Publications by authors named "Georgios Tsakonas"

22 Publications

  • Page 1 of 1

Correlation of Clinical Parameters with Intracranial Outcome in Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Pd-1/Pd-L1 Inhibitors as Monotherapy.

Cancers (Basel) 2021 Mar 29;13(7). Epub 2021 Mar 29.

Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, 17164 Stockholm, Sweden.

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and University Hospital of Heraklion, Greece. The inclusion criteria for response assessment were brain metastases (BM) prior to ICI administration, radiological evaluation with CT or MRI for IC response assessment, PD-1/PD-L1 inhibitors as monotherapy, and no local central nervous system (CNS) treatment modalities for ≥3 months before ICI initiation. In the IC response analysis, 33 pts were included. Non-primary (BM not present at diagnosis) BM, odds ratio (OR): 13.33 (95% CI: 1.424-124.880, = 0.023); no previous brain radiation therapy (RT), OR: 5.49 (95% CI: 1.210-25.000, = 0.027); and age ≥70 years, OR: 6.19 (95% CI: 1.27-30.170, = 0.024) were associated with increased probability of IC disease progression. Two prognostic groups (immunotherapy (I-O) CNS score) were created based on the abovementioned parameters. The I-O CNS poor prognostic group B exhibited a higher probability for IC disease progression, OR: 27.50 (95% CI: 2.88-262.34, = 0.004). Age, CNS radiotherapy before the start of ICI treatment, and primary brain metastatic disease can potentially affect the IC outcome of NSCLC pts with BM.
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http://dx.doi.org/10.3390/cancers13071562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036699PMC
March 2021

High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.

Lancet Oncol 2021 03;22(3):321-331

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival.

Methods: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845.

Findings: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group).

Interpretation: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.

Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.
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http://dx.doi.org/10.1016/S1470-2045(20)30742-7DOI Listing
March 2021

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.

Acta Oncol 2021 Mar 15;60(3):305-311. Epub 2021 Jan 15.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Background And Purpose: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting.

Material And Methods: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012.

Results: We included 164 patients with 175 tumours located in the thorax ( = 86), the liver ( = 27) and the abdomen ( = 62) and treated with a median prescribed dose (BED) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax.

Conclusion: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.
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http://dx.doi.org/10.1080/0284186X.2020.1866776DOI Listing
March 2021

Effect of corticosteroids on the outcome of patients with advanced non-small cell lung cancer treated with immune-checkpoint inhibitors.

Eur J Cancer 2021 Mar 5;145:245-254. Epub 2021 Jan 5.

Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Introduction: We analysed patients with advanced non-small cell lung cancer (NSCLC) who were treated with immune-checkpoint inhibitors (ICIs) to address the effect of the timeline and reason for corticosteroid administration on survival outcomes.

Methods: We retrospectively collected clinical data of non-oncogenic driven, advanced NSCLC patients treated with ICIs at Karolinska University Hospital, including the timeline and reason for steroid administration. Steroid administration was defined as > 10 mg prednisolone equivalent for ≥10 days. We subcategorized patients based on the aetiology of steroid administration into three subgroups: a) steroids for supportive reasons but not for cancer palliation; b) steroids for the palliation of cancer-related symptoms; c) steroids for the management of immune-related adverse events (irAEs). Furthermore, to analyse the timeline, patients were categorised into two groups; those who received corticosteroids within 2 weeks before until 2 days after ICI initiation and those who received steroids later during their treatment course.

Results: Analysed data from 196 patients showed 46.3% of patients received corticosteroids. Steroid administration due to irAEs did not affect overall survival (OS) (p = 0.38) compared with the steroid naïve group. Only steroid administration for the palliation of cancer-related symptoms was an independent predictor for shorter OS (HR = 2.7; 95% CI, 1.5-4.9). The timeline of steroid administration did not affect OS (p = 0.456) in our cohort.

