Tumor do estroma gastrintestinal (GIST): relato de caso

The authors report a case of a male patient in his forties with progressive abdominal pain associated with weight loss, dyspnea, and edema of the inferior limbs, culminating in a surgical acute abdomen. A segmental enterectomy containing a lesion of about 10cm in diameter was performed. It was later confirmed, by means of immuno-hystochemistry, as being a Gastrointestinal Stromal Tumor of high biological aggressiveness. Etiology, diagnosis, classification, prognosis and therapeutic with Imatinib Mesylate - STI-571 (Glivec® - Novartis) are hence discussed.

Mechanisms Contributing to Tyrosin Kinase Inhibitor Resistance in GISTs: Toward a Personalized Therapy

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. This work considers the pharmacological response in GIST patients treated with imatinib by two different angles: the genetic and somatic point of view. We analyzed polymorphisms influence on treatment outcome, keeping in consideration SNPs in genes involved in drug transport and folate pathway. Naturally, all these intriguing results cannot be considered as the only main mechanism in imatinib response. GIST mainly depends by oncogenic gain of function mutations in tyrosin kinase receptor genes, KIT or PDGFRA, and the mutational status of these two genes or acquisition of secondary mutation is considered the main player in GIST development and progression. To this purpose we analyzed the secondary mutations to better understand how these are involved in imatinib resistance. In our analysis we considered both imatinib and the second line treatment, sunitinib, in a subset of progressive patients. KIT/PDGFRA mutation analysis is an important tool for physicians, as specific mutations may guide therapeutic choices. Currently, the only adaptations in treatment strategy include imatinib starting dose of 800 mg/daily in KIT exon-9-mutated GISTs. In the attempt to individualize treatment, genetic polymorphisms represent a novelty in the definition of biomarkers of imatinib response in addition to the use of tumor genotype. Accumulating data indicate a contributing role of pharmacokinetics in imatinib efficacy, as well as initial response, time to progression and acquired resistance. At the same time it is becoming evident that genetic host factors may contribute to the observed pharmacokinetic inter-patient variability. Genetic polymorphisms in transporters and metabolism may affect the activity or stability of the encoded enzymes. Thus, integrating pharmacogenetic data of imatinib transporters and metabolizing genes, whose interplay has yet to be fully unraveled, has the potential to provide further insight into imatinib response/resistance mechanisms.

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.

p.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib?

Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.

Retrocaval mass in patient with von Recklinghausen disease. Case report

Type I Neurofibromatosis (NF1) is an autosomal-dominant inheritable disorder, with an incidence of 1:3,000, and a prevalence of 1:4,000 to 5,000. Pathogenesis is based on mutations of the NF1 gene, a tumor suppressor gene encoding a cytoplasmic protein named neurofibromin that controls cellular proliferation. Patients affected by NF1 typically present with cutaneous neurofibromas, cafè au lait spots and eye involvement, but they can also be affected by various visceral tumors, such as neurofibromas (nodular or plexiform type), gastrointestinal stromal tumors or endocrine tumors, such as pheochromocytomas. Visceral neurofibromas are often asymptomatic but when growing in size they may present with pain, palpable abdominal mass, symptoms secondary to bowel obstruction or main vessels compression, and even gastrointestinal bleeding when mucosa or submucosa are involved. In these cases surgery becomes mandatory in order to remove all neoplastic tissue. The Authors describe a case of a young man affected by NF1 with associated retrocaval abdominal mass with compression and displacement of the inferior vena cava, thus requiring a complex surgical procedure.

Laparoscopic-endoscopic rendez-vous resection of iuxta-cardial gastric GIST

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and they often require a surgical removal. Gastrointestinal stromal tumors can originate from any part of the gastrointestinal tract but gastric location is the most common. In the past the risk of rupture of pseudocapsula and peritoneal dissemination have discouraged surgeons from making a minimally invasive surgical treatment. Recently laparoscopic wedge resection has been proposed. Performance of this mini-invasive technique is however difficult in some gastric location of gastrointestinal stromal tumors, such as iuxta-cardial region. The Authors report and discuss a new technique they used to remove a gastrointestinal stromal tumor located just below the cardia, using a rendez-vous endoscopic and laparoscopic technique.

