Metabolic pseudoprogression in a patient with metastatic KIT exon 11 GIST after 1 month of first-line imatinib: a case report.

Background: Positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) has proven to be highly sensitive in the early assessment of tumor response in gastrointestinal stromal tumors (GIST), especially in cases where there is doubt or when the early prediction of the response could be clinically useful for patient management. As widely known, kinase mutations have an undoubtful predictive value for sensitivity to imatinib, and the inclusion of KIT and PDGFRa mutational analysis in the diagnostic workup of all GIST is now considered standard practice. Case presentation: Herein, we described in detail a case of an exon 11 KIT mutated-metastatic GIST patient, who presented an unexpected metabolic progression at the early 18FDG-PET evaluation after 1 month of first-line imatinib, unconfirmed at the liver biopsy performed near after, which has conversely shown a complete pathological response. Conclusions: This report aims to highlight the existence of this metabolic pseudoprogression in GIST at the beginning of imatinib therapy in order to avoid early treatment discontinuation. Therefore, an early metabolic progression during a molecular targeted therapy always deserves to be evaluated in the context of the disease molecular profiling, and in case of a discordant finding between functional imaging and molecular background, a short-term longitudinal control should be suggested.

Spontaneous Evolution of COVID-19 Lung Sequelae: Results from a Double-Step Follow-Up.

BACKGROUND: Few studies have reported a double-step follow-up of patients after hospitalization for COVID-19. OBJECTIVES: We designed an observational double-step follow-up study with a clinical, functional, and radiological evaluation at 2 and 6 months after COVID-19. The primary outcome was to describe symptoms, spirometry, and 6-minute walking test (6MWT) at 2 and 6 months. Secondary outcomes were to identify if the lowest PaO2/FiO2 during hospitalization is related with functional and radiological evolution and to assess the correlation between radiological and functional abnormalities at 6 months. METHODS: Symptoms, spirometry, and 6MWT were assessed at 2 and 6 months; arterial blood gas, chest x-ray, and lung ultrasound were performed at 2 months; body plethysmography, diffusing capacity for carbon monoxide (DLCO), and CT scan were performed at 6 months. RESULTS: Sixty-four per cent and 42% of patients reported at least one symptom at 2 and 6 months, respectively. The most common 6-month functional alteration was DLCO impairment (57% of patients). An improvement of FEV1, FVC, and 6MWT was observed between 2 and 6 months (p < 0.001). Patients with PaO2/FiO2 <200 during hospitalization performed worse at 6MWT at 2 and 6 months (p < 0.05) and reported more extended radiological abnormalities at 6 months (p < 0.001) compared with patients with PaO2/FiO2>200. At 6 months, more extended radiological abnormalities were related with worse 6MWT, DLCO, and total lung capacity (p < 0.05). DISCUSSION: DLCO and 6MWT impairment seem to be the functional hallmark of COVID-19 and are related with the severity of acute pneumonia. At 6 months, radiological abnormalities were related to functional impairment.

Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors.

BACKGROUND: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy. METHODS: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated. RESULTS: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures. CONCLUSIONS: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.

Case Report: The Complete Remission of a Mixed Germ Cell Tumor With Somatic Type Malignancy of Sarcoma Type With a GCT-Oriented Therapy: Clinical Findings and Genomic Profiling.

Somatic malignant transformation in a germ cell tumor (GCT) is the development of non-germ malignancies; much of available literature refers to teratoma with malignant transformation (TMT). There are various transformation histologies such as sarcoma, adenocarcinoma, primitive neuroectodermal tumors, and more rarely carcinoid tumors, hemangioendothelioma, lymphoma, or nephroblastoma. The treatments of these entities include surgery and/or chemotherapy. A standard approach in choosing chemotherapy in TMT cases has not yet been established. Many authors suggest using chemotherapeutic agents based on the transformed histology, while others recommend GCT-oriented therapy combined with surgery as the primary treatment, reserving histology-driven chemotherapies for metastatic relapse. We report the clinical findings and the genomic profile of a mixed GCT case with somatic-type malignancy of sarcoma type. We achieved a complete radiological response with GCT-oriented chemotherapy performed as salvage therapy after sarcoma-histology therapy. In addition, molecular profiles with RNA-sequencing and exome sequencing analyses of the primary tumor and the tumor with somatic-type malignancy of sarcoma type were explored.