Conclusions: Steroids due to irAEs do not appear to hamper ICI efficacy. However, the administration of high-dose steroids to palliate malignancy-associated symptoms might reflect the dismal prognosis of this patient group.
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http://dx.doi.org/10.1016/j.ejca.2020.12.012DOI Listing
March 2021

Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a 'Real-Life' Setting.

Cancers (Basel) 2020 Dec 10;12(12). Epub 2020 Dec 10.

Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, 17164 Stockholm, Sweden.

There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic driven NSCLC with BM who were treated with ICIs at two medical oncology institutes in Sweden and Greece from 2016 to 2019. IC efficacy was assessed in patients who had not received local treatment for BM less than three months prior to the initiation of ICIs and had adequate radiological evaluation. We screened 280 patients, of which 51 had BM. BM was an independent predictor for inferior PFS (HR = 2.27; 95% CI, 1.53-3.36) but not OS (HR = 1.58; 95% CI, 0.97-2.60) for the whole patient population. IC response assessment was done on 33 patients. IC objective response rate (ORR) was 24.2%. The presence of neurological symptoms related to BM did not affect IC ORR ( = 0.48). High PD-L1 levels from extracranial biopsies were not a predictive factor for IC ORR ( = 0.13). ICIs are active in NSCLC patients with BM regardless of the presence of neurological symptoms and can achieve durable IC disease stabilization in a subgroup of patients.
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http://dx.doi.org/10.3390/cancers12123707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764720PMC
December 2020

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial).

Cancers (Basel) 2020 Oct 24;12(11). Epub 2020 Oct 24.

Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, 17176 Stockholm, Sweden.

Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed.

Methods: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A.

Results: Median PFS in arm A was 4.37 months (95% CI: 2.9-5.9 m) and 6.5 months (95% CI: 4.8-8.2 m) in arm B, ( = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3-11.5 m) in arm A and 10.2 months (95% CI: 5.4-15 m) in arm B, (HR = 0.71; 95% CI: 0.43-1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41-1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; = 0.034).

Conclusion: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy.
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http://dx.doi.org/10.3390/cancers12113110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693024PMC
October 2020

Treatment of rheumatic immune-related adverse events due to cancer immunotherapy with immune checkpoint inhibitors-is it time for a paradigm shift?

Clin Rheumatol 2020 Sep 28. Epub 2020 Sep 28.

Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden.

Immunotherapy has revolutionized cancer treatment during the last years. Several monoclonal antibodies that are specific for regulatory checkpoint molecules, that is, immune checkpoint inhibitors (ICIs), have been approved and are currently in use for various types of cancer in different lines of treatment. Cancer immunotherapy aims for enhancing the immune response against cancer cells. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events of autoimmune origin, often referred to as immune-related adverse events (irAEs), which limit the utility of these drugs. These irAEs are quite common and can affect almost every organ. The grade of toxicity varies from very mild to life-threatening. The pathophysiological mechanisms behind these events are not fully understood. In this review, we will summarize current evidence specifically regarding the rheumatic irAEs and we will focus on current and future treatment strategies. Treatment guidelines largely support the use of glucocorticoids as first-line therapy, when symptomatic therapy is not efficient, and for more persistent and/or moderate/severe degree of inflammation. Targeted therapies are higher up in the treatment pyramid, after inadequate response to glucocorticoids and conventional, broad immunosuppressive agents, and for severe forms of irAEs. However, preclinical data provide evidence that raise concerns regarding the potential risk of impaired antitumoral effect. This potential risk of glucocorticoids, together with the high efficacy and potential synergistic effect of newer, targeted immunomodulation, such as tumor necrosis factor and interleukin-6 blockade, could support a paradigm shift, where more targeted treatments are considered earlier in the treatment sequence.
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http://dx.doi.org/10.1007/s10067-020-05420-wDOI Listing
September 2020

ALK-Brain Prognostic Index-Preliminary Study of a Prognostic Tool for Patients with ALK-Rearranged, Non-small Cell Lung Cancer and Brain Metastases.

