Daniel Buergy

Tumor-platelet interaction in solid tumors.

Elevated platelet counts in patients diagnosed with malignant tumors were first described more than 100 years ago. Today it is well known that in many types of solid tumors, thrombocytosis at the time of diagnosis is associated with shorter survival. From this well‐documented clinical correlation between platelet count and prognosis of solid tumors, the following questions arise: (i) Are the increased platelet counts the reason for shortened survival as platelet‐secreted cytokines might boost tumor growth and angiogenesis? (ii) Do platelets affect tumor metastasis thereby shortening survival time? or (iii) Are increased platelet counts simply an epiphenomenon of tumor growth with larger tumors resulting in higher platelet counts and shorter survival times? We address these three questions within our review of the current literature to provide a comprehensive overview of the current concepts in tumor–platelet interaction.

Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies

The identification of high‐risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging. Our study was conducted to analyze whether the quantification of matrix metalloproteinases (MMPs) and urokinase‐type plasminogen activator receptor (u‐PAR) and transcription factor binding to the u‐PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors. Tumor/normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas (papillary, medullary, follicular and anaplastic, PTC, MTC, FTC and ATC) or follicular adenomas. U‐PAR, MMP‐1, MMP‐7 and MMP‐9 amounts were determined by ELISA, and transcription factor binding was determined by electrophoretic mobility shift assay. Binding of transcription factors to the u‐PAR promoter was observed, but not associated with u‐PAR expression. Carcinomas except MTC expressed significantly more u‐PAR/MMPs than adenomas/normal tissues, this being associated with advanced pT‐ or M‐stages. MMP‐1 and MMP‐9 were significantly higher in follicular carcinomas than in adenomas. In carcinomas, high u‐PAR‐gene expression correlated significantly with high MMP‐9, the latter being associated with MMP‐7 in normal tissues. Poor survival in differentiated tumors was associated in trend (p = 0.07); poor survival of all patients (p = 0.043) and especially of patients with carcinomas of follicular origin (including ATC), but not medullary carcinomas, were significantly associated with high u‐PAR‐protein (p = 0.015). Quantification of u‐PAR is of prognostic relevance in thyroid carcinomas of non‐c‐cell origin, and u‐PAR in part may be regulated nontranscriptionally in thyroid cancers. This is the first study to suggest MMP‐1/‐9 as significant differentiation markers between follicular adenoma and follicular carcinoma.

Prognostic impact of extracellular matrix metalloprotease inducer: Immunohistochemical analyses of colorectal tumors and immunocytochemical screening of disseminated tumor cells in bone marrow from patients with gastrointestinal cancer

Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor‐stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow‐disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities.

CD24 Induces Expression of the Oncomir miR-21 via Src, and CD24 and Src Are Both Post-Transcriptionally Downregulated by the Tumor Suppressor miR-34a

Cancer is a complex disease process that evolves as a consequence of multiple malfunctions in key regulatory molecular networks. Understanding these networks will be essential to combat cancer. In this study, we focussed on central players in such networks. In a series of colon and breast cancer cell lines, we found that CD24 activates Src, and induces the activation of c-Jun and expression of c-Jun and c-Fos. Thereby CD24 increases the promoter activity and expression of miR-21, which in turn suppresses expression of Pdcd4 and PTEN. Co-transfection of a CD24 expression construct and an siRNA that silences Src showed that CD24-dependent upregulation of miR-21 is mediated by Src. Additionally, we found that miR-34a post-transcriptionally downregulates CD24 and Src expression, leading to the deactivation of c-Jun, reduced expression of c-Jun and c-Fos, inhibition of miR-21, and upregulation of Pdcd4 and PTEN. Furthermore, miR-34a-mediated inhibition of Src expression reduced migration and invasion of colorectal cancer cells. Resected tumor tissues from 26 colorectal patients showed significantly lower expression of Pdcd4 and miR-34a, and higher expression of CD24, Src and miR-21 compared to the corresponding normal tissues. Moreover, CD24 positively correlated with the amount of Src protein in tumor tissues, and a trend towards an inverse correlation between miR-34a and Src protein levels was also observed. Our results reveal essential players in the complex networks that regulate the progression of solid tumors such as colorectal cancer. These findings therefore identify novel therapeutic approaches for combating tumor growth and progression.

