High-risk Gastrointestinal Stromal Tumors Research Articles

Gastrointestinal stromal tumor: Our experience

Gastrointestinal stromal tumor: Our experience

The role of surgery in the multidisciplinary management of patients with localized gastrointestinal stromal tumors

Surgical resection of localized gastrointestinal stromal tumors (GISTs) is associated with recurrence rates of approximately 50% at 5 years of follow-up. The introduction of tyrosine kinase inhibitors, such as imatinib, improved overall survival rates in advanced disease, while in the adjuvant setting, improved recurrence-free survival following resection of high-risk GIST. The demonstration of the clinical benefit of tyrosine kinase inhibitors in both the metastatic and adjuvant settings generated interest in neoadjuvant approaches for patients with operable locally advanced disease, particularly in difficult anatomic locations. The potential impact of tumor downsizing in areas such as the gastroesophageal junction, the duodenum or the rectum, on the extent of surgical resection and morbidity is real. The ongoing research regarding neoadjuvant therapy, the duration of adjuvant therapy and the optimal means by which to risk stratify patients with GIST continues to keep the treatment of this disease at the forefront of personalized cancer care.

Patient with high-risk GIST not associated with c-KIT mutations

A patient was diagnosed with neurofibromatosis type 1 (NF1) and gastrointestinal stromal tumour (GIST). This is not simply a coincidence; numerous molecular and genetic studies have established a close relationship between the two disorders, suggesting that GIST should be included in the clinical spectrum of NF1. In NF1 presenting GIST, the tumour usually develops in the small intestine. We present a 51-year-old woman diagnosed with NF1, who on follow-up showed an intra-abdominal mass. The pathological study of the mass after surgery led to the diagnosis of GIST with no mutations in exons 9, 11, 13 and 17 of the c-KIT gene or in exons 12, 14 and 18 of the platelet-derived growth factor receptor α gene. Imatinib was initiated as coadjuvant therapy with good tolerance, no toxicity and without evidence of relapse during follow-up.

P-0133 Long Term Follow up of Managing Patients with Metastatic Gastrointestinal Stromal Tumour with Imatinib Mesylate at an Indian Centre

ABSTRACT Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most commonly originate in the stomach and small intestine. One third of high risk, malignant GIST have poor prognosis after surgery. The most common site of the metastasis is the liver. Imatinib mesylate is a KIT tyrosine kinase inhibitor with effect on metastatic GIST. We report our long term follow up in patients with metastatic GIST receiving Imatinib. Methods Retrospective analysis of patients diagnosed with metastatic GIST from 2004 to 2011 at our centre, who received Imatinib mesylate at a dose of 400 mg per day over 6 months. Patients' profile, tumor response, side effects, time to progression and survival were evaluated. Results Eight C-Kit or CD 117 positive GIST patients were enrolled at our centre, there were 6 (75%) male and 2 (25%) female. Median age of patients was 64 years (range 38 to 86 years). Four GISTs originated from stomach, 2 from Rectum, 1 each from jejunum & ileum. Most common symptoms were anaemia and pain abdomen. Liver metastasis in 5, lung in 2 and breast in 1. Four patients underwent surgical treatment. Majority of them (75%) were of the high-risk malignant category. Histologically, the majority had a pure spindle cell morphology. All of them started on Imatinib, all had palliative benefit, half had significant shrinkage of tumour mass. Most common side effects were periorbital oedema, muscle cramps, and diarrhea. Follow-up of 4 cases, treated with adjuvant Imatinib for 6 months after surgical resection showed stable disease for periods from 5 to 8 years. However, 2 cases treated with Imatinib for longer than 6 months had problems due to recurrent, metastatic, or inoperable disease. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up of 38 months (range 13 to 96 months), the 5 year survival rate was 88%. Conclusion Adjuvant therapy Imatinib should be used for patients with high-risk advanced GISTs. The Imatinib mesylate treatment can prolong the survival of the patients who have metastatic GIST before or after radical surgery without toxicity of chemotherapy.