Cancers (Basel) 2020 Jul 6;12(7). Epub 2020 Jul 6.

Theme Cancer, Medical Unit Head & Neck, Lung and Skin Cancer, Karolinska University Hospital, 17176 Stockholm, Sweden.

Background: Disease-specific Graded Prognostic Assessment (DS-GPA) is the most validated prognostic tool for patients with brain metastasized lung cancer. The Lung-molGPA scoring system was recently introduced for oncogenic-driven brain metastasized lung cancer, but has not yet been validated in cohorts including only ALK-translocated tumors.

Methods: We designed a retrospective cohort study consisting of 44 patients with brain metastasized ALK-positive, non-small cell lung cancer (NSCLC) who were treated between January 2009 and November 2019 at Karolinska University Hospital in Stockholm, Sweden. Information about demographics and clinicopathological parameters were collected. Predictors of overall survival (OS) were identified by Cox regression analyses. A bootstrap validation with 1000 samples was performed in order to compare the different prognostic scores.

Results: The variables found to independently influence OS in the multivariate analysis, i.e., PS, sex and brain metastases at diagnosis, were used as prognostic variables in our new prognostic index (ALK-BPI). Patients were divided into two prognostic groups. The median OS was 65.7 months for the good prognostic group and 22.7 months for the poor prognostic group ( = 0.0068). In the univariate analysis of the different prognostic scores, ALK-BPI performed better than the others (HR = 3.6; 95% CI: 1.3-9.9). The mean C-statistics of the different prognostic scores were compared to each other, and no significant difference was observed.

Conclusion: We propose the ALK-BPI score as a new prognostic tool that can easily be applied for ALK-positive lung cancer patients with brain metastases in daily clinical practice, as it has at least the same prognostic value as Lung-molGPA.
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http://dx.doi.org/10.3390/cancers12071804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408161PMC
July 2020

Primary CNS Metastatic BRAF-mutated Lung Adenocarcinoma With Complete Intracranial Response to BRAF/MEK Inhibition.

Clin Lung Cancer 2020 11 12;21(6):e544-e546. Epub 2020 May 12.

Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1016/j.cllc.2020.05.006DOI Listing
November 2020

An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer.

Eur J Cancer 2020 06 20;132:24-34. Epub 2020 Apr 20.

Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology and Pathology, Karolinska Institutet, Visionsgatan 4, 17164 Stockholm, Sweden. Electronic address:

Background: Dissemination of non-small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts.

Methods: We identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter® PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software.

Results: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours.

Conclusions: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.
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http://dx.doi.org/10.1016/j.ejca.2020.03.014DOI Listing
June 2020

c-MET as a biomarker in patients with surgically resected non-small cell lung cancer.

Lung Cancer 2019 07 1;133:69-74. Epub 2019 May 1.

Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital/Department of Oncology- Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet.

Patients And Methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored.

Results: c-MET H-score ≥20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64-0.97). The prognostic effect of c-MET H-score ≥20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40-0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43-0.83).

Conclusion: c-MET H-score ≥20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score ≥20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2019.04.028DOI Listing
July 2019

Corrigendum to "Validation of the 8th TNM classification for small-cell lung cancer in a retrospective material from Sweden" [Lung Cancer 120 (June) (2018) 75-81].

Lung Cancer 2018 09 14;123:178-179. Epub 2018 Jul 14.

Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.lungcan.2018.07.008DOI Listing
September 2018

Oncogene-addicted non-small cell lung cancer and immunotherapy.

J Thorac Dis 2018 May;10(Suppl 13):S1547-S1555

Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.

