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Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.

In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.

Background: About 85% of paediatric gastrointestinal stromal tumours (GISTs) and about 10-15% of adult GISTs do not harbour any mutations in the KIT and PDGFRA genes and are defined as KIT/PDGFRA wild type (WT). Over the years it has been demonstrated that KIT/PDGFRA WT GISTs are profoundly different from mutant GIST in clinical and molecular profiles, so that they are now considered a separate pathological entity. Moreover, due to their extreme molecular and clinical heterogeneity, KIT/PDGFRA WT GIST should be considered as a family of diseases and not as a single disease entity. However, although several genetic alterations belonging only to KIT/PDGFRA WT GIST have been identified, the exact role of these molecules in the pathogenesis and development of this subgroup is not yet defined., Methods: The aim of this review is to report all current data about the molecular biology of syndromic and non-syndromic KIT/PDGFRA WT GIST, focusing on the potential clinical implication of each biological feature shared by this subgroup and discussing unresolved problems and future research perspectives on this topic., Results: WT GIST is definitely a set of different diseases sustained by specific molecular alterations not yet completely known., Conclusion: Large series of patients are required for defining the biological fingerprint of each subtype and integrating it with clinical data. This will allow the transfer of biological information to clinical practice and its use as an additional tool for diagnosis, prognosis and selection of medical treatment.

The advent of imatinib mesilate, an oral target therapy, has dramatically changed the natural history of gastrointestinal stromal tumours (GISTs). This rare neoplasm has become the paradigm of targeted therapies in solid tumours, also introducing a home-based cure concept in oncology. However, it should be retained that oral drug administration entails new and relevant management problems. Multiple studies have demonstrated the efficacy of imatinib in GISTs associated with a good toxicity profile. However, the efficacy of imatinib, according to its mechanism of action and pharmacokinetics, is closely related to daily assumption. No interruption or "jerky" assumption is permitted in order to avoid efficacy loss. Thus, the issue of treatment adherence is crucial for a successful strategy and should not be overlooked. We think that dealing with the problem means assessing a wide spectrum of not only clinical and general but also psychological and individual aspects. Furthermore, both patient and family should play an active role in the "cure process" and physicians should reduce the distance separating them from their patients due to home-based target therapy, promoting communication and consolidation of a trust-based physician-patient relationship. Several advantages have been introduced by oral target therapies in oncology. However, chronic drug administration, even if generally well tolerated, when prolonged for an undetermined time could heavily impact on patients' quality of life. This could induce non-prescribed drug suspension, with negative impact on disease control. More studies would be necessary in order to detect real patients' adherence, to correlate drug assumption with clinical outcome and to optimize imatinib treatment strategy.

In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence within 5 years of the primary tumour excision, whereas 6 patients developed the recurrence 5 years after primary tumour excision diagnosed during follow-up or casually for other reasons. All patients had distant recurrence, involving liver and peritoneum, whereas no local relapse was observed. These patients were heterogeneous in primary tumour site, risk classification and molecular analysis. Duration of the follow-up for radically excised patients with GIST remains still unsettled; however, the integration of every clinical, pathological and molecular parameter is essential to optimize the duration and intensity of the follow-up for each single patient.

Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settings results in a gain-of-survival. However, the discontinuation, and the duration of treatment in disease-free patients who have undergone radical surgical resection of metastases from gastrointestinal stromal tumours (GISTs) have yet to be evaluated. We retrospectively reviewed 40 patients with advanced and recurrent GIST, included in our GIST database, focusing on patients (5 males and 2 females; median age 56 years) who continued medical treatment following radical surgical resection of metastatic lesions. Seven out of 40 patients underwent surgery and continued medical treatment following radical surgical resection of metastatic lesions. The duration of adjuvant therapy was 3, 12, 16, 24, 35, 37 and 52 months, respectively, with a median of 26 months. No patients discontinued therapy and all were disease-free at the final CT-scan evaluation. Considering that the discontinuation of imatinib in responding patients with advanced GIST (even in complete remission) results in a rapid high risk of progression, and a short adjuvant therapy results in a shorter disease-free and overall survival in high-risk GIST patients, it is also likely that treatment should not be discontinued in this setting. However, large-scale studies are required to better assess the optimal duration of treatment, particularly after 5 years, by focusing on the identification of predictive factors for the selection of patients who may benefit from a prolonged or lifelong imatinib treatment.

The problem of the surveillance for colorectal cancer after radical surgery is a widely debated argument. Like for other solid tumors, the issue is divided in 2 main routes: the early diagnosis of recurrence and the early diagnosis of a second primary cancer. Genetic and molecular features have been recognized as useful tools to measure these risks, however, the instruments are still insufficient to design a personalized strategy for the patient. In an era of "tailored therapies" in oncology, even the follow-up of the surgically treated patient for colorectal cancer should enter "a tailor's shop in which several competent tailors" should be available to manage a complex problem., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that most frequently arise in the gastrointestinal tract. The liver and peritoneum are common sites of distant GIST lesions, whereas lung metastases are infrequent, accounting for 7% of all lesions. The clinical significance of these metastases remains unknown. Although lung metastases are relatively rare in the natural history of GIST, they may become more prevalent due to increased patient life expectancy. The present report describes four patients with GIST who had lung metastases. Two were female (54 and 28 years of age), and two were male (64 and 44 years of age). The primary GISTs were localized in the stomach in two patients and in the small intestine in the other two patients. Three patients presented with multiple lung lesions and one presented with one lung lesion. Lung metastases were present at the time of initial diagnosis in one patients, and were observed during the follow-up period in the other three. In this report we detail the clinical presentation and radiological features of the lung lesions as observed by computed tomography (CT) and computed tomography/ positron emission tomography (CT/PET). We describe each patient's clinical history and treatment which included surgery and the tyrosine kinase inhibitors, imatinib and sunitinib, and the novel therapy, nilotinib. Moreover, we discuss some biological aspects of this relatively rare occurrence and the resulting clinical implications. These findings may help clinicians to manage lung metastases arising from GISTs in future.

