Publications by authors named "Alessandra Curioni-Fontecedro"

35 Publications

A pilot study on lung cancer detection based on regional metabolic activity distribution in digital low-dose 18F-FDG PET.

Br J Radiol 2021 Mar 2;94(1119):20200244. Epub 2021 Feb 2.

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

Objectives: To investigate the potential of automatic lung cancer detection on submillisievert dose F-fludeoxyglucose (F-FDG) scans using different positron emission tomography (PET) parameters, as a primary step towards a potential new indication for F-FDG PET in lung cancer screening.

Methods: We performed a retrospective cohort analysis with 83 patients referred for F-FDG PET/CT, including of 34 patients with histology-proven lung cancer and 49 patients without lung disease. Aside clinical standard PET images (PET) two additional low-dose PET reconstructions were generated, using only 15 s and 5 s of the 150 s list mode raw data of the full-dose PET, corresponding to 10% and 3.3% of the original F-FDG activity. The lungs were subdivided into three segments on each side, and each segment was classified as normal or containing cancer. The following standardized uptake values (SUVs) were extracted from PET per lung segment: SUV, SUV, SUV, SUV and SUV. A multivariate linear regression model was used and cross-validated. The accuracy for lung cancer detection was tested with receiver operating characteristics analysis and T-statistics was used to calculate the weight of each parameter.

Results: The T-statistics showed that SUV was the most important discriminative factor for lung cancer detection. The multivariate model achieved an area under the curve of 0.97 for full-dose PET, 0.85 for PET with PET reconstructions resulting in a still high sensitivity the PET reconstruction of 80%.

Conclusion: This pilot study indicates that segment-based, quantitative PET parameters of low-dose PET reconstructions could be used to automatically detect lung cancer with high sensitivity.

Advances In Knowledge: Automated assessment of PET parameters in low-dose PET may aid for an early detection of lung cancer.
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http://dx.doi.org/10.1259/bjr.20200244DOI Listing
March 2021

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

Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.

Nat Metab 2020 11 19;2(11):1212-1222. Epub 2020 Oct 19.

Institute of Biochemistry, Department of Biology, ETH Zurich, Zurich, Switzerland.

Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc). However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.
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http://dx.doi.org/10.1038/s42255-020-00297-0DOI Listing
November 2020

Real-World Treatment Patterns and Survival Outcome in Advanced Anaplastic Lymphoma Kinase (ALK) Rearranged Non-Small-Cell Lung Cancer Patients.

Front Oncol 2020 21;10:1299. Epub 2020 Aug 21.

Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Survival of ALK-rearranged NSCLC patients has dramatically improved by the use of multiple ALK-tyrosine kinase inhibitors (ALK-TKI). However, still little is known about the impact of drug sequencing and clinical features on survival in a real-world setting. Patients with stage IV ALK-rearranged NSCLC treated at six centers in Switzerland and Italy were identified and standard clinical variables collected. OS curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Multivariate Cox proportional hazard analysis was applied to determine the correlations between clinical features and OS. In four patients, biopsies were subjected to NGS. One-hundred and twenty-one patients with stage IV ALK-rearranged NSCLC diagnosed between 2011 and 2016 were included. With a median follow-up time of 39.5 months, the median OS from diagnosis of stage IV disease was 48.0 months. First-line treatment consisted of an ALK-TKI in 24% of patients, with crizotinib in 83% of them. Chemotherapy as first-line treatment did not influence OS ( = 0.955). The use of more than one ALK-TKI line positively correlated with OS ( = 0.016), as well as the use of alectinib or lorlatinib in any treatment line, as compared to the use of crizotinib ± ceritinib ( = 0.022). A never smoking history was an independent prognostic factor for OS ( = 0.032). Moreover, treatment with alectinib significantly improved OS. Targeted treatment for ALK-positive NSCLC patients lead to prolonged OS. Smoking status was a negative independent prognostic factor in a multi-variate analysis. The use of alectinib or lorlatinib in any treatment line improved overall outcome.
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http://dx.doi.org/10.3389/fonc.2020.01299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472246PMC
August 2020

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

J Thorac Oncol 2020 10 18;15(10):1647-1656. Epub 2020 Jun 18.