A majority of non-small cell lung cancer (NSCLC), especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. The treatment of these oncogene-addicted tumors has dramatically changed the outcome of these patients, where tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor (EGFR) and rearranged anaplastic lymphoma kinase (ALK) have paved the way for a new era of precision cancer medicine. Another paradigm shift in the treatment of NSCLC, as well as numerous other tumor types, has been the introduction of immunotherapy (IO) with immune checkpoint inhibitors targeting mainly programmed cell death-1 (PD-1) or its ligand PDL-L1, where studies have demonstrated an increased survival versus standard treatment with chemotherapy, both in the first- and second-line setting. However, the role of IO in oncogene-addicted NSCLC is still unclear where most clinical data come from subgroup analyses with low number of patients in larger randomized trials, and these data do not support the use of IO after TKI in this category of NSCLC patients. The purpose of this review is to summarize the existing evidence about the use of IO in oncogenic-addicted NSCLC and highlight the issues that should be addressed in the future in order to define the role of IO for these patients.
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http://dx.doi.org/10.21037/jtd.2018.01.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994494PMC
May 2018

Validation of the 8th TNM classification for small-cell lung cancer in a retrospective material from Sweden.

Lung Cancer 2018 06 30;120:75-81. Epub 2018 Mar 30.

Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden. Electronic address:

Background: The purpose of this study was to evaluate on a Swedish cohort of small cell lung cancer (SCLC) patients whether the 8th TNM staging system can provide additional prognostic information in comparison with the previous 6th and 7th TNM versions and the older 2-stage LD vs ED system.

Methods: We reviewed the medical records of patients (pts) with SCLC diagnosed between January 2008 and February 2016 in the Stockholm and Gotland region. Each patient file was revised and reclassified from the VASGL system to the 6, 7 and 8 TNM system respectively. We assessed overall survival (OS) according to the T, N, M-descriptor and compared LD/ED with the 6 -7, -8 editions of TNM. Four separate multivariate models adjusted for basic patient characteristics were performed.

Results: In total, 706 pts were eligible for the study. Median OS was 7.7 months. Differences in survival between less advanced stages (IA-IIB) were difficult to assess since there were few patients (n = 32). The majority of patients (78%) migrated to new stage categories in the 8th TNM edition; IIIC, IVA and IVB. In the 8th TNM edition subjects with M1a disease had a similar prognosis to patients with multiple metastatic diseases, M1c. Conversely, subjects with a single metastasis had a similar prognosis to M0-disease. On multivariate analysis, stage was an independent prognostic factor independently of the classification system used.

Conclusion: In this cohort, the 8th TNM classification system seems to provide more accurate prognostic information in patients with SCLC when compared to the previous TNM versions. There were few cases with Stages I and II and therefore no robust conclusions can be drawn in this category. The reason single metastatic lesions (M1b) had a better prognosis when compared to M1c could be due to a more aggressive treatment approach in these patients.
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http://dx.doi.org/10.1016/j.lungcan.2018.03.026DOI Listing
June 2018

Prognostic factors affecting survival after whole brain radiotherapy in patients with brain metastasized lung cancer.

Acta Oncol 2018 Feb 6;57(2):231-238. Epub 2017 Oct 6.

a Department of Oncology , Karolinska University Hospital , Stockholm , Sweden.

Background: Whole-brain radiotherapy (WBRT) has been the standard of care for multiple NSCLC brain metastases but due to its toxicity and lack of survival benefit, its use in the palliative setting is being questioned.

Patient And Methods: This was a single institution cohort study including brain metastasized lung cancer patients who received WBRT at Karolinska University Hospital. Information about Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) scores, demographics, histopathological results and received oncological therapy were collected. Predictors of overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes were compared by pairwise log rank test. A subgroup OS analysis was performed stratified by RPA class.

Results: The cohort consisted of 280 patients. RPA 1 and 2 classes had better OS compared to class 3, patients with GPA <1.5 points had better OS compared to GPA≥ 1.5 points and age >70 years was associated with worse OS (p< .0001 for all comparisons). In RPA class 2 subgroup analysis GPA ≥1.5 points, age ≤70 years and CNS surgery before salvage WBRT were independent positive prognostic factors.

