications. Response rates were significantly improved by the addition of bevacizumab.
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http://dx.doi.org/10.3389/fonc.2020.588563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693632PMC
November 2020

Lung volume reduction surgery as salvage procedure after previous use of endobronchial valves.

Interact Cardiovasc Thorac Surg 2021 01;32(2):263-269

Department of Pulmonary Medicine, University Hospital Zurich, Zurich, Switzerland.

Objectives: Lung volume reduction (LVR) is an efficient and approved treatment for selected emphysema patients. There is some evidence that repeated LVR surgery (LVRS) might be beneficial, but there are no current data on LVRS after unsuccessful bronchoscopic LVR (BLVR) with endobronchial valves (EBVs). We hypothesize good outcome of LVRS after BLVR with valves.

Methods: In this study, we retrospectively investigated all patients who underwent LVRS between 2015 and 2019 at 2 centres after previous unsuccessful EBV treatment. They were further divided into subgroups with patients who never achieved the intended improvement after BLVR (primary failure) and patients whose benefit was fading over time due to the natural development of emphysema (secondary failure). Patients with severe air leak after BLVR and immediate concomitant LVRS and fistula closure thereafter were analysed separately.

Results: A total of 38 patients were included. Of these, 19 patients had primary failure, 15 secondary failure and 4 were treated as an emergency due to severe air leak. At 3 months after LVRS, forced expiratory volume in 1 s had improved significantly by 12.5% (P = 0.011) and there was no 90-day mortality. Considering subgroups, patients with primary failure after BLVR seem to profit more than those with secondary failure. Patients with severe air leak after BLVR did not profit from fistula closure with concomitant LVRS.

Conclusions: LVRS after previous BLVR with EBVs can provide significant clinical improvement with low morbidity, although results might not be as good as after primary LVRS.
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http://dx.doi.org/10.1093/icvts/ivaa261DOI Listing
January 2021

Is There a Prognostic Difference Between Stage IIIA Subgroups in Lung Cancer?

Ann Thorac Surg 2020 Nov 26. Epub 2020 Nov 26.

Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Background: Treatment of stage IIIA lung cancer remains controversial because it includes a very heterogeneous group of patients. The purpose of our study was to compare survival between stage IIIA subsets and to externally validate our results with another center's database.

Methods: Patients with completely resected stage IIIA/B lung cancer were retrospectively analyzed. There were 424 patients with stage IIIA and 82 patients with stage IIIB (T3/4 N2) (study cohort). Stage IIIA was divided into 2 subsets according to the tumor localization and tumor size (T3 N1-T4 N0/1, IIIA-T group; n = 308) and the extension of nodal disease (T1/2 N2, IIIA-N2 group; n = 116). The study cohort results were used to create a model for stage IIIA patients, which was validated with another center's database (validation cohort).

Results: The multivariate analyses showed age, stage IIIB, and pN2 were independent negative prognostic factors (P < .0001). Survival at 5 years was 51.3% (median, 64 months) for patients in the IIIA-T group and was 25.7% (median, 31 months) in the IIIA-N2 patients (hazard ratio, 1.834; P < .0001). There was no statistical difference in survival between the IIIA-N2 and stage IIIB groups (25.7% vs 25.3%, P = .442). The created model was performed on patients in the validation cohort as a model IIIA-T (T3 N1-T4 N0/1, n = 139) and model IIIA-N2 (T1/2 N2, n = 104). Model IIIA-T patients had a statistically better survival rate than model IIIA-N2 patients (median, 62 months vs 37 months; hazard ratio, 1.707, P < 0.001).

Conclusions: There is a prognostic difference between stage IIIA subgroups in lung cancer patients who undergo surgical treatment.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.033DOI Listing
November 2020

Functional, Metabolic and Morphologic Results of Ex Vivo Donor Lung Perfusion with a Perfluorocarbon-Based Oxygen Carrier Nanoemulsion in a Large Animal Transplantation Model.

Cells 2020 11 18;9(11). Epub 2020 Nov 18.

Institute of Anesthesiology, University Hospital Zurich-University of Zurich, CH-8091 Zurich, Switzerland.

Background: Ex vivo lung perfusion (EVLP) is a technology that allows the re-evaluation of questionable donor lung before implantation and it has the potential to repair injured donor lungs that are otherwise unsuitable for transplantation. We hypothesized that perfluorocarbon-based oxygen carrier, a novel reconditioning strategy instilled during EVLP would improve graft function.

Methods: We utilized perfluorocarbon-based oxygen carrier (PFCOC) during EVLP to recondition and improve lung graft function in a pig model of EVLP and lung transplantation. Lungs were retrieved and stored for 24 h at 4 °C. EVLP was done for 6 h with or without PFCOC. In the transplantation groups, left lung transplantation was done after EVLP with or without PFCOC. Allograft function was assessed by means of pulmonary gas exchange, lung mechanics and vascular pressures, histology and transmission electron microscopy (TEM).