Comprehensive characterization of SDH-deficient GIST using NGS data and iPSC models

Gastrointestinal stromal tumors (GIST) are the most common di tumors of the gastrointestinal tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. The vast majority of GISTs (75–85% of GIST) harbor KIT or PDGFRA mutations. A small percentage of GIST (about 10‐15%) do not harbor any of these driver mutations and have historically been called wild-type (WT). Among them, from 20% to 40% show loss of function of the succinate dehydrogenase complex (SDH), also defined as SDH‐deficient GIST. SDH-deficient GISTs display distinctive clinical and pathological features, and can be sporadic or associated with Carney triad or Carney-Stratakis syndrome. These tumors arise most frequently in the stomach with predilection to distal stomach and antrum, have a multi-nodular growth, display a histological epithelioid phenotype, and present frequent lympho-vascular invasion. Occurrence of lymph node metastases and indolent course are representative features of SDH-deficient GISTs. This subset of GIST is known for the immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals the loss of function of the entire SDH-complex. The overall aim of my PhD project consists of the comprehensive characterization of SDH deficient GIST. Throughout the project, clinical, molecular and cellular characterizations were performed using next-generation sequencing technologies (NGS), that has the potential to allow the identification of molecular patterns useful for the diagnosis and development of novel treatments. Moreover, while there are many different cell lines and preclinical models of KIT/PDGFRA mutant GIST, no reliable cell model of SDH-deficient GIST has currently been developed, which could be used for studies on tumor evolution and in vitro assessments of drug response. Therefore, another aim of this project was to develop a pre-clinical model of SDH deficient GIST using the novel technology of induced pluripotent stem cells (iPSC).

Diffusion-weighted MRI in metastatic gastrointestinal tumors (GIST): A pilot study on the assessment of treatment response in comparison with 18F-FDG PET/CT

Purpose: To evaluate the clinical potential of diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) mapping for the assessment of gastrointestinal stromal tumor (GIST) response to targeted therapy in comparison with 18F-FDG PET/CT. Methods and materials: Five patients (3W/2M, aged 56 ± 13 y) with metastatic GIST underwent both a 18F-FDG PET/CT (Discovery LS, GE Healthcare) and a MRI (VIBE T1 Gd, DWI [b = 50,300,600] and ADC mapping) before and after change in therapy. Exams were first analyzed blindly, then PET/CT images were coregistered to T1 Gd MR images for lesion detection. SUVmax and ADC were measured for the six largest lesions on MRI. The relationship between SUVmax and ADC was analyzed using Spearman's correlation. Results: Altogether, 24 lesions (15 hepatic and 9 non-hepatic) were analyzed on both modalities. Three PET/CT lesions (12.5%) were initially not considered on ADC and 4 lesions on the second PET/CT were excluded because of hepatic vascular activity spillover. SUVmax decreased from 7.2 ± 7.7 g/mL to 5.9 ± 5.9 g/mL (P = 0.53) and ADC increased from 1.2x10-3 mm2/s ± 0.4 to 1.4x10-3 mm2/s ± 0.4 (P = 0.07). There was a significant association between SUVmax decrease and ADC increase (rho= -0.64, P = 0.004). Conclusion: Changes in ADC from diffusion-weighted MRI reflect response of 18F-FDG-avid GIST to therapy. The exact diagnostic value of DWI needs to be investigated further, as well as the effect of lesion size and time under therapy before imaging. Furthermore, the proven association between SUVmax and ADC may be useful for the assessment of treatment response in 18F-FDG non-avid GIST.

Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4weeks on/2weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand-foot syndrome, and hypertension.

Role of double-balloon enteroscopy in malignant small bowel tumors.