Conclusions: RPA class 3 patients should not receive WBRT, whereas RPA class 1 patients should receive WBRT if clinically indicated. RPA class 2 patients with age ≤70 years and GPA ≥1.5 points should be treated as RPA 1. WBRT should be omitted in RPA 2 patients with age >70. In RPA 2 patients with age ≤70 years and GPA <1.5 points WBRT could be a reasonable option.
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http://dx.doi.org/10.1080/0284186X.2017.1386799DOI Listing
February 2018

Dabigatran plasma levels, aPTT and thromboelastography in patients with AF: implications for allowing early non-elective surgical procedures.

J Thromb Thrombolysis 2017 Jul;44(1):9-13

Haematology Anticoagulation Department, Diagnostic and Therapeutic Centre of Athens "Hygeia", 4, Erythrou Stavrou Str, Maroussi, 151 23, Athens, Greece.

According to current recommendations, patients on dabigatran should stop the drug 24-96 h before scheduled surgery. This may seem too long for non-elective cases. The aim of our study was to assess the number of patients on dabigatran who could theoretically undergo surgery 12 h post last drug dosing. We measured dabigatran plasma trough concentration by Hemoclot assay in 75 consecutive patients receiving dabigatran. Coagulation was assessed by aPTT and thromboelastography (TEG). Plasma levels ≤30 ng/ml were considered low. TEG parameters measured were clot reaction time (R), clot growth index (k), angle (α), maximal amplitude (MA) and the percentage of clot lysed after 30 min (LY30). Twelve patients (16%) had low plasma dabigatran levels 11.6 ± 0.9 h post last dosing. These patients compared to those with higher levels had significantly different aPTT (37.7 ± 4.4 vs. 49.6 ± 9.2 s; p < 0.001) and TEG R (6.7 ± 1.3 vs. 8.4 ± 2.6 min; p = 0.002). Only three of the patients with low levels had an aPTT >40 s. Within those with levels >30 ng/ml, four patients (6.4%) had plasma dabigatran levels ≥200 ng/ml, all with aPTT >65 s and TEG R >11 min. When the analysis was restricted to patients with creatinine clearance >80 ml/min, six (27.3%) had low plasma dabigatran levels. In this theoretical study, with a low risk population, it is suggested that one-sixth of patients receiving dabigatran have low drug concentrations at 12 h. Further studies are needed to confirm that such patients with low trough levels can actually undergo safely early surgery if necessary.
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http://dx.doi.org/10.1007/s11239-017-1503-3DOI Listing
July 2017

High incidence of thyroid cancer among patients with acromegaly.

J BUON 2016 Jul-Aug;21(4):989-993

Third Department of Internal Medicine, University of Athens, Sotiria General Hospital, Athens, Greece.

Purpose: Several studies have suggested that patients with acromegaly have an increased risk of thyroid, colorectal, breast and prostate cancers. In this study we determined the prevalence of malignant neoplasms in patients with acromegaly.

Methods: Cancer risk was evaluated in a cohort of 110 patients (M/F 48/62, age 58.63±13.8 years, range 30-86) with acromegaly. Mean age at diagnosis of acromegaly was 46.37±13.11 years. Mean period of time since diagnosis of acromegaly was 12.26+9.6 years.

Results: From 110 patients, cancer was diagnosed in 26 (23.6%) patients. Thyroid cancer was the most common cancer and was diagnosed in 13 patients (11.8%); other cancers encountered were gastric cancer (N=2), endometrial cancer (N-2), and breast cancer, colon cancer, prostate cancer (N-2), myelodysplastic syndrome, renal cell carcinoma, lung cancer and pancreatic carcinoma, one case each. Age, gender, age at the time of diagnosis of acromegaly, tumor size of pituitary adenoma and duration of disease were not associated with cancer development.

Conclusions: This study suggests that patients with acromegaly have an increased risk of thyroid cancer and therefore they should undergo regular screening with hormonal and ultrasound evaluation of the thyroid and FNAB when required.
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March 2017

PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas.

Tumour Biol 2014 May 9;35(5):4479-88. Epub 2014 Feb 9.