Risk of disease recurrence and mortality in gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib adjuvant therapy: A chart review analysis.

e20511 Background: The benefits of long-term (36 months) use of adjuvant imatinib (IM) in high risk GIST patients (pts) have been demonstrated in a recent multicenter, prospective clinical trial that compared efficacy and safety of 3 years vs 1 year IM treatment. However, in clinical practice, there is no consensus on the optimal IM treatment duration after surgery. The objective of this retrospective observational study was to compare the risk of recurrence and survival among primary resectable Kit positive GIST pts treated with adjuvant IM for a short vs an extended period of time in a real-world setting. Methods: Information on adult pts with primary resectable Kit positive GIST initiating imatinib ≤84 days after surgery was collected from 248 U.S. oncologists using an online data collection form. Detailed pt information following first GIST diagnosis, including demographic, GIST-related characteristics (e.g., risk profile), comorbidity profile, IM treatment characteristics, disease recurrence and mortality was collected for pts with short-term (6-12 months) and long-term IM use (≥24 months). Disease recurrence and mortality rates were estimated from the 1st surgery date to the 1st evidence of recurrence, mortality, or end of observation period. Multivariate Cox proportional hazard models were used to compare recurrence and mortality rates between short vs long term IM use pts. Results: Among the 246 short-term and 395 long-term IM pts, the median follow up was 884 and 963 days, respectively. The average age was similar [59.0 (10.4) vs 58.1 (9.5); p=.23] but short-term pts had less males [57.7% vs 69.6% (p<.01)] and a lower Miettinen risk score [0.3 vs 0.4, p< .01)] than long-term pts. Disease recurrence [7.3 vs 1.8%, (p< .01)] and mortality rates [6.9% vs 2.3%, (p < .01)] were also higher in short- vs long-term pts. The adjusted risk of recurrence was 4.77 times [95% CI: 1.98 – 11.48, (p<.01)] higher and mortality risk was 3.44 times [CI: 1.53 – 7.75, (p<.01)] higher in short- vs long-term pts. Conclusions: Use of IM over an extended period of time is associated with a reduction in long-term risk of disease recurrence and mortality.

Integrating Bioinformatics and Clinicopathological Research of Gastrointestinal Stromal Tumors: Identification of Aurora Kinase A as a Poor Risk Marker

For completely resected primary gastrointestinal stromal tumors (GISTs), mitotic rate, tumor size, and tumor location are important risk factors for recurrence. However, molecular markers for recurrence are still lacking. We reanalyzed GIST gene expression profile GSE8167 available from the Gene Expression Omnibus (GEO) and confirmed the prognostic influence of one selected gene, aurora kinase A (AURKA), in another cohort of 142 patients using immunohistochemistry (IHC). Thirty-two cases in GSE8167 were classified into two risk groups with distinct recurrence-free survival (RFS) and expression profiles using modified criteria of Miettinen et al. from the Armed Forces Institute of Pathology (AFIP-Miettinen). AURKA was among the 19 genes common to the top 50 features of the high-risk phenotype and a 67-gene signature called the complexity index in sarcomas. AURKA was significantly overexpressed in the high-risk group, and patients with high AURKA expression had significantly worse RFS than those with low expression. In the IHC-validated cohort, AURKA expression was significantly higher in nongastric tumors than in gastric tumors and was significantly correlated with AFIP-Miettinen risk group. Univariate analysis showed that RFS was significantly influenced by tumor size, mitotic count, AFIP-Miettinen risk group classification, and AURKA expression. However, only tumor size (P = 0.017), mitotic count (P = 0.007), and AURKA expression (P = 0.039) were identified as independent unfavorable prognostic factors for RFS in multivariate analysis. By integrating bioinformatics and clinicopathological studies, AURKA was identified as a marker for high-risk GIST.