Department for Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC.

Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate.

Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%.

Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.
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http://dx.doi.org/10.1016/j.jtho.2020.06.011DOI Listing
October 2020

Reply to Authors.

ESMO Open 2020 05;4(Suppl 2):e000809

Department of Oncology, University Hospital of Geneva, Geneva, Switzerland. Electronic address:

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http://dx.doi.org/10.1136/esmoopen-2020-000809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245396PMC
May 2020

In vitro cell culture of patient derived malignant pleural and peritoneal effusions for personalised drug screening.

J Transl Med 2020 04 10;18(1):163. Epub 2020 Apr 10.

ADMED Pathology, Rue de la Maladière 45, 2000, Neuchâtel, Switzerland.

Background: Malignant serous effusion (MSE) denotes a manifestation of metastatic disease with typical high concentrations of both cancer and immune cells, making them an ideal resource for in vitro cytologic studies. Hence, the aim of the study was to investigate the features of 2D and 3D MSE culture systems as well as their feasibilities for in vitro drug screening.

Methods: Pleural and peritoneal effusions from 8 patients were collected and processed for 2D monolayer and 3D hanging drop cell culture into GravityPLUS™ plates. Representative markers for cell components, proliferation rate and tumour classification were investigated by immunohistochemistry, followed by absolute quantification using a digitalised image analysis approach. Further, we implemented another 3D cell culture model based on a low attachment method for in vitro drug sensitivity testing of carboplatin, pemetrexed and pembrolizumab for 5 patients.

Results: Monolayer cell culture was favourable for the growth of mesothelial cells, while hanging drop culture in GravityPLUS™ plates showed better ability for preserving cancer cells, inducing positive diagnostic markers expression and restraining the growth of mesothelial cells. For in vitro drug testing, MSE from five patients presented various drug sensitivities, and one case showed strong response to PD-1 checkpoint inhibition (pembrolizumab). For some patients, the application of combinatorial drugs had better therapeutic responses compared to monotherapy.

Conclusions: Digitalised quantification of data offers a better understanding of different MSE culture models. More importantly, the proposed platforms are practical and amenable for performing in vitro chemo-/immunotherapeutic drug testing by using routine cytologic MSE in a personalised manner. Next to cell blocks, our work demonstrates the prognostic and predictive value of cytologic effusion samples.
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http://dx.doi.org/10.1186/s12967-020-02331-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149866PMC
April 2020

How we treat patients with lung cancer during the SARS-CoV-2 pandemic: .

ESMO Open 2020 04;5(2):e000765

Department of Oncology, University Hospital of Geneva, Geneva, Switzerland. Electronic address:

New cases of the novel coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to rise worldwide. A few reports have showed that mortality due to SARS-CoV-2 is higher in elderly patients and other active comorbidities including cancer. To date, no effective treatment has been identified and management for critically ill patients relies on management in intensive care units. Patients with lung cancer are at risk of pulmonary complications from COVID-19. Furthermore, the use of chemotherapy might have a negative impact in patient's outcome. Therefore, the risk/benefit ratio of systemic anticancer treatment (SACT) has to be considered. For each patient, several factors including age and comorbidities, as well as the number of hospital visits for treatment, can influence this risk. Each hospital around the world has issued some internal policy guidelines for oncologists, aiming to limit risks during this difficult time. We hereby propose a tool to support oncologists and physicians in treatment decision for patients with lung cancer. There are several variables to consider, including the extent of the epidemic, the local healthcare structure capacity, the risk of infection to the individual, the status of cancer, patients' comorbidities, age and details of the treatment. Given this heterogeneity, we have based our suggestions bearing in mind some general factors There is not easy, universal solution to oncological care during this crisis and, to complicate matters, the duration of this pandemic is hard to predict. It is important to weigh the impact of each of our decisions in these trying times rather than rely on routine automatisms.
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http://dx.doi.org/10.1136/esmoopen-2020-000765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211064PMC
April 2020

18F-FET PET for Diagnosis of Pseudoprogression of Brain Metastases in Patients With Non-Small Cell Lung Cancer.