Radiotherapy for tumors of the stomach and gastroesophageal junction – a review of its role in multimodal therapy

There is broad consensus on surgical resection being the backbone of curative therapy of gastric- and gastroesophageal junction carcinoma. Nevertheless, details on therapeutic approaches in addition to surgery, such as chemotherapy, radiotherapy or radiochemotherapy are discussed controversially; especially whether external beam radiotherapy should be applied in addition to chemotherapy and surgery is debated in both entities and differs widely between regions and centers. Early landmark trials such as the Intergroup-0116 and the MAGIC trial must be interpreted in the context of potentially insufficient lymph node resection. Despite shortcomings of both trials, benefits on overall survival by radiochemotherapy and adjuvant chemotherapy were confirmed in populations of D2-resected gastric cancer patients by Asian trials.Recent results on junctional carcinoma patients strongly suggest a survival benefit of neoadjuvant radiochemotherapy in curatively resectable patients. An effect of chemotherapy in the perioperative setting as given in the MAGIC study has been confirmed by the ACCORD07 trial for junctional carcinomas; however both the studies by Stahl et al. and the excellent outcome in the CROSS trial as compared to all other therapeutic approaches indicate a superiority of neoadjuvant radiochemotherapy as compared to perioperative chemotherapy in junctional carcinoma patients. Surgery alone without neoadjuvant or perioperative therapy is considered suboptimal in patients with locally advanced disease.In gastric carcinoma patients, perioperative chemotherapy has not been compared to adjuvant radiochemotherapy in a randomized setting. Nevertheless, the results of the recently published ARTIST trial and the Chinese data by Zhu and coworkers, indicate a superiority of adjuvant radiochemotherapy as compared to adjuvant chemotherapy in terms of disease free survival in Asian patients with advanced gastric carcinoma. The ongoing CRITICS trial is supposed to provide reliable conclusions about which therapy should be preferred in Western patients with gastric carcinoma. If radiotherapy is performed, modern approaches such as intensity-modulated radiotherapy and image guidance should be applied, as these methods reduce dose to organs at risk and provide a more homogenous coverage of planning target volumes.

Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer.

BackgroundTri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics.MethodsExtracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman’s rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts.ResultsIncreased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p = 0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts.ConclusionsIncreased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.

Genital invasion or perigenital spread may pose a risk of marginal misses for Intensity Modulated Radiotherapy (IMRT) in anal cancer

BackgroundWhile intensity modulated radiotherapy (IMRT) in anal cancer is feasible and improves high-dose conformality, the current RTOG/AGITG contouring atlas and planning guidelines lack specific instructions on how to proceed with external genitalia. Meanwhile, the RTOG-Protocol 0529 explicitly recommends genital sparing on the basis of specific genital dose constraints. Recent pattern-of-relapse studies based on conventional techniques suggest that marginal miss might be a potential consequence of genital sparing. Our goal is to outline the potential scope and increase the awareness for this clinical issue.MethodsWe present and discuss four patients with perigenital spread in anal cancer in both early and advanced stages (three at time of first diagnosis and one in form of relapse). Genital/perigenital spread was observed once as direct genital infiltration and thrice in form of perigenital lymphatic spread.ResultsWe review the available data regarding the potential consequences of genital sparing in anal cancer. Pattern-of-relapse studies in anal cancer after conventional radiotherapy and the current use of IMRT in anal cancer are equivocal but suggest that genital sparing may occasionally result in marginal miss. An obvious hypothesis suggested by our report is that perigenital lymphovascular invasion might be associated with manifest inguinal N+ disease.ConclusionsLocal failure has low salvage rates in recent anal cancer treatment series. Perigenital spread may pose a risk of marginal misses in IMRT in anal cancer. To prevent marginal misses, meticulous pattern-of-relapse analyses of controlled IMRT-series are warranted. Until their publication, genital sparing should be applied with caution, PET/CT should be used when possible and meeting genital dose constraints should not be prioritized over CTV coverage, especially (but not only) in stage T3/4 and N+ disease.