Adjuvant treatment of GIST: patient selection and treatment strategies

Tyrosine kinase inhibitors that target the key molecular drivers of gastrointestinal stromal tumour (GIST) are effective treatments of advanced-stage GIST. Yet, most of these patients succumb to the disease. Approximately 60% of patients with GIST are cured by surgery, and these individuals can be identified by risk stratification schemes based on tumour size, mitosis count and site, and assessment of rupture. Two large randomized trials have evaluated imatinib as adjuvant treatment for operable, KIT-positive GIST; adjuvant imatinib substantially improved time to recurrence. One of these trials reported that 3 years of adjuvant imatinib improves overall survival of patients who have a high estimated risk for recurrence of GIST compared with 1 year of imatinib. The optimal adjuvant strategy remains unknown and some patients might benefit from longer than 3 years of imatinib treatment. However, a strategy that involves GIST risk assessment following surgery using a validated scheme, administration of adjuvant imatinib for 3 years, patient monitoring during and after completion of imatinib to detect recurrence early, and reinstitution of imatinib if GIST recurs is a reasonable choice for care of patients with high-risk GIST.

Abstract LB-471: Upregulation of miR-196a and HOTAIR is associated with the malignancy of gastrointestinal stromal tumors

Abstract Although dysregulation of microRNA (miRNA) expression is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. In the present study, we aimed to identify miRNAs associated with the malignant potential of GISTs. miRNA microarray analysis enabled us to detect the frequent upregulation of miR-196a in high-risk GISTs. Quantitative RT-PCR analysis of 56 fresh frozen and 100 formalin-fixed paraffin-embedded (FFPE) specimens confirmed that overexpression of miR-196a is associated with a high-risk grade, metastasis and poor survival among GIST patients (hazard ratio, 9.1; P < 0.001). The miR-196a genes are located within the HOX gene clusters, and gene expression microarray analysis revealed that HOXC genes and a large intergenic non-coding RNA (lincRNA), HOTAIR, were concurrently upregulated in GISTs overexpressing miR-196a. Elevated HOTAIR expression was also strongly associated with the high-risk category, metastasis and poor clinical outcome of GISTs (hazard ratio, 9.0; P = 0.034). RNAi-mediated knockdown of HOTAIR suppressed the invasiveness of GIST cells, and induced a significant change in the expression profile of genes that included previously reported HOTAIR target genes. This is the first report of concurrent overexpression of HOX genes and collinear non-coding RNAs in human malignancy, and our data suggest that miR-196a and HOTAIR could be useful biomarkers and novel therapeutic targets in malignant GISTs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-471. doi:1538-7445.AM2012-LB-471

Upregulation of miR-196a andHOTAIRDrive Malignant Character in Gastrointestinal Stromal Tumors

Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs.

Greater omentum gastrointestinal stromal tumor withPDGFRA-mutation and hemoperitoneum

Although gastrointestinal stromal tumor (GIST) occurs generally in the digestive tract, omental GIST is very rare. We report the first case of an adult greater omental GIST with a new platelet-derived growth factor receptor α gene (PDGFRA)-mutation with hemoperitoneum. A 43-year-old man was admitted to our hospital complaining of acute abdominal pain. Abdominal contrast-enhanced computed tomography revealed a huge mass in the right abdominal cavity, and a large accumulation of fluid in the pelvic cavity, suggesting hemoperitoneum. We diagnosed the rupture as an intra-abdominal tumor, and an emergency tumorectomy was performed with resection of the greater omentum. This tumor was located in the distal right side of the greater omentum, and showed no continuity with the gastric wall. The tumor occurred primarily in the greater omentum. The resected tumor was about 19 cm × 12 cm × 14 cm in diameter, and weighed 1529 g. Histologically, the tumor was composed of epithelioid-shaped cells with high cellularity, and was positive for CD117 and CD34, and negative for S-100, α-smooth muscle actin. The mitosis was 6/50 under high power field. This case showed exon 18 mutation of PDGFRA with 846 (Asp to Glu) substitution, 848 (Asn to Lys) substitution. This is the first report of this PDGFRA mutation in omental GIST, and this might play an important role in the tumorigenesis of this case. Based on these findings, the tumor was diagnosed as high risk GIST primarily occurring in the greater omentum. The patient was treated with imatinib at a dose of 400 mg/d as adjuvant chemotherapy, and has been followed up for 24 mo with no evidence of recurrence.

Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132

Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.

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.

Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients

Imatinib mesylate, a small-molecule tyrosine kinase inhibitor, is currently used for adjuvant therapy of patients who have undergone resection of high-risk gastrointestinal stromal tumors (GISTs). There are no data concerning the efficacy and safety of postoperative adjuvant therapy with imatinib for Japanese or East Asian patients with GIST. A single-arm, open-label, multicenter trial was conducted in 17 hospitals in Japan. The eligibility criteria included histologically proven primary high-risk GISTs with macroscopic complete resection. Patients were treated with imatinib at a dose of 400 mg/day for 1 year after surgery. The primary endpoint was recurrence-free survival as assessed by Kaplan-Meier analysis. The secondary endpoints were overall survival and safety. This study was registered with ClinicalTrials.gov, number NCT00171977. A total of 64 patients were enrolled between September 2004 and July 2006. The median age of the patients was 59.5 years. Forty-nine (76.6%) patients completed the 1-year treatment, whereas 15 (23.4%) patients did not complete the treatment owing to recurrence, toxicities, and consent withdrawal. At the median follow-up period of 109 weeks, 20 patients had recurrence. The 3-year recurrence rate was 42.7% (95% confidence interval 29.2-56.3%), which exceeded the expected recurrence rate in this trial. The recurrence-free and overall survival rates at 2 years were 71.1 and 93.7%, respectively. The most frequent adverse drug reaction of any grade was eyelid edema (48.4%), followed by neutropenia (40.6%), leukopenia (39.1%), nausea (39.1%), rash (37.5%), and peripheral edema (37.5%), most of which were mild and manageable. Adjuvant therapy with imatinib at 400 mg/day for 1 year is well tolerated by Japanese patients and possibly reduces the risk of early recurrence of high-risk GISTs.

Adjuvant imatinib therapy for gastrointestinal stromal tumors

Surgery is the standard of care for primary resectable gastrointestinal stromal tumors (GISTs), but half of surgically treated patients relapse. Imatinib (IM) has been shown to prolong recurrence-free survival after complete surgery and is now approved as adjuvant therapy (400 mg/day) for high-risk GIST patients. IM is well tolerated, with mild to moderate side effects observed. Whether adjuvant IM prolongs overall survival is under evaluation in two ongoing clinical trials.

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

This is the first study from Central America to analyze genetic mutations and histopathological features associated with gastrointestinal stromal tumors (GIST). Mutations found in the tyrosine kinase membrane receptors c-kit and pdgfra are associated with clinical and pathological characteristics of GIST. New drugs that inhibit the expression of these oncogenes at the molecular level substantially improve the quality of life for patients with this tumor. It is therefore essential for patient care in Panama that genetic analysis of GIST tumors continues to develop from the pilot study presented herein into routine clinical use. This study evaluated 39 cases of GIST in Panama, using samples archived at the Instituto Oncológico Nacional from 1994 to 2004. DNA from paraffin‑embedded tumor tissues was isolated and amplified for the exons of c-kit and pdgfra associated with a high frequency of mutations. Direct PCR sequencing of specific exons was performed, and those with different alleles were cloned and re-sequenced. Amino acid sequences were inferred from DNA and aligned to Genbank reference sequences to determine the position and type of mutation. The highest frequency of mutations was found in exon 11 of the c-kit gene (70%). Mutations found in this exon were heterogeneous, while only one type of mutation (p.A502_Y503dup) was observed in c-kit exon 9. Mutations in the pdgfra gene constituted several substitutions, with the deletion p.D842V being observed most frequently. The observed GIST-associated mutations were previously described. Four patients with mutations associated with familial GIST were also found. The majority (66%) of patients with mutations in exon 11 (residues 550-591) were considered to be at high risk and 75% of patients with mutations specifically within residues 556-560 (exon 11) were considered to have high-risk GIST. This is the first molecular study of GIST in Central America. It was performed to gain a better understanding of the cancer-associated mutations of KIT and platelet‑derived growth factor receptorα (PDGFRA) receptors. This may aid in the prediction of clinical evolution and guide the use of specific drug treatments in patients with GIST in Panama.

