Genomic Complexity as a Biomarker to De-Escalate Adjuvant Imatinib Treatment in High-Risk Gastrointestinal Stromal Tumor.

Purpose: Adjuvant imatinib treatment is recommended for patients with localized gastrointestinal stromal tumor (GIST) at high risk of recurrence. Almost half of high-risk patients are cured by surgery alone, indicating a need for improved selection of patients for adjuvant therapy. The aim of this study was to investigate if genomic tumor complexity could be used as a prognostic biomarker.

Evolutionary patterns of chromosomal instability and mismatch repair deficiency in proximal and distal colorectal cancer.

Aim: Colorectal carcinomas (CRCs) progress through heterogeneous pathways. The aim of this study was to analyse whether or not the cytogenetic evolution of CRC is linked to tumour site, level of chromosomal imbalance and metastasis.

Method: A set of therapy-naïve pT3 CRCs comprising 26 proximal and 49 distal pT3 CRCs was studied by combining immunohistochemistry of mismatch repair (MMR) proteins, microsatellite analyses and molecular karyotyping as well as clinical parameters.

Optimal thresholds of risk parameters for gastrointestinal stromal tumors.

Background: Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal neoplasms of the gastrointestinal tract with highly variable potential for relapse. Tumor size and mitotic index (MI) are major risk factors that predict the outcome of GIST patients. Recent risk stratification schemes include some or all of the empirical size thresholds of 2 cm, 5 cm, and 10 cm and MI thresholds of 5 per 50 high-power fields (hpf) and 10 per 50 hpf.

Predictive chromosomal clusters of synchronous and metachronous brain metastases in clear cell renal cell carcinoma.

Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events.

Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal stromal tumors.

Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor receptor α (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series.

Etiologic influence on chromosomal aberrations in European hepatocellular carcinoma identified by CGH.

Previous studies suggest different pathways in the molecular development of hepatocellular carcinoma (HCC). We investigated the pattern of chromosomal imbalances in HCC depending on the type of underlying liver disease as detected by comparative genomic hybridization in 67 cases of primary HCC occurring in non-cirrhotic livers (n=30), in liver cirrhosis (LC) related to alcohol intake (n=9), cryptogenic or metabolic changes (n=11), and chronic viral hepatitis B or C (n=17). HCC were treated by liver resection in 48 patients and transplantation in 19 patients.

13-year-old tuberous sclerosis patient with renal cell carcinoma associated with multiple renal angiomyolipomas developing multifocal micronodular pneumocyte hyperplasia.

Background: The autosomal dominant tumor syndrome tuberous sclerosis complex is caused by the mutated TSC1 gene, hamartin, and the TSC2 gene, tuberin. Patients with this complex develop typical cutaneus symptoms such as peau chagrin or angiofibromas of the skin as well as other lesions such as astrocytomas in the brain and lymphangioleiomyomatosis in the lung. Only a few tuberous sclerosis patients have been described who showed a multifocal micronodular pneumocyte hyperplasia of the lung.

Prognostic value of chromosomal imbalances in squamous cell carcinoma and adenocarcinoma of the lung.

Background: Non-small cell lung cancer (NSCLC) is one of the most aggressive tumors, with a very low overall survival rate. We investigated surgically resected squamous cell carcinoma (SCC) and adenocarcinoma (AC) to identify chromosomal imbalances and their value for individual prognostication.

Methods: A total of 80 cases, including 55 SCC and 25 AC, were retrospectively analyzed by comparative genomic hybridization.

Comparison of chromosomal aberrations in primary colorectal carcinomas to their pulmonary metastases.

Pulmonary metastases (PM) are frequent in colorectal carcinoma (CRC). However, little is known about the chromosomal imbalances in CRC that accompany metastatic pulmonary disease. We investigated tumor specimens of CRC (n=30) and their corresponding PM by comparative genomic hybridization (CGH).

Common molecular cytogenetic pathway in papillary tumors of the pineal region (PTPR).

Primary papillary tumors of the central nervous system and particularly the pineal region are rare. Papillary tumor of the pineal region (PTPR) is a recently described neoplasm that has been formally recognized in the 2007 World Health Organization Classification of Tumors of the Nervous System. Because of their rarity, further pheno- and genotypical observations as well as therapeutic experience are necessary to differentiate PTPR from other primary or secondary papillary tumors of this region.

Common genomic aberrations in basaloid squamous cell carcinoma and carcinosarcoma of the esophagus detected by CGH and array CGH.

Basaloid squamous cell carcinoma (BSCC) and carcinosarcoma of the esophagus are rare entities, making up fewer than 2% of esophageal malignancies. Comparative genomic hybridization (CGH) in 1 case of BSCC and 2 cases of carcinosarcoma and subsequent array CGH in 1 case each of BSCC and carcinosarcoma revealed common chromosomal gains at 2p25.3-2p12, 7q21.

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival.

In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray.

Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis.

Aims: To determine the prognostic impact of p16INK4A expression in gastrointestinal stromal tumours (GISTs), which is currently being questioned, with both loss and overexpression said to be correlated with poor prognosis.