Impact of Chemotherapy in the Adjuvant Setting of Early Stage Uterine Leiomyosarcoma: A Systematic Review and Updated Meta-Analysis.

BACKGROUND: Although the use of adjuvant chemotherapy (AC) appears to be increasing over the past few years, several clinical trials and previous meta-analyses failed to determine whether AC could improve clinical outcomes in uterine leiomyosarcoma (uLMS). The aim of this systematic review and meta-analysis was to compare AC (with or without radiotherapy) versus observation (obs) after primary surgery in early stage uLMS. MATERIALS AND METHODS: Randomized controlled (RCTs) and non-randomized studies (NRSs) were retrieved. Outcomes of interest were as follows: distant recurrence rate, locoregional recurrence rate and overall recurrence rate. Results about distant recurrence rate, locoregional recurrence rate and overall recurrence rate were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method. RESULTS: Nine studies were included in the analysis, involving 545 patients (AC: 252, obs: 293). Compared with obs, AC did not reduce locoregional and distant recurrence rate, with a pooled OR of 1.36 and 0.63, respectively. Similarly, administration of AC did not decrease overall recurrence rate in comparison to obs. CONCLUSION: According to our results, AC (with or without radiotherapy) did not decrease recurrence rate in early stage uLMS; thus, the role of AC in this setting remains unclear.

Paratesticular Mesenchymal Malignancies: A Single-Center Case Series, Clinical Management, and Review of Literature.

Background: Primary soft tissue sarcomas arising from the male urinary and genital tract are rare tumors, only accounting for 1% to 2% of all malignancies of the genitourinary tract. Clinical management of advanced disease is lacking in standardized recommendations due to the rarity of the disease. To date, complete and extensive surgery represents the only curative and standardized approach for localized disease, while the impact of retroperitoneal lymphadenectomy and adjuvant treatments on clinical outcomes are still unclear. Similarly, a standardized systemic treatment for advanced metastatic disease is still missing. Cases Presentation: Four out of 274 patients have been identified in our sarcoma population. The mean age was 54 years (range = 45-73). The histotypes showed liposarcoma in 2 cases and leiomyosarcoma in the remaining 2 cases. In all 4 cases, the disease was localized at presentation, patients underwent complete surgery, and no adjuvant treatments were done. Three cases presented a recurrence of disease at a mean follow-up of 86 months (range = 60-106 months), more than 7 years. Two cases were treated with a second surgery and chemotherapy and 1 case only with chemotherapy. Discussion and Conclusions: Sharing data about clinical management of paratesticular mesenchymal tumors is a key issue due to the rarity of this tumor's subtype. In this article, we report the clinical history of 4 patients affected by paratesticular mesenchymal tumor. In particular, main issues of interest are the decision of postoperative treatment and systemic treatment at time of disease recurrence.

Molecular modelling evaluation of exon 18 His845_Asn848delinsPro PDGFRα mutation in a metastatic GIST patient responding to imatinib.

Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in approximately 5-7% of gastrointestinal stromal tumours (GIST). Over half of all PDGFRA mutations are represented by the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), recognized as D842V, conferring primary resistance to imatinib in vitro and in clinical observations due to the conformation of the kinase domain, which negatively affects imatinib binding. The lack of interaction between imatinib and the D842V PDGFRA mutated model has been established and widely confirmed in vivo. However, for the other PDGFRA mutations, the correlation between pre-clinical and clinical data is still unclear. An in silico evaluation of the p.His845_Asn848delinsPro mutation involving exon 18 of PDGFRA in a metastatic GIST patient responding to first-line imatinib has been provided. Docking analyses were performed, and the ligand-receptor interactions were evaluated with the jCE algorithm for structural alignment. The docking simulation and structural superimposition analysis show that PDGFRA p.His845_Asn848delinsPro stabilizes the imatinib binding site with the residues that are conserved in KIT. The in vivo evidence that PDGFRA p.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.