Clin Nucl Med 2020 Feb;45(2):113-117

From the Departments of Medical Oncology and Hematology.

Purpose: To evaluate whether F-fluoroethyltyrosine (FET) PET can discriminate progression from pseudoprogression of brain metastases in patients with non-small cell lung cancer undergoing immunotherapy and radiotherapy to the brain.

Methods: Retrospective analysis of F-FET PET scans in cases with documented progression of brain metastases on MRI in a cohort of 53 patients with non-small cell lung cancer receiving immune-checkpoint inhibitors and radiotherapy of brain metastases at the University Hospital of Zürich from June 2015 until January 2019. Response to radiotherapy was assessed by MRI. In case of equivocal findings and/or radiological progression in clinically asymptomatic patients, further assessment with F-FET PET was performed.

Results: From the cohort of 53 patients, the restaging MRI showed in 30 patients (56.6%) progression of at least 1 treated metastasis. Thereof, F-FET PET was performed in 11 patients, based on the absence of neurological symptoms or presence of systemic response and physicians' decision. F-FET PET correctly identified pseudoprogression in 9 of 11 patients (81.8%). In patients who did not undergo F-FET PET, 5 of 19 (26.3%) were diagnosed with pseudoprogression.

Conclusions: Pseudoprogression of brain metastases occurred in 50% of patients diagnosed with progression on MRI. F-FET PET may help differentiate pseudoprogression from real progression in order to avoid discontinuation of effective therapy or unneeded interventions.
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http://dx.doi.org/10.1097/RLU.0000000000002890DOI Listing
February 2020

Evolution and Clinical Impact of EGFR Mutations in Circulating Free DNA in the BELIEF Trial.

J Thorac Oncol 2020 03 5;15(3):416-425. Epub 2019 Dec 5.

Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Barcelona, Spain.

Introduction: Longitudinal evaluation of mutations in blood samples was a prespecified secondary objective in the BELIEF trial of erlotinib and bevacizumab in advanced EGFR-positive NSCLC. Here, we report the testing results and explore the correlation of EGFR status in blood with clinical outcomes.

Methods: Blood samples were prospectively collected from patients at baseline, at response evaluation, and at progression and sent to a central laboratory. Circulating free DNA was purified and EGFR mutations were analyzed with a validated real-time quantitative polymerase chain reaction assay.

Results: EGFR exon 19/21 mutations were detected in 55 of 91 baseline blood samples (60.4%) and correlated with a significantly worse progression-free survival: 11.4 months (95% confidence interval [CI]: 9.0-14.8 mo) for the patients who were positive versus 22.9 months (95% CI: 9.5-33.9 mo) for those who were negative (log-rank p = 0.0020). Among the 74 samples at response, exon 19/21 mutations were detected only in three samples (4.1%). In contrast, 29 of 58 patients (50.0%) were exon 19/21 positive at progression and showed a significantly worse median overall survival of 21.7 months (95% CI: 17.0-30.9 mo) compared with 37.4 months (95% CI: 22.6-53.1 mo) for those who were negative (log-rank p = 0.011). Blood samples at the three time points were available for 48 patients. Of those, among 14 exon 19/21 EGFR-negative at presentation, 13 (93%) were persistently negative for the sensitizing mutations after progression and the p.T790M could only be detected in the blood of two patients.

Conclusions: Longitudinal testing of EGFR mutations in blood can offer valuable clinical information. In patients of the BELIEF study, detection of EGFR mutations in circulating free DNA at presentation was associated with shorter progression-free survival, whereas positivity at progression correlated with shorter overall survival. Finally, patients negative in blood at presentation were almost invariably negative at relapse.
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http://dx.doi.org/10.1016/j.jtho.2019.11.023DOI Listing
March 2020

Predictive impact of antibiotics in patients with advanced non small-cell lung cancer receiving immune checkpoint inhibitors : Antibiotics immune checkpoint inhibitors in advanced NSCLC.