Treatment of Adrenal Metastases with Conventional or Hypofractionated Image-guided Radiation Therapy – Patterns and Outcomes

Background/Aim: Metastases involving the adrenal glands can be treated surgically or with radiation therapy. Retrospective studies indicate that radiotherapy for this indication is safe, well-tolerated and associated with symptom palliation and good local control. We conducted this analysis to report on patterns and outcomes of patients with adrenal metastases treated with hypo- or conventionally fractionated image-guided radiotherapy. Patients and Methods: Patients with adrenal metastases from solid tumors treated at our department between 01/2010-12/2017 were reviewed. A total of 22 lesions were treated in 18 patients with a median dose of 35 Gy (20-60 Gy) in a median number of 7 (4-25) fractions. Results: No grade ≥3 toxicity occurred. Median overall survival was 11.9 months. Five local failures occurred (22.7%). Lesion sizes or radiation dose were not correlated with local control. Patients treated for oligometastatic and oligoprogressive disease had a median overall survival of 33 and 6.5 months, respectively (palliative/polymetastatic: 1.6 months). Symptoms improved in all patients treated for clinically apparent lesions. Conclusion: Stereotactic radiotherapy of adrenal metastases was safe and effective in patients with oligometastases or oligoprogression. In palliative patients, short-course radiotherapy complemented with supportive care should be preferred.

Overall survival after reirradiation of spinal metastases – independent validation of predictive models

BackgroundIt is unknown if survival prediction tools (SPTs) sufficiently predict survival in patients who undergo palliative reirradiation of spinal metastases. We therefore set out to clarify if SPTs can predict survival in this patient population.MethodsWe retrospectively analyzed spinal reirradiations performed (n = 58, 52 patients, 44 included in analysis). SPTs for patients with spinal metastases were identified and compared to a general palliative score and to a dedicated SPT to estimate prognosis in palliative reirradiation independent of site (SPT-Nieder).ResultsConsistently in all tests, SPT-Nieder showed best predictive performance as compared to other tools. Items associated with survival were general condition (KPS), liver metastases, and steroid use. Other factors like primary tumor site, pleural effusion, and bone metastases were not correlated with survival. We adapted an own score to the data which performed comparable to SPT-Nieder but avoids the pleural effusion item. Both scores showed good performance in identifying long-term survivors with late recurrences.ConclusionsSurvival prediction in case of spinal reirradiation is possible with sufficient predictive separation. Applying SPTs in case of reirradiation helps to identify patients with good life expectancy who might benefit from dose escalation or longer treatment courses.

Fallserie zur SBRT bei ventrikulärer Tachykardie zeigt beeindruckenden Therapieeffekt

Hintergrund Magnetresonanztomographie (MRT) oder Computertomographie (CT) können in Kombination mit einer nichtinvasiven Lokalisationsdiagnostik zur Lokalisation arrhythmogener Areale und myokardialer Narben eingesetzt werden [1, 2]. Durch die Kombination dieser Verfahren kann eine nichtinvasive Lokalisation arrhythmogener myokardialer Zonen erfolgen, die wiederum mittels einer nichtinvasiven Ablationstechnik behandelt werden können. Die vorliegende Studie [3] beschreibt eine kleine Fallserie von 5 Patienten, bei denen mittels stereotaktischer Radiotherapie (SBRT) versucht wurde, die anhand elektrokardiographischer Bildgebung lokalisierten arrhythmogenen Areale zu behandeln. Das Behandlungsziel ist hierbei die myokardiale Fibrosierung, die damit elektrisch inert wird und das Wiederauftreten einer Kammertachykardie/Kammerflimmern verhindert. Tierexperimentelle Daten und einzelne klinische Fallberichte wurden von den Autoren als Grundlage zur Dosisfindung angewandt [4, 5]. Diese Daten deuten darauf hin, dass mit einer einmalig ap-