Results: In the EVLP only groups, physiological and biochemical markers during the 6-h perfusion period were comparable. However, perfusate lactate potassium levels were lower and ATP levels were higher in the PFCOC group. Radiologic assessment revealed significantly more lung infiltrates in the controls than in the PFCOC group ( = 0.04). In transplantation groups, perfusate glucose consumption was higher in the control group. Lactate levels were significantly lower in the PFCOC group ( = 0.02). Perfusate flavin mononucleotide (FMN) was significantly higher in the controls ( = 0.008). Post-transplant gas exchange was significantly better during the 4-h reperfusion period in the PFCOC group ( = 0.01). Plasma IL-8 and IL-12 levels were significantly lower in the PFCOC group ( = 0.01, = 0.03, respectively). ATP lung tissue levels at the end of the transplantation were higher and myeloperoxidase (MPO) levels in lung tissue were lower in the PFCOC group compared to the control group. In the PFCOC group, TEM showed better tissue preservation and cellular viability.

Conclusion: PFCOC application is safe during EVLP in lungs preserved 24 h at 4 °C. Although this strategy did not significantly affect the EVLP physiology, metabolic markers of the donor quality such as lactate production, glucose consumption, neutrophil infiltration and preservation of mitochondrial function were better in the PFCOC group. Following transplantation, PFCOC resulted in better graft function and TEM showed better tissue preservation, cellular viability and improved gas transport.
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http://dx.doi.org/10.3390/cells9112501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698917PMC
November 2020

Identification of target zones for lung volume reduction surgery using three-dimensional computed tomography rendering.

ERJ Open Res 2020 Jul 14;6(3). Epub 2020 Sep 14.

Dept of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Background: The key issues for performing lung volume reduction surgery (LVRS) is the identification of the target zones. Recently introduced three-dimensional computed tomography rendering methods are used to identify the morphological distribution and its severity of lung emphysema by densitometry. We demonstrate a new software for emphysema imaging and show the pre- and post-operative results in patients undergoing LVRS planned based on this new technology.

Methods: A real-time three-dimensional image analysis software system was used pre- and 3 months post-operatively in five patients with heterogeneous emphysema and a single patient with homogeneous morphology scheduled for LVRS. Focus was on low attenuation areas with <950 HU, distribution on both lungs and the value of the three-dimensional images for planning surgery. Functional outcome was assessed by pulmonary function tests after 3 months.

Results: Five patients underwent bilateral LVRS and one patient had unilateral LVRS. All patients showed a median increase in forced expiratory volume in 1 s of 70% (range 30-120%), compared with baseline values. Hyperinflation (expressed as residual volume/total lung capacity ratio) was reduced by 30% (range 5-32%). In the patients with heterogeneous emphysema, the pre- and post-operative computed tomography scans and the densitometries showed a decrease in low attenuation areas by 23% (right side) and by 17% (left side), respectively.

Conclusion: We demonstrate three-dimensional computed tomography-rendered images for planning personalised remodelling of hyperinflated lungs using LVRS. This user-friendly software has the potential to assist surgeons and interventional pulmonologists to select patients and to visualise target areas in LVRS procedures.
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http://dx.doi.org/10.1183/23120541.00305-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487346PMC
July 2020

Bioengineered carina reconstruction using In-Vivo Bioreactor technique in human: proof of concept study.

Transl Lung Cancer Res 2020 Jun;9(3):705-712

Shanghai Lung Cancer Center, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.

Backgrounds: Long-segment airway defect reconstruction, especially when carina is invaded, remains a challenge in clinical setting. Previous attempts at bioengineered carina reconstruction failed within 90 days due to delayed revascularization and recurrent infection.

Methods: To establish the feasibility of carina bioengineering use In-Vivo Bioreactor technique. Uncontrolled single-center cohort study including three patients with long-segment airway lesions invading carina. Radical resection of the lesions was performed using standard surgical techniques. After resection, In-Vivo Bioreactor airway reconstruction was performed using a nitinol stent wrapped in two layers of acellularized dermis matrix (ADM). Two Port-a-Cath catheters connected to two portable peristaltic pumps were inserted between the ADM layers. The implanted bioengineered airway was continuously perfused with an antibiotic solution via the pump system. Peripheral total nucleated cells (TNCs) were harvested and seeded into the airway substitute via a Port-a-Cath twice a week for 1 month. The patients were treated as a bioreactor for in situ regeneration of their own bioengineered airway substitute.

Results: Three patients were included in the study (mean age, 54.7 years). The first patient underwent 8 cm long trachea and carina reconstruction, the second patient 6 cm long trachea, carina and main bronchus reconstruction. The third patient right main bronchus and carina reconstruction. Major morbidity included gastric retention and pneumonia. All three patients survived till last follow-up and bronchoscopy follow-up showed well-vascularized regenerated tissue without leakage.

Conclusions: In this uncontrolled study, In-Vivo Bioreactor technique demonstrated potential to be applied for long-segment trachea, carina and bronchi reconstruction. Further research is needed to assess efficacy and safety.
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http://dx.doi.org/10.21037/tlcr-20-534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354144PMC
June 2020

Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma.