Rudbeck Laboratory, Section of Oncology, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, 751 85, Uppsala, Sweden,

The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the response to chemotherapy.
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http://dx.doi.org/10.1007/s13277-013-1590-5DOI Listing
May 2014

Cancer incidence and mortality patterns in women with anorexia nervosa.

Int J Cancer 2014 Apr 8;134(7):1751-7. Epub 2013 Oct 8.

Department of Neurosciences, Psychiatry, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.

Caloric restriction in animals is an effective way to reduce carcinogenesis. Anorexia nervosa (AN) is considered a model of extreme caloric restriction in humans. The aim of our study was to assess cancer incidence and mortality in women with AN. A total of 6,009 women with at least one inpatient treatment for AN during the period 1973-2003 were included in the study. Standardized incidence ratios (SIR) and standardized mortality ratios (SMR) were calculated. Overall, there was no statistically significant difference in cancer incidence compared to women in the general population. At a statistically significant or borderline significant level, a higher incidence for lung cancer and cancer of lymphoid, hematopoietic and related tissue was observed along with a reduced breast cancer incidence. Women with AN had twice as high mortality from cancer in general, and more specifically from melanoma, cancers of genital organs and cancers of ill-defined, secondary and unspecified sites. The increased lung cancer incidence may be due to smoking habits among women with AN. The worse prognosis with higher mortality from melanoma, cancers of genital organs and cancers of ill-defined, secondary and unspecified sites may be explained by AN-specific attitudes toward seeking medical care, adherence to treatment or worse biological precondition due to starvation and cachexia.
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http://dx.doi.org/10.1002/ijc.28495DOI Listing
April 2014

Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival.

Med Oncol 2013 20;30(3):638. Epub 2013 Jun 20.

Section of Oncology, Department of Radiology, Oncology and Radiation Sciences, Rudbeck Laboratory, 751 85 Uppsala, Sweden.

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.
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http://dx.doi.org/10.1007/s12032-013-0638-0DOI Listing
April 2014

Triple antithrombotic therapy with aspirin, a thienopyridine derivative plus oral anticoagulation in patients with atrial fibrillation undergoing coronary stenting.

Hellenic J Cardiol 2010 Jul-Aug;51(4):330-7

First Cardiology Department, "Hygeia" Diagnostic and Therapeutic Centre of Athens, Greece.

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November 2010

Overestimation and underestimation of cardiovascular risk in clinical practice: usefulness of risk estimation charts.

Hellenic J Cardiol 2007 Nov-Dec;48(6):341-5

1st Cardiology Clinic, "Hygeia" Diagnostic and Therapeutic Centre, Athens, Greece.

Introduction: Charts for the estimation of cardiovascular risk contribute greatly to clinical decision making in the management of asymptomatic individuals. However, most decisions are taken without consulting the charts. The aim of our study was to record the degree of overestimation or underestimation of cardiovascular risk in everyday clinical practice.

Methods: Seven cases of asymptomatic individuals at different levels of cardiovascular risk as a result of different combinations of risk factors (one at very low, one at very high and five at intermediate risk) were presented in random order to 30 doctors who deal with primary prevention consultations in their daily clinical practice. They were asked if hypolipidaemic therapy was needed and their answers were compared with the recommended management of the current European guidelines on prevention using the risk charts of the European Society of Cardiology.

Results: The mean percentage of agreement was 70%. In the two extreme cases agreement with the guidelines was absolute, but in the intermediate cases it varied widely. Particularly in those cases with cholesterol level 200-240 mg/dl it was just 40%, due either to overestimation or to underestimation of the risk.

Conclusion: In the cases of obviously low or obviously high risk, clinical judgement is in accordance with the guidelines. However, in cases of intermediate risk there is either overestimation of risk with non-indicated prescription of hypolipidaemic treatment, or underestimation of risk with no administration of indicated therapy. The use of risk charts in clinical practice may provide substantial help towards a more objective practice of prevention.
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February 2008