Methods And Results: Two different forms of p16INK4A were identified, presenting with predominantly nuclear and cytoplasmic expression pattern, respectively. The immunohistochemical expression of the two forms and their correlation with E2F1 and prognosis were analysed in a series of 120 GISTs with clinical follow-up.

High chromosomal instability in brain metastases of colorectal carcinoma.

Information on structural chromosomal changes in brain metastases (BM) of colorectal carcinoma (CRC) is very limited. Therapeutic and diagnostic strategies to reduce the risk of BM have potential impact on cancer mortality. By using comparative genomic hybridization, the primary CRC of 11 patients and their corresponding 13 BM were analyzed.

Localization- and mutation-dependent microRNA (miRNA) expression signatures in gastrointestinal stromal tumours (GISTs), with a cluster of co-expressed miRNAs located at 14q32.31.

The molecular biology and clinical behaviour of gastrointestinal stromal tumours (GISTs) are associated with their anatomical localization (stomach or intestine), and also with the mutation status of the receptor tyrosine kinases KIT and PDGFRA. Twelve GISTs were evaluated for differential miRNA expression signatures by use of microarrays representing 734 human miRNAs. Thirty-two miRNAs were found to be differentially expressed according to localization and mutation status.

Nasopharyngeal carcinoma in adults: treatment results after long-term follow-up with special reference to adjuvant interferon-beta in undifferentiated carcinomas.

Purpose: Nasopharyngeal carcinomas (NPC) are radiosensitive, and radiotherapy is the standard curative treatment. Furthermore, it has been shown that combined radiochemotherapy improves prognosis in locally advanced stages. Further encouraging results have been obtained with adjuvant interferon-beta after primary radio(chemo)therapy in childhood undifferentiated NPC.

Does imatinib turn recurrent and/or metastasized gastrointestinal stromal tumors into a chronic disease? - single center experience.

Background: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors of the gastrointestinal tract supposed to arise from the cells of Cajal because of gain-of-function mutations of the tyrosine receptor kinases c-kit or platelet-derived growth factor receptor A. Imatinib selectively inhibits the kinase activity of both receptors. Despite this breakthrough in the treatment of GIST, resistance against imatinib has been reported to be as high as 50% after the first 2 years of treatment.

CNS tumor 22 years after spinal neuroblastoma IV: diagnostic dilemma between recurrence and secondary malignancy.

We present the very unusual case of a young woman suffering from a brain tumor 22 years after a stage IV spinal neuroblastoma as an infant, demonstrating the difficulties of differentiating late neuroblastoma relapse from secondary supratentorial primitive neuroectodermal tumor (sPNET). Lacking specific immunohistochemical features, the first cerebral tumor at the age of 21 was regarded as sPNET, and we pursued a therapeutic approach consisting of neurosurgical resection as well as irradiation and high-dose alkylator-based chemotherapy according to the HIT2000 protocol. Two years later the patient suffered from a diffusely infiltrating local recurrence, changing its imaging appearance as well as its immunohistochemical characteristics, now revealing disseminated positivity for neuron-specific enolase and neural cell adhesion molecule.

Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression.

Aims: The morphological diversity of gastrointestinal stromal tumours (GISTs) is well appreciated. The aim of this study was to shed light on the molecular pathogenesis of GISTs displaying a distinct biphasic histomorphological pattern, which is poorly understood.

Methods And Results: Six biphasic gastric GISTs (four high, one intermediate and one low risk for aggressive behaviour) were studied by histological, immunohistochemical, molecular and comparative genomic hybridization methods.

Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization.

Little is known about the molecular cytogenetic changes in cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma, and on the prognostic significance of chromosomal imbalances in hepatocellular carcinoma. Seventy-eight cases of primary liver cancer with available median follow-up of 16.5 months, including 49 hepatocellular carcinomas, 22 cholangiocarcinomas, and 7 combined hepatocellular-cholangiocarcinomas, were examined by comparative genomic hybridization.

Establishment, characterization and drug sensitivity testing in primary cultures of human thymoma and thymic carcinoma.

Thymomas and thymic carcinomas are peculiar epithelial tumors of the anterior mediastinum. They may show aggressive clinical behavior and are a paradigm for the interaction between the tumor and the immune system. So far, adequate functional studies enabling a better understanding of this malignancy have not been performed, since human thymoma/thymic carcinoma cell lines have not been available.

Immune cells in primary gastrointestinal stromal tumors.

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They are regarded as having relatively uniform histology, although their potential for malignant behavior varies. Despite a strong promoting role of tumor-infiltrating innate immune cells in neoplastic progression, the presence of immune cells in GISTs has not yet been studied.

Site-dependent differential KIT and PDGFRA expression in gastric and intestinal gastrointestinal stromal tumors.

In gastrointestinal stromal tumors (GISTs), mutually exclusive gain-of-function mutations of KIT and PDGFRA are associated with different mutation-dependent clinical behavior. Taking into account the well-known different clinical behavior of GISTs from the stomach or the intestine, the aim of the current study is to evaluate the mutation- and site-dependent effects on mRNA and protein expression of KIT and PDGFRA in a large series of primary GISTs. Fresh-frozen tissue of 53 primary GISTs from gastric (75%) or intestinal (25%) sites were analyzed for mutation of KIT or PDGFRA using direct sequencing.