Lung Cancer 2020 09 23;147:30-38. Epub 2020 Jun 23.

Department of Medical Oncology and Hematology, Cantonal Hospital, CH-9007, St. Gallen, Switzerland.

Objectives: DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD-L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC).

Materials And Methods: Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1.

Results: Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r = ‒0.422, p < 0.0001), CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42-0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68.

Conclusions: In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemo- or radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.025DOI Listing
September 2020

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

Eur Respir J 2020 06 11;55(6). Epub 2020 Jun 11.

Dept of Radiation Oncology, Kantonsspital St Gallen, St Gallen, Switzerland.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including and () for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.
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http://dx.doi.org/10.1183/13993003.00953-2019DOI Listing
June 2020

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

Eur J Cardiothorac Surg 2020 07;58(1):1-24

Unit of Thoracic Surgery, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A (p16) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pretherapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasize that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.
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http://dx.doi.org/10.1093/ejcts/ezaa158DOI Listing
July 2020

Perfusate adsorption during ex vivo lung perfusion improves early post-transplant lung function.

J Thorac Cardiovasc Surg 2021 02 20;161(2):e109-e121. Epub 2020 Feb 20.

Department of Thoracic Surgery, University Hospital Zurich-University of Zurich, Zurich, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jtcvs.2019.12.128DOI Listing
February 2021

Prognostic factors of oligometastatic non-small-cell lung cancer following radical therapy: a multicentre analysis.

Eur J Cardiothorac Surg 2020 06;57(6):1166-1172

Department of Thoracic Surgery, University Hospital of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1093/ejcts/ezz384DOI Listing
June 2020

IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy.

J Thorac Oncol 2020 05 28;15(5):709-740. Epub 2020 Jan 28.

Department of Pathology, University of Turin, Torino, Italy.

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.
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http://dx.doi.org/10.1016/j.jtho.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173999PMC
May 2020

Complex sleeve lobectomy has the same surgical outcome when compared with conventional lobectomy in patients with lung cancer.

Eur J Cardiothorac Surg 2020 05;57(5):860-866

Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1093/ejcts/ezz357DOI Listing
May 2020

Predictors of blood loss in lung transplant surgery-a single center retrospective cohort analysis.

J Thorac Dis 2019 Nov;11(11):4755-4761

Department of Anesthesiology, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland.

Background: This retrospective study aims to identify clinical predictors of intraoperative blood loss during lung transplantation. While for other surgical specialties predictors of blood loss have been identified such as previous likewise located surgery, poor preoperative health status of patients, blood coagulation status, and use of extra corporeal circulation, predictors of blood loss during lung transplantation are not yet established.

Methods: A total of 326 lung transplants were performed between January 2000 and February 2014 at a tertiary hospital. The primary aim was to associate blood loss with the following potential predictors: pulmonary arterial hypertension, pre- or intraoperative extracorporeal life support (ECLS), previous thoracic surgery, previous lung transplant, and Charlson Comorbidity Index (CCI). Postoperative complications and 30-day mortality were secondary endpoints of the study.

Results: Median estimated blood loss during lung transplant was 1,500 mL (IQR, 1,000-2,875 mL). Pre- and intraoperative ECLS (P=0.02, P<0.001) independently increased blood loss by 59% and 107%, respectively. The higher blood loss during re-transplant marginally missed the significance level (P=0.05). Pulmonary arterial hypertension, previous thoracic surgery and high CCI were not associated with increased blood loss. As secondary outcomes, postoperative complications were more common in patients with a higher blood loss (P=0.04) but was not associated with higher 30-day mortality (P=0.18).

Conclusions: Pre- and intraoperative ECLS were significant risk factors for higher blood loss during lung transplantation. Higher blood loss was associated with higher incidence of postoperative complications but not with a higher 30-day mortality.
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http://dx.doi.org/10.21037/jtd.2019.10.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940236PMC
November 2019

Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition.

Mol Cancer Ther 2020 02 16;19(2):552-563. Epub 2019 Oct 16.

Laboratory of Molecular Oncology, Lungen- und Thoraxonkologie Zentrum, University Hospital Zürich, Zürich, Switzerland.

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 -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 ( ) overexpressing C91A (catalytically dead mutant) was more resistant to RNR inhibition, while knockdown in the -proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in -proficient cell line-derived spheroids compared with deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with -WT but not with C91A. Upregulation of RRM2 in NCI-H2452- 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.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0356DOI Listing
February 2020

Stereotactic Body Radiation Therapy (SBRT) as Salvage Therapy for Oligorecurrent Pleural Mesothelioma After Multi-Modality Therapy.

Front Oncol 2019 26;9:961. Epub 2019 Sep 26.

Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

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. 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. At primary diagnosis, 57% of the patients presented with stage III disease. Initial treatment of MPM consisted of induction chemotherapy ( = 12) prior to a macroscopic complete resection ( = 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. 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.
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http://dx.doi.org/10.3389/fonc.2019.00961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775182PMC
September 2019
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