Cancer Chemother Pharmacol 2020 01 19;85(1):121-131. Epub 2019 Nov 19.

University of Basel, Basel, Switzerland.

Purpose: In this study, we test the hypothesis that the use of ATB reduces the efficacy of PD(L)1-targeting mAb.

Methods: We included patients with locally advanced, inoperable or metastatic, EGFR wildtype and ALK-negative non-small-cell lung cancer (NSCLC) who received a PD(L)1 targeting mAb (immune checkpoint inhibitor, ICI) between January 2013 and December 2017. The primary study objective was to assess the predictive impact of ATB use within 2 months prior to starting ICI treatment on overall survival from the time of starting ICI treatment (OS-ICI).

Results: 33 out of 218 evaluable patients (15.1%) received ATB within 2 months prior to starting ICI treatment. The use of ATB prior to starting ICI was associated with a lower rate of radiological response (18.2 vs. 28.3%, respectively, P = 0.02). PFS was significantly shorter in patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median PFS 1.4 vs. 5.5 months, HR = 2.22, P < 0.01). OS-ICI was significantly shorter in NSCLC patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median OS-ICI 1.8 vs. 15.4 months, HR = 2.61, P < 0.01; adjusted HR = 3.73, P < 0.01).

Conclusion: The results of this study suggest that ATB may have a deleterious effect in patients with advanced NSCLC receiving ICI treatment, and more research seems to be justified to explore potential mechanisms.
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http://dx.doi.org/10.1007/s00280-019-03993-1DOI Listing
January 2020

Adjuvant Chemotherapy Increases Programmed Death-Ligand 1 (PD-L1) Expression in Non-small Cell Lung Cancer Recurrence.

Clin Lung Cancer 2019 09 5;20(5):391-396. Epub 2019 Jun 5.

Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cllc.2019.05.013DOI Listing
September 2019

Melanoma patients with additional primary cancers: a single-center retrospective analysis.

Oncotarget 2019 May 21;10(36):3373-3384. Epub 2019 May 21.

Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.

Recent progress in the diagnosis and treatment of primary and metastatic cutaneous melanoma (CM) has led to a significant increase in the patients` expectancy of life. The development of additional primary tumors (APT) other than CM represents an important survival issue. Of a total of 1764 CM patients, 80 (4.5%) patients developed APT. For tumors diagnosed after CM, there was a 2.7 fold excess risk for APT compared to the swiss german population. A significantly increased risk was noted for female breast (SIR, 2.46), male larynx (SIR, 76.92), male multiple myeloma (SIR, 11.2), male oesophagus (SIR, 10.8) and thyroid on males (SIR, 58.8) and females (SIR, 38.1). All thyroid cancer cases had a common papillary histological subtype and a high rate of BRAFV600E mutation. Melanoma was the primary cause of death in the vast majority of patients. We used the cancer registry from the Comprehensive Cancer Center Zurich (CCCZ) and retrospectively analyzed patients with CM and APT between 2008 and 2018. We calculated the risk of APT compared to the swiss german population using the standardized incidence ratio (SIR). Patients with CM have an increased risk for hematologic and solid APT. Long-term follow-up is indicated.
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http://dx.doi.org/10.18632/oncotarget.26931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534365PMC
May 2019

Preoperative chemotherapy and radiotherapy concomitant to cetuximab in resectable stage IIIB NSCLC: a multicentre phase 2 trial (SAKK 16/08).

Br J Cancer 2019 05 16;120(10):968-974. Epub 2019 Apr 16.

University Hospitals of Vaud, Lausanne, Switzerland.