Personalization of regorafenib treatment in metastatic gastrointestinal stromal tumours in real-life clinical practice.

BACKGROUND: Regorafenib (REG) has now been approved as the standard third-line therapy in metastatic gastrointestinal stromal tumour (GIST) patients at the recommended dose and schedule of 160 mg once daily for the first 3 weeks of each 4-week cycle. However, it has a relevant toxicity profile that mainly occurs within the first cycles of therapy, and dose and schedule adjustments are often required to reduce the frequency or severity of adverse events and to avoid early treatment discontinuation. To date, large amounts of data on the use of REG in metastatic GIST patients in daily clinical practice are not available, and we lack information about how this treatment personalization really affects the quality of life (QoL) of patients. The aim of the present retrospective study is to build a comprehensive picture of all alternative REG strategies adopted in daily clinical practice for use in metastatic GIST patients. METHODS: Metastatic GIST patients treated with dose adjustment or alternative schedules of REG at seven reference Italian centres were retrospectively included. RESULTS: For a total of 62 metastatic GIST patients, we confirmed that REG treatment adjustment is common in clinical practice and that it is very heterogeneous, with approximately 20 different strategies being adopted. Independent of which strategy is chosen, treatment personalization has led to a clinical benefit defined as complete or partial resolution of side effects in almost all patients, affecting the duration of REG treatment. CONCLUSIONS: The personalization of REG, even if it is heterogeneous, seems to be crucial to maximize the overall treatment duration.

Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug-drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a 'real' population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control.

Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations.

PURPOSE: A subset of patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors show loss of function of succinate dehydrogenase, mostly due to germ-line mutations of succinate dehydrogenase subunits, with a predominance of succinate dehydrogenase subunit A. The clinical outcome of these patients seems favorable, as reported in small series in which patients were individually described. This work evaluates a retrospective survival analysis of a series of patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors. METHODS: Sixty-nine patients with metastatic gastrointestinal stromal tumors were included in the study (11 KIT/PDGFRA wild-type, of whom 6 were succinate dehydrogenase deficient, 5 were non-succinate dehydrogenase deficient, and 58 were KIT/PDGFRA mutant). All six succinate dehydrogenase-deficient patients harbored SDHA mutations. Kaplan-Meier curves and log-rank tests were used to compare the survival of patients with succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors with that of KIT/PDGFRA wild-type patients without succinate dehydrogenase deficiency and patients with KIT/PDGFRA-mutant gastrointestinal stromal tumors. RESULTS: Follow-up ranged from 8.5 to 200.7 months. The difference between succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors and KIT/PDGFRA-mutant or KIT/PDGFRA wild-type non-succinate dehydrogenase deficient gastrointestinal stromal tumors was significant considering different analyses (P = 0.007 and P = 0.033, respectively, from diagnosis of gastrointestinal stromal tumor for the whole study population; P = 0.005 and P = 0.018, respectively, from diagnosis of metastatic disease for the whole study population; P = 0.007 for only patients who were metastatic at diagnosis). CONCLUSION: Patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors harboring succinate dehydrogenase subunit A mutations present an impressively long survival. These patients should be identified in clinical practice to better tailor treatments and follow-up over time.

Alternative schedules or integration strategies to maximise treatment duration with sunitinib in patients with gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumour of the gastrointestinal tract. The advent of targeted kinase-inhibitors has revolutionised treatment strategies and clinical outcomes for patients with advanced GIST. In the majority of countries, sunitinib is the only approved second-line treatment option for advanced GIST patients, who are resistant or intolerant to imatinib. However, sunitinib is associated with various adverse events, which often result in a reduction of the dosage, and interruption or suspension of therapy. Effective therapy management is essential to obtain the maximum clinical benefit, and includes adequate side effect management as well as optimization of dosing and treatment duration. In the current study, examples of maximization of treatment with sunitinib are presented, describing three clinical cases in which therapy with sunitinib was continued via the adoption of alternative reduced schedules or an additional loco-regional treatment, in order to manage toxicities or overcome progressive disease.

Microscopic margins of resection influence primary gastrointestinal stromal tumor survival.