Incorporation of adjuvant therapy into the multimodality management of gastrointestinal stromal tumors of the stomach in the United States.

Gastrointestinal stromal tumors (GIST) treatment changed considerably with introduction of imatinib in 2001 and reports of early successes. However, little is known about imatinib incorporation into practice. Our objective was to examine the integration of adjuvant systemic therapy into GIST management. Patients with gastric GIST were identified (n=4508) from the National Cancer Data Base (2001-2007). Separate regression models were developed to examine factors associated with adjuvant and neoadjuvant therapy use. A total of 3050 patients underwent surgical resection. From 2001-2003 to 2006-2007, use of adjuvant therapy increased from 29 to 47% (P<0.001). Patients were less likely to receive adjuvant therapy if tumors were <3cm, low grade, had negative margins, were treated at low-volume centers, or were diagnosed during 2001-2003 (P<0.01). Adjuvant systemic therapy for lesions <3cm also increased (17 to 25%, P=0.001). For high-risk GISTs, adjuvant therapy use increased from 41 to 58% overall, with increases of 46 to 70% at high-volume centers and 40 to 48% at low-volume centers (P<0.001). Neoadjuvant therapy increased from 0 to 8%; patients were more likely to receive neoadjuvant treatment if their tumor was >6cm, treated at high-volume centers, or were diagnosed during 2006-2007 (P<0.001). Adjuvant systemic therapy use for GISTs was increasing and widespread prior to FDA approval of adjuvant imatinib, suggesting that contemporaneous advances in management of advanced GIST were being simultaneously and rapidly translated into the adjuvant setting. As relatively costly therapies are integrated into practice, more robust tracking systems are needed to monitor the incorporation of new treatments.

Adjuvant Imatinib treatment after R0 resection for patients with high‐risk gastrointestinal stromal tumors: A median follow‐up of 44 months

The optimal duration of Imatinib adjuvant treatment for patients with high-risk gastrointestinal stromal tumors (GISTs) is uncertain. A total of 90 patients with high-risk GISTs after curative resection were recruited into this non-randomized case-control study, including 35 having Imatinib adjuvant therapy and 55 having follow-up alone. The recurrence-free survival (RFS) was compared. After a median follow-up of 44.0 months, a significantly reduced recurrence rate was observed in the treatment group than the control group (17.1% vs. 78.2%, P = 0.000). One-year, 2-year, and 3-year RFS rates were 100% vs. 70.9%, 88.0% vs. 37.8%, and 88.0% vs. 27.5%, respectively; with a significant advantage for Imatinib adjuvant therapy versus the surgery only (P = 0.000, HR 0.122, 95% CI 0.041-0.363). Continuation Imatinib treatment further improved RFS by comparison with the interruption treatment (both 2-year and 3-year RFS were 95.8% vs. 63.6%, P = 0.011, HR 0.103, 95% CI 0.012-0.883). There were no serious adverse events in the adjuvant therapy group. Imatinib Adjuvant therapy could significantly prolong the RFS of patients with high-risk GISTs. Extended Imatinib adjuvant treatment strategy may further reduce the risk of relapse with a low drug resistance rate and toxicity profile.

Bone metastases from gastrointestinal stromal tumors (GISTs).