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/m and docetaxel 85 mg/m d1, q3w) followed by RT (44 Gy in 22 fractions) with concomitant cetuximab (250 mg/m, 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.
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http://dx.doi.org/10.1038/s41416-019-0447-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734655PMC
May 2019

Automated detection of lung cancer at ultralow dose PET/CT by deep neural networks - Initial results.

Lung Cancer 2018 12 3;126:170-173. Epub 2018 Nov 3.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Switzerland. Electronic address:

Objectives: We evaluated whether machine learning may be helpful for the detection of lung cancer in FDG-PET imaging in the setting of ultralow dose PET scans.

Materials And Methods: We studied the performance of an artificial neural network discriminating lung cancer patients (n = 50) from controls (n = 50) without pulmonary malignancies. A total of 3936 PET slices including images in which the lung tumor is visually present and image slices of patients with no lung cancer were exported. The diagnostic performance of the artificial neural network based on clinical standard dose PET images (PET) as well as with a tenfold (PET) and thirtyfold (PET) reduced radiation dose (∼0.11 mSv) was assessed.

Results: The area under the curve of the deep learning algorithm for lung cancer detection was 0.989, 0.983 and 0.970 for standard dose images (PET), and reduced dose PET, and PET reconstruction, respectively. The artificial neural network achieved a sensitivity of 95.9% and 91.5% and a specificity of 98.1% and 94.2%, at standard dose and ultralow dose PET, respectively.

Conclusion: Our results suggest that machine learning algorithms may aid fully automated lung cancer detection even at very low effective radiation doses of 0.11 mSv. Further improvement of this technology might improve the specificity of lung cancer screening efforts and could lead to new applications of FDG-PET.
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http://dx.doi.org/10.1016/j.lungcan.2018.11.001DOI Listing
December 2018

Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients.

Clin Cancer Res 2018 12 28;24(24):6345-6354. Epub 2018 Aug 28.

Department of Hematology and Oncology, University Hospital Zurich, Zurich, Switzerland.

Purpose: Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment.

Experimental Design: We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options.

Results: The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a preclinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Furthermore, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two patients with mesothelioma, who were resistant to gemcitabine or anti-PD-1 as monotherapy.

Conclusions: Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared with single treatment in the absence of steroids.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1231DOI Listing
December 2018

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program.

J Thorac Oncol 2018 12 7;13(12):1897-1905. Epub 2018 Aug 7.

Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

Introduction: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup.

Methods: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC.

Results: Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six).

Conclusions: This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.
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http://dx.doi.org/10.1016/j.jtho.2018.07.093DOI Listing
December 2018

Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer.

Radiat Oncol 2018 May 31;13(1):102. Epub 2018 May 31.

Department of Hematology and Oncology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.

Background: The existence of abscopal effects has been suggested already a long time ago, but only recently with the advent of immune checkpoint inhibition in clinical oncology and modern imaging techniques has it become possible to directly observe such effects in patients. They have been well described in patients with malignant melanoma being treated with immune-checkpoint inhibitors and stereotactic radiotherapy, but experience in other malignancies is very limited.

Case Presentation: Here, we describe a case of a patient with metastatic non-small cell lung cancer, who experienced a complete response secondary to an abscopal effect on treatment with anti-PD-1 therapy and stereotactic body radiotherapy to some of the involved sites.

Conclusions: Our case reports confirms the existence of abscopal effects in NSCLC and suggests synergism between immune-checkpoint inhibition and local ablative RT. We suggest that this approach is now further studied in prospective clinical trials on oligo-metastatic or oligo-progressing NSCLC.
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http://dx.doi.org/10.1186/s13014-018-1049-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984389PMC
May 2018

Germinal Centers Determine the Prognostic Relevance of Tertiary Lymphoid Structures and Are Impaired by Corticosteroids in Lung Squamous Cell Carcinoma.

Cancer Res 2018 03 26;78(5):1308-1320. Epub 2017 Dec 26.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13 perivascular and CXCL12LTB and PD-L1 epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naïve LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment. Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1987DOI Listing
March 2018

A new era of oncology through artificial intelligence.