BACKGROUND: Primary gastrointestinal stromal tumors (GISTs) are stromal tumors that arise from the gastrointestinal tract. Both surgical resection and molecular therapy are crucial in the treatment of these tumors. This study analyzes the outcomes of 151 patients with GIST treated at 3 institutions. These institutions comprise the GISTologist Study Group and provided follow-up data. PATIENTS AND METHODS: 151 patients with primary GIST were admitted and treated at the St. Orsola-Malpighi University Hospital in Bologna, Italy, the Catholic University Hospital in Rome, Italy, and the Modena University Hospital and National Cancer Institute in Naples, Italy, over the past 11 years. Patient data as well as tumor and therapy variables were studied to identify factors predicting survival with a focus on the microscopic margins of resection. RESULTS: All 151 patients had primary disease without metastasis and underwent complete resection of gross disease. The 5-year disease-free survival rate was 77%. Disease-free survival was predicted by tumor size, mitotic count, and margins of resection. Recurrence of disease after resection was predominantly intra-abdominal. CONCLUSIONS: Tumor size, mitotic count, and microscopic margins of resection predict disease-free survival in patients with primary GIST.

Duration of adjuvant treatment following radical resection of metastases from gastrointestinal stromal tumours.

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.

Impressive long-term disease stabilization by nilotinib in two pretreated patients with KIT/PDGFRA wild-type metastatic gastrointestinal stromal tumours.

KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features.

Late recurrences of gastrointestinal stromal tumours (GISTs) after 5 years of follow-up.

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.

Three cases of bone metastases in patients with gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib) are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age), and one man (62 years of age). Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

Clinical, radiological and biological features of lung metastases in gastrointestinal stromal tumors (case reports).

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.

Efficacy of hormonal suppression in a patient with chyluria due to lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare lung disease affecting almost exclusively young women, characterised by abnormal proliferation of atypical smooth muscle cells. We describe a young woman presenting with chyluria secondary to the presence of a large retroperitoneal lymphangioleiomyoma. Immunohistochemical analysis revealed HMB45-negative LAM cells (HMB45 staining is absent only in rare cases) expressing low levels of estrogen receptors. Estrogen suppressive treatment with triptoreline, a synthetic analogue of Gn-RH, resulted in dramatic reduction of the retroperitoneal mass size. The role of estrogens in the pathogenesis of LAM remains poorly understood, and hormonal therapy is still debated, but this case suggests that at least in some LAM patients, possibly those with HMB45-negative disease and estrogen receptor expression, hormonal therapy may be effective in controlling the disease process.

Management of patients with gastrointestinal stromal tumor in clinical practice in Italy: a critical "event tree model" analysis of decision-making processes and outcomes.

AIMS AND BACKGROUND: Even though the standard treatment of patients affected by gastrointestinal stromal tumors has been well defined by clinical trials and clinical guidelines, in practice it may be different from those proposed in the literature. This paper reports and comments on a critical picture of the management of patients with gastrointestinal stromal tumors who received at least one treatment before arriving at our GIST Study Group. METHODS AND STUDY DESIGN: Attention was focused on 60 patients from various hospitals. Retrospective clinical data were recorded and analyzed with the "event tree" model, which describes the algorithm of all treatment options that each patient received before. Responses from first to fourth line of therapy, time to progression, and survival analysis were also analyzed. RESULTS: Starting from the diagnosis of disease, seven possible therapeutic event trees were identified: one for 7 unresectable patients and six different trees for 53 recurred patients who initially underwent surgery. The event trees describe the multitude of different treatments that patients with gastrointestinal stromal tumors received during the course of their disease. CONCLUSIONS: In clinical practice, the treatment of patients affected by gastrointestinal stromal tumor is still difficult, and the published recommendations often do not cover all therapeutic decisions for all clinical presentations of disease. Multidisciplinary dedicated teams are needed to offer the possibility to receive appropriate surgery and innovative medical therapies. The formation of formalized GIST Units is in progress in several parts of Italy. The GIST Units can be organized in a network to facilitate discussion and agreement for the wide variety of clinical presentation.

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number.

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.