e20527 Background: Liver and peritoneum are the most common site of recurrences from gastrointestinal stromal tumors (GISTs). Bone metastases represent a rare finding in clinical practice and their biological significance and clinical management remain unsettled. Methods: We reviewed all patients with advanced/metastatic GIST at our institution and focused on cases with bone metastases, describing the clinical and radiological features of these lesions. Results: Among 71 patients, four had bone metastases. Two were female (82 and 54 years of age) and two were male (62 and 44 years of age). All four of them had an high-risk primary GIST, localized in small intestine in three cases, and in the stomach in the other one. One patient harboured a KIT esone 11 mutation (T>A 69429(p.V559d), one patient had a WT GIST and in the other patients mutational analysis was not assessable. Bone tumour involvement was present at the time of initial diagnosis in two patients, and occurred during the follow-up period after 7 and 2 years in the other two. In all patients bone metastases were associated to other visceral site of relapse. Radiologically, the lesions were diagnosed by CT-scan and had a lytic pattern in all cases, with a widespread skeletal involvement. In no case a single lesion was found. Clinically, bone metastases were symptomatic in three patients and presenting with a pathological fracture in a single case. In only one patient bone lesions were asymptomatic and diagnosed as occasional finding. All patients received zoledronic acid in association with TK inhibitors, obtaining a long stable disease in two cases whereas there was a quick disease progression in the other two cases. Only one patient was also treated with radiotherapy for palliative purpose. Conclusions: Although bone metastases are an infrequent site of recurrence from GISTs, they may become more prevalent due to increased patient life expectancy as well as the improvement in imaging techniques. By now their biological background and prognostic value and their clinical management are unknown. Moreover standard imaging and metabolic criteria for diagnosis and tumor response assessment are still lacking. These data should be collected in large series.

Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Long-term follow-up results of RTOG 0132.

10057 Background: Imatinib mesylate (IM), which inhibits the KIT and PDGFR tyrosine kinases, has known activity against GIST. We previously reported early results of the first reported multi-institutional prospective trial (RTOG 0132) using neoadjuvant imatinib mesylate (IM) either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic GIST (Eisenberg et al., JSO 2009). Methods: Patients with primary GIST (≥5cm, Group A) or operable metastatic/recurrent GIST (≥2 cm, Group B) received neoadjuvant IM (600 mg/day) for approximately two months and maintenance IM after surgery for 2 years. We have now updated the clinical outcomes including progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) at a median follow-up of 5.1 years and correlate these endpoints with duration of IM therapy. Results: Sixty-three patients were originally entered (53 analyzable), 31 patients in Group A and 22 in Group B. Estimated 5-year PFS and DSS were 57% A, 30% B; and 77% A, 77% B, respectively. Estimated 5-year OS was 77% for A, and 68% for B. Median time to progression has not been yet reached for Group A and is 4.4 years for Group B. In Cohort A, 7/11 patients progressed > 2 years from registration; 6/7 progressing patients had stopped IM prior to progression. In Cohort B, 10/13 patients progressed> 2 years from registration; 6/10 progressing patients had stopped IM prior to progression. The rate of treatment-related grade 4/5 toxicities was 23% (12/53). There was no increase in long term surgical complications using neoadjuvant and extended IM therapy. Conclusions: This long-term analysis of RTOG 0132 suggests a high percentage of patients progressed after discontinuation of 2-year maintenance IM therapy following surgical resection. Consideration should be given to studying longer treatment durations in high-risk GIST patients.

Synchronous well differentiated neuroendocrine tumour and gastrointestinal stromal tumour of the stomach: a case report

BackgroundWell differentiated neuroendocrine tumours (carcinoids), arising from cells of the diffuse neuroendocrine system, represent the most commonly encountered gastric endocrine tumours. Gastrointestinal stromal tumours (GISTs), which stem from interstitial Cajal cells located within the wall of the gastrointestinal tract and have a characteristic immunoreactivity for CD117 (c-kit protein), account for the majority of gastrointestinal mesenchymal neoplasms. Simultaneous occurrence of a GIST with a well differentiated neuroendocrine tumour in the stomach is very rare.MethodsClinical history, endoscopy and histopathological findings were utilized for our diagnostic considerations.ResultsWe report the coexistence of a high risk GIST with a well differentiated neuroendocrine tumour of benign clinical behavior, both located in the stomach, in a 62-year-old man previously operated for a gastric well differentiated neuroendocrine tumour with uncertain malignant behaviour.ConclusionsEven single well differentiated, sporadic, NETs of small size may coexist with GISTs. An appropriate initial therapeutic approach combined with a scrupulous follow-up seems to play a significant role in terms of preventing a metastatic disease.