ESMO Open 2017 15;2(2):e000198. Epub 2017 May 15.

Hematology and Oncology, Division of Oncology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1136/esmoopen-2017-000198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519782PMC
May 2017

Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

Lancet Respir Med 2017 05 10;5(5):435-444. Epub 2017 Apr 10.

University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. Electronic address:

Background: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation.

Methods: BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028.

Findings: Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis.

Interpretation: The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations.

Funding: European Thoracic Oncology Platform, Roche.
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http://dx.doi.org/10.1016/S2213-2600(17)30129-7DOI Listing
May 2017

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

J Thorac Oncol 2017 04 23;12(4):752-762. Epub 2016 Dec 23.

Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

Introduction: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial.

Methods: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC.

Results: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events.

Conclusions: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).
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http://dx.doi.org/10.1016/j.jtho.2016.12.017DOI Listing
April 2017

Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma.

PLoS One 2016 28;11(1):e0147682. Epub 2016 Jan 28.

Department of Gastroenterology and Hepatology, UniversityHospital Zurich, Zurich, Switzerland.

High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147682PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731059PMC
July 2016

Mutant HRAS as novel target for MEK and mTOR inhibitors.

Oncotarget 2015 Dec;6(39):42183-96

Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an impact on viability. However, inhibition of mTOR or combined inhibition of MEK and mTOR reduced cell growth in a synergistic manner. Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition. Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.
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http://dx.doi.org/10.18632/oncotarget.5619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747218PMC
December 2015

Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort.

J Thorac Oncol 2015 Oct;10(10):1451-7

*Tumorzentrum, Luzerner Kantonsspital, Luzern, Switzerland; †Hôpital Larrey, Centre Hospital-Universitaire, Université Paul Sabatier, Toulouse, France; ‡Institut Claudius Regaud IUCT-O, Toulouse, France; §Institut Gustave Roussy, Villejuif, France; ¶VU University Medical Center, Amsterdam, The Netherlands; ‖Center of Integrated Oncology Cologne, University Hospital Cologne, Cologne, Germany; #Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; **Onkologie/Hämatologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; ††Medizinische Klinik, St. Claraspital, Basel, Switzerland; ‡‡Service de pneumologie et oncologie thoracique, Hopital Universitaire, Caen, France; §§University Hospital Essen, Essen, Germany; ¶¶University Hospital Zurich, Zurich, Switzerland; ‖‖Clinique Teissier, Valenciennes, France; ##Centre Hospitalier Intercommunal de Creteil, Créteil, France; ***University Hospital Innsbruck, Innsbruck, Austria; †††University Hospital Basel, Basel, Switzerland; ‡‡‡Heidelberg University Medical Center, Mannheim, Germany; §§§Hopital du Haut Lévèque, Pessac, France; ¶¶¶Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and ‖‖‖Centre Hospitalier Universitaire, Université de Caen-Basse Normandie, Caen, France.

Introduction: Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials.

Methods: We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1.

Results: We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42-85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months.

Conclusions: These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.
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http://dx.doi.org/10.1097/JTO.0000000000000625DOI Listing
October 2015

Chromosomal aberrations of cancer-testis antigens in myeloma patients.

Hematol Oncol 2015 Sep 13;33(3):159-63. Epub 2014 May 13.

Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

Cancer-testis antigens (CTAgs) play a major role in the immune response against cancer, but their biological functions in germ and cancer cells is still unclear. MAGE-C1 and MAGE-C2 are two CTAgs located at the Xq27 region of chromosome X and frequently expressed in multiple myeloma. Chromosomal rearrangements often occur in myeloma. We therefore investigated whether numerical and structural chromosomal aberrations correlate with their protein expression in primary multiple myelomas. To this aim, we designed new fluorescence in situ hybridization probes specific for the MAGE region in the Xq27 region and evaluated simultaneously aberrations of the X chromosome centromere. The comparison of MAGE copy number and chromosome X status revealed that MAGE copy number changes occurred in 6/43 (14%) cases, independent of concomitant X chromosome alterations. These numerical aberrations are less frequent than the expression of MAGE-C1 and MAGE-C2 (63% and 27% of patients, respectively) and do not always correlate with MAGE-C1 and MAGE-C2 expressions, suggesting alternative regulatory mechanisms in the expression of these genes.
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http://dx.doi.org/10.1002/hon.2143DOI Listing
September 2015

An Aggressive Hypoxia Related Subpopulation of Melanoma Cells is TRP-2 Negative.