AIMTo assess the double-balloon enteroscopy (DBE) role in malignant small bowel tumors (MSBT). METHODS This is a retrospective descriptive study performed in a single center. All consecutive patients who underwent a DBE with final diagnosis of a malignant neoplasm from 2004 to 2014 in our referral center were included. Patient demographic and clinical pathological characteristics were recorded and reviewed. MSBT diagnosis was achieved either by DBE directed biopsy with multiple tissue sampling, endoscopic findings or histological analysis of surgical specimen. We have analyzed double-balloon enteroscopy impact in outcome and clinical course of these patients. RESULTS Of 627 patients, 28 (4.5%) (mean age = 60 ± 17.3 years) underwent 30 procedures (25 anterograde, 5 retrograde) and were diagnosed of a malignant tumor. Patients presented with obscure gastrointestinal bleeding (n = 19, 67.9%), occlusion syndrome (n = 7, 25%) and diarrhea (n = 1, 3.6%). They were diagnosed by DBE biopsy (n = 18, 64.3%), histological analysis of surgical specimen (n = 7, 25%) and unequivocal endoscopic findings (n = 2, 7.1%). Gastrointestinal stromal tumor (n = 8, 28.6%), adenocarcinoma (n = 7, 25%), lymphoma (n = 4, 14.3%), neuroendocrine tumor (n = 4, 14.3%), metastatic (n = 3, 10.7%) and Kaposi sarcoma (n = 1, 3.6%) were identified. DBE modified outcome in 7 cases (25%), delaying or avoiding emergency surgery (n = 3), modifying surgery approach (n = 2) and indicating emergency SB partial resection instead of elective approach (n = 2). CONCLUSION DBE may be critical in the management of MSBT providing additional information that may be decisive in the clinical course of these patients.

Tumor estromal gastrointestinal de intestino delgado

Stromal tumors of the gastrointestinal tract (gists) represent relatively rare lesions that arise from connective tissue elements located along the entire length of the gut. They were initially identified by immunohistochemical investigation, proving their origin from nondifferentiated mesenchymal cells. Only a minority of this lesions, mainly those confined to the esophagus and rectum, have been shown to correspond to mature, well-differentiated types of neoplasms such as leiomyoma or leiomyosarcoma. The majority of gists corresponds to a heterogeneous group of lesions that have as their common denominator an immature proliferation of epithelioid or spindle cells arising from its muscle layers, or between them, showing partial or incomplete myoide, neural, ganglionic, or mixed features of differentiation. This case report intends to show a gist of small bowel in a male, 46 years old, with a two-year of evolution.

Ovarian sertoli-leydig cell tumour with heterologous elements of gastrointestinal type associated with elevated serum alpha-fetoprotein level: an unusual case and literature review

Here we describe the case of a 19-year-old woman with a poorly differentiated ovarian Sertoli-Leydig cell tumor and an elevated serum alphafetoprotein level. The patient presented with diffuse abdominal pain and bloating. Physical examination, ultrasound, and magnetic resonance imaging revealed a right ovarian tumor that was histopathologically diagnosed as a poorly differentiated Sertoli-Leydig cell tumor with heterologous elements. Her alpha-fetoprotein serum level was undetectable after tumor resection. Sertoli-Leydig cell tumors are rare sex cord-stromal tumors that account for 0.5% of all ovarian neoplasms. Sertoli-Leydig cell tumors tend to be unilateral and occur in women under 30 years of age. Although they are the most common virilizing tumor of the ovary, about 60% are endocrineinactive tumors. Elevated serum levels of alpha-fetoprotein are rarely associated with Sertoli-Leydig cell tumors, with only approximately 30 such cases previously reported in the literature. The differential diagnosis should include common alpha-fetoprotein-producing ovarian entities such as germ cell tumors, as well as other non-germ cell tumors that have been rarely reported to produce this tumor marker.

[preservation Of The Fertility And The Ovaries In Women With Benign Adnexal Tumors].

