Neoadjuvant Imatinib Mesylate Research Articles

Prone Jack-Knife Transanal Minimally Invasive Surgery: A Safe and Effective Approach for Anterior Low Rectal GI Stromal Tumors.

Subepithelial rectal lesions, including gastrointestinal stromal tumours (GIST), leiomyomas, neuroendocrine tumours, lipomas, and schwannomas, are rare surgical conditions. 1 Surgical management in this region often entails radical surgical excisions with stoma creation. Radical surgical excisions with stoma creation are often required for surgical management in this region. In this video, we demonstrate a transanal minimally invasive surgery (TAMIS) approach to anterior low rectal GIST. Patient underwent neoadjuvant Imatinib Mesylate after multidisciplinary team discussion, and were evaluated preoperatively with colonoscopy, pelvis MRI, and endoscopic ultrasound-guided tissue biopsy. 2,3 The procedure was performed with the patient in the prone jack-knife position and using the GelPOINT® Path transanal access, providing an excellent surgical platform. 4 The access channel was chosen based on the lesion's location from the anal verge, and ports were placed in a triangular fashion onto the GelSeal Cap, including an apex 10 mm sleeve for the telescope connected to the insufflation stabilization bag, two lower 10 mm working ports, and an additional port if traction was necessary. The RapidVac TM smoke evacuator was used for smooth surgery without fluctuating the surgical field and to achieve optimal vision. Dissection was initiated over the lower margin of the mass into the subepithelial plane and then performed along and around the mass in the desired plane. This approach and positioning in prone jack-knife, allowed dissection under direct vision with excellent surgical ergonomics and avoided radical resection. Our video demonstrates the feasibility and safety of TAMIS for the management of anterior low rectal subepithelial lesion, providing an alternative to more radical surgical approaches. See Video Vignette.

60 Neoadjuvant Imatinib Mesylate – an Ace of Spaces for Surgical Management of