Transl Oncol 2014 Apr 17;7(2):206-12. Epub 2014 Apr 17.

Institute of Surgical Pathology, University Hospital, Zurich, Switzerland. Electronic address:

Despite existing vaccination strategies targeting TRP-2, its function is not yet fully understood. TRP-2 is an enzyme involved in melanin biosynthesis and therefore discussed as a differentiation antigen. However, in mice Trp-2 was shown to be expressed in melanocyte stem cells of the hair follicle and therefore also considered as an indicator of stemness. A proper understanding of the TRP-2 function is crucial, considering a vaccination targeting cells with stemness properties would be highly effective in contrast to a therapy targeting differentiated melanoma cells. Analysing over 200 melanomas including primaries, partly matched metastases and patients' cell cultures we show that TRP-2 is correlated with Melan A expression and decreases with tumor progression. In mice it is expressed in differentiated melanocytes as well as in stem cells. Furthermore, we identify a TRP-2 negative, proliferative, hypoxia related cell subpopulation which is significantly associated with tumor thickness and diseases progression. Patients with a higher percentage of those cells have a less favourable tumor specific survival. Our findings underline that TRP-2 is a differentiation antigen, highlighting the importance to combine TRP-2 vaccination with other strategies targeting the aggressive undifferentiated hypoxia related subpopulation.
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http://dx.doi.org/10.1016/j.tranon.2014.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101291PMC
April 2014

The combined expression of the stromal markers fibronectin and SPARC improves the prediction of survival in diffuse large B-cell lymphoma.

Exp Hematol Oncol 2013 Oct 8;2(1):27. Epub 2013 Oct 8.

Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

Background: In diffuse large B-cell lymphomas, gene expression profiling studies attributed a major biologic role to non-neoplastic cells of the tumour microenvironment as its composition and characteristics were shown to predict survival. In particular, the expression of selected genes encoding components of the extracellular matrix was reported to be associated with clinical outcome. Nevertheless, the translation of these data into robust, routinely applicable immunohistochemical markers is still warranted. Therefore, in this study, we analysed the combination of the expression of the extracellular matrix components Fibronectin and SPARC on formalin-fixed paraffin embedded tissue derived from 173 patients with DLBCL in order to recapitulate gene expression profiling data.

Results: The expression of Fibronectin and SPARC was detected in 77/173 (44.5%) and 125/173 (72.3%) cases, respectively, and 55/173 (31.8%) cases were double positive. Patients with lymphomas expressing Fibronectin showed significantly longer overall survival when compared to negative ones (6.3 versus 3.6 years). Moreover, patients with double positive lymphomas also presented with significantly longer overall survival when compared with the remaining cases (11.6 versus 3.6 years) and this combined expression of both markers results in a better association with overall survival data than the expression of SPARC or Fibronectin taken separately (Hazard ratio 0.41, 95% confidence interval 0.17 to 0.95, p = 0.037). Finally, neither Fibronectin nor SPARC expression was associated with any of the collected clinico-pathological parameters.

Conclusions: The combined immunohistochemical assessment of Fibronectin and SPARC, two components of the extracellular matrix, represents an important tool for the prediction of survival in diffuse large B-cell lymphomas. Our study suggests that translation of gene expression profiling data on tumour microenvironment into routinely applicable immunohistochemical markers is a useful approach for a further characterization of this heterogeneous type of lymphoma.
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http://dx.doi.org/10.1186/2162-3619-2-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852975PMC
October 2013