To evaluate the sparing of fertility and ovaries in women submitted to surgical treatment for benign adnexal tumors. Between February 2010 and January 2014, 206 patients were included in this observational study as they were submitted to surgical treatment for benign ovarian tumors at CAISM, a tertiary hospital. Fertility sparing surgery was defined as tumorectomy or unilateral salpingoophorectomy without hysterectomy in premenopausal women. Preservation of the ovary occurred when at least one ovary or part of it was mantained. Of the 206 women with benign tumors, 120 (58%) were premenopausal and 86 (42%) were postmenopausal. There were 36 (30%) ovarian germ cell tumors, 31 (26%) epithelial neoplasms and 11 (9%) sex-cord stromal tumors among premenopausal women. In the group of postmenopausal women, 35 (41%) epithelial neoplasms, 27 (31%) sex-cord stromal tumors and 8 (9%) ovarian germ cell tumors were identified. Among 36 women with non-neoplastic ovarian tumors, 21 (58%) had endometriomas and 8 (22%) functional cysts. Among 22 women with extra-ovarian tumors, uterine leiomyomatosis was the most frequent finding (50%). In the group of women who were ≤ 35 years old, 26 (57%) were treated by tumorectomy and 18 (39%) were submitted to unilateral salpingoophorectomy with sparing of the uterus and the contralateral ovary. Women who were ≤ 35 years old were more frequently operated by laparoscopy which was associated with a higher number of fertility sparing procedures when compared to laparotomy (p<0.01). Twenty-six (28%) women submitted to hysterectomy with bilateral salpingoophorectomy were premenopausal. Although there is a trend to perform only tumorectomy in women who are ≤ 35 years old, a significant number of young women is still treated by salpingoophorectomy. Among 36- to 45-year-old women, only 70% had their fertility spared, while 20% had both ovaries removed. However, whenever possible, we must try to preserve the ovaries, mainly in premenopausal women.

Diffusion-weighted MRI in metastatic gastrointestinal tumours (GIST): a pilot study on the assessment of treatment response in comparison with 18 F-FDG PET/CT

Purpose: To evaluate the clinical potential of diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) mapping for the assessment of gastrointestinal stromal tumour (GIST) response to targeted therapy in comparison with 18F-FDG PET/CT Methods and Materials: Five patients (3 W/2M, aged 56±13 y) with metastatic GIST underwent both a 18F-FDG PET/CT (Discovery LS, GE Healthcare) and a MRI (VIBE T1 Gd, DWI [b = 50,300,600] and ADC mapping) before and after change in therapy. Exams were first analysed blindly and then PET/CT images were coregistered to T1 Gd MR images for lesion detection. SUVmax and ADC were measured for the six largest lesions on MRI. The relationship between SUVmax and ADC was analysed using Spearman's correlation. Results: Altogether, 24 lesions (15 hepatic and 9 non-hepatic) were analysed on both modalities. Three PET/CT lesions (12.5%) were initially not considered on ADC and 4 lesions on the second PET/CT were excluded because of hepatic vascular activity spillover. SUVmax decreased from 7.2±7.7 g/mL to 5.9±5.9 g/mL (P = 0.53) and ADC increased from 1.2x10-3 mm2/s ± 0.4 to 1.4x10-3 mm2/s ± 0.4 (P = 0.07). There was a significant association between SUVmax decrease and ADC increase (rho= -0.64, P = 0.004). Conclusion: Changes in ADC from diffusion-weighted MRI reflect response of 18F-FDG-avid GIST to therapy. The exact diagnostic value of DWI needs to be investigated further, as well as the effect of lesion size and time under therapy before imaging. Furthermore, the proven association between SUVmax and ADC may be useful for the assessment of treatment response in 18F-FDG non-avid GIST.

Tumor estromal do trato gastrintestinal primário da papila duodenal

The majority gastrointestinal wall tumors previously considered leiomyomas or leiomyosarcomas were reclassified into Gastrointestinal Stromal Tumours because of typical imunohistochemic, genetic and biologic behaviors findings. We present a case report of Gastrointestinal Stromal Tumor primary of the duodenal papilla causing digestive haemorrage that was submitted to surgical treatment.