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- Pathologisches Institut (191) (remove)
Sonstige beteiligte Institutionen
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (1)
- Department of Paediatric Radiology, Institute of Diagnostic and Interventional Radiology, Josef-Schneider-Straße 2, Wuerzburg 97080, Germany (1)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (1)
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- Muskuloskelettales Centrum Würzburg (MCW) (1)
To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.
Purpose
Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity.
Experimental Design
To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features.
Results
Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET.
Conclusion
These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.
Background
Kaposi sarcoma (KS) is a malignant disease most commonly diagnosed in the setting of a human immunodeficiency virus (HIV) infection and in patients receiving immunosuppressive treatment. Pulmonary KS has never been reported in association with endogenous Cushing’s syndrome (CS).
Case presentation
A 60-year-old woman presented with symptoms and signs of CS. Adrenal CS was confirmed by standard biochemical evaluation. Imaging revealed a right adrenal lesion (diameter 3.5 cm) and multiple pulmonary nodules, suggesting a cortisol-secreting adrenal carcinoma with pulmonary metastases. The patient underwent right adrenalectomy with a pathohistological diagnosis of an adrenal adenoma. Subsequent thoracoscopic wedge resection of one lung lesion revealed pulmonary KS with positive immunostaining for human herpes virus 8 (HHV-8). HIV-serology was negative. Hydrocortisone replacement was initiated for secondary adrenal insufficiency after surgery. Post-operative follow up imaging showed complete remission of all KS-related pulmonary nodules solely after resolution of hypercortisolism.
Conclusion
KS may occur in the setting of endogenous CS and may go into remission after cure of hypercortisolism without further specific treatment.
Background
Glioblastoma multiforme located in the posterior fossa is extremely rare with a frequency up to 3.4%. Compared with glioblastoma of the hemispheres the prognosis of infratentorial glioblastoma seems to be slightly better. Absence of brainstem invasion and low expression rates of epidermal growth factor receptor are described as factors for long-time survival due to the higher radiosensitivity of these tumors.
Case presentation
In this case study, we report a German female patient with an exophytic glioblastoma multiforme arising from the cerebellar tonsil and a secondary spinal manifestation. Furthermore, the tumor showed no O (6)-Methylguanine-DNA methyltransferase promotor-hypermethylation and no isocitrate dehydrogenase 1 mutations. All these signs are accompanied by significantly shorter median overall survival. A long-term tumor control of the spinal metastases was achieved by a combined temozolomide/bevacizumab and irradiation therapy, as part of a standard care administered by the treating physician team.
Conclusion
To our knowledge this is the first published case of a combined cerebellar exophytic glioblastoma with a subsequent solid spinal manifestation. Furthermore this case demonstrates a benefit undergoing this special adjuvant therapy regime in terms of overall survival. Due to the limited overall prognosis of the disease, spinal manifestations of glioma are rarely clinically relevant. The results of our instructive case, however, with a positive effect on both life quality and survival warrant treating future patients in the frame of a prospective clinical study.
Introduction
Spindle cell rhabdomyosarcoma of the head and neck is a very rare tumor in adults. We report on one case with long-term survival.
Case presentation
A 41-year-old nonsmoking Caucasian man presented in June 2007 with a painless swelling under his tongue. A diagnosis of a soft tissue sarcoma, and a myofibrosarcoma in particular, was made via biopsy. After multimodal treatment, including local and systemic therapy, our patient remained disease-free until September 2010. The local recurrence was treated unsuccessfully with various chemotherapy regimens. In September 2011, our patient underwent surgical resection again, and a spindle cell rhabdomyosarcoma was diagnosed. To analyze the mismatch between the original diagnosis of a myofibrosarcoma and the second diagnosis, the two specimens were reassessed, and a final diagnosis of a spindle cell rhabdomyosarcoma was made. In 2012 and 2013, our patient suffered further recurrences that were surgically treated, and he is still alive with disease six years and 10 months after the initial diagnosis in June 2007.
Conclusions
In adults, the spindle cell rhabdomyosarcoma tumor is very rare in the head and neck region. In contrast to childhood tumors, spindle cell rhabdomyosarcoma in adulthood is often associated with a poor prognosis. In the present case, the radical surgical treatment might have helped to prolong the patient’s overall survival, which has lasted more than six years. To our knowledge, this is the longest overall survival reported so far for this tumor entity in the head and neck region.
Background
Rhabdomyosarcoma is the most frequent malignant intraorbital tumour in paediatric patients. Differentiation of tumour recurrence or metastases from post-therapeutic signal alteration can be challenging, using standard MR imaging techniques. Diffusion-weighted MRI (DWI) is increasingly considered a helpful supplementary imaging tool for differentiation of orbital masses.
Case presentation
We report on a 15-year-old female adolescent of Caucasian ethnicity who developed isolated bilateral thickening of extraocular eye muscles about two years after successful multimodal treatment of orbital alveolar rhabdomyosarcoma. Intramuscular restricted diffusion was the first diagnostic indicator suggestive of metastatic disease to the eye muscles. DWI subsequently showed signal changes consistent with tumour progression, complete remission under chemoradiotherapy and tumour recurrence.
Conclusions
Restricted diffusivity is a strong early indicator of malignancy in orbital tumours. DWI can be the key to correct diagnosis in unusual tumour manifestations and can provide additional diagnostic information beyond standard MRI and PET/CT. Diffusion-weighted MRI is useful for monitoring therapy response and for detecting tumour recurrence.
Background
Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs.
Methods
Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC).
Results
RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease.
Conclusions
A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.
Background
Suboccipital craniectomy is a conventional approach for exploring cerebellopontine angle lesions. A variety of techniques have been successfully employed to reconstruct a craniectomy. This is the first report about the histological findings after performing a cranioplasty by using a mixture of autologous bone chips and human allogenic fibrin glue.
Case presentation
A 53-year-old German woman underwent left lateral suboccipital retrosigmoidal craniectomy for treatment of trigeminal neuralgia in 2008. Cranioplasty was perfomed by using a mixture of autologous bone chips and human allogenic fibrin glue. Due to recurrent neuralgia, a second left lateral suboccipital craniectomy was performed in 2012. The intraoperative findings revealed a complete ossification of the former craniotomy including widely mature trabecular bone tissue in the histological examination.
Conclusion
A mixture of autologous bone chips and human allogenic fibrin glue seems to provide sufficient bone-regeneration revealed by histological and neuroradiological examinations.
Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients.
Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.