In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression.

Resistance to tyrosine-kinase inhibitors remains an open issue in the treatment of patients with gastrointestinal stromal tumors. The complex biology of disease in the multi-resistant setting has led a progressively growing urgency and interest in development combined or integrated therapies. This mini-review outlines the rationale for developing new combined therapeutic approaches, and describes the state of the art of the various potential strategies and the promising research perspectives., (2009 Elsevier Ltd. All rights reserved.)

Aberrations of the Insulin-like Growth Factor (IGF) system have been found in association with a variety of cancer types. The potential role of IGF1R has been postulated in a small subset of GISTs, but until now the implications of its aberrations have not been defined. The aim of the study was to examine the IGF1R status in patients with gastric GIST in regard to KIT and PDGFRA genotype. Fresh resection specimens were collected from 8 primary tumours [2 wild-type (WT) and 6 mutant cases]. IGF1R was studied as gene expression profiling with Affymetrix GeneChip HG-U133Plus 2.0 arrays and as genomic copy number with SNP array analysis Affymetrix Genome Wide Human SNP 6.0 arrays, and at protein level with western blotting (WB) and immunohistochemistry (IHC). The unsupervised analysis of gene expression profiling of our patients merged with a data set from gastric GISTs identified 2 patients out of 8 with different expression of IGF1R. The data were confirmed by WB and IHC. In particular, IGF1R was upregulated in 2 young patients (<30-years old), who had both WT disease and metastases at diagnosis. The SNP array analysis showed that none of the tumours had IGF1R amplification. GISTs are characterized by abnormalities of the KIT and PDGFRA receptors that affect prognosis and response to tyrosine kinase inhibitors. Both young adult with WT GIST had the over-expression of IGF1R at mRNA and protein level. These results further confirm the hypothesis that IGF1R may be a potential therapeutic target in GISTs lacking KIT and PDGFRA mutations., (Copyright (c) 2009 UICC.)

Treatment of patients affected by advanced or inoperable GIST was revolutionized by the use of the tyrosine kinase inhibitors. Despite the fact that most patients have a good durable response of disease, they develop a resistance to treatments after a median time of 24 months. The acquired resistance is an emerging aspect in medical oncology especially in the era of target therapies. The aim of this review is to report all known mechanisms of secondary resistance to tyrosine kinase inhibitors and to highlight their clinical implications. In general, they may be divided in mechanisms related to the acquisition of new molecular abnormalities associated to KIT and PDGFRA receptor signalling pathway, such as the loss of KIT expression, the genomic amplification of KIT, the activation of an alternative downstream signalling pathways such as AKT/mTOR and the acquisition of new receptor mutations, and other mechanisms different to KIT/PDGFRA receptors. Future research perspectives on target therapy and early resistance evaluation are also discussed.

Purpose: We investigated the efficacy and toxicity of metronomic capecitabine administered at a fixed dose of 1,000 mg daily in three elderly or poor performance status patients with advanced colorectal cancer (CRC) and gastric cancer., Methods: In this study a pretreated advanced CRC patient (patient 1), a not previously treated advanced gastric cancer patient (patient 2), and a not previously treated advanced rectal cancer patient (patient 3) were given metronomic capecitabine administered at a fixed dose of 1,000 mg daily (day 1-28 continuously). The efficacy was evaluated every 3 months by instrumental evaluation and the treatment was continued until progression of disease or toxicity., Results: A stable disease was observed in all three patients. The duration of treatment was above 3 months and no major toxicities occurred., Conclusions: Our results indicate that metronomic capecitabine may be considered a safe and valid treatment option for advanced CRC and gastric cancer patients, both after failure of previous lines of chemotherapy or in front-line when standard chemotherapy is contraindicated, especially when the aim of medical treatment is to achieve disease control and to arrest tumour growth without affecting the patient's quality of life. Nevertheless, further clinical studies, as well as a greater clinical experience are required in order to better define the role of this strategy in medical oncology.

Nowadays molecular biology represents one of the most interesting topics in medical oncology, because it provides a global and detailed view on the molecular changes involved in tumour progression, leading to a better understanding of the carcinogenesis process, to discovering new prognostic markers and novel therapeutic targets. The gene expression profiling analysis with microarray technology has shown a great potential in cancer research and in medical oncology, mapping simultaneously the expression of thousands of genes in a single tumour sample and giving a measurement of articulated genes expression patterns. Colorectal cancer represents a wide and exciting area of research for molecular biology, due to the growing need of a molecular classification as well as prognostic and predictive molecular factors that may guide oncologists in patient's clinical management. The aim of this review is to analyze the state of art of gene expression profile in colorectal cancer using microarrays technologies and to explore some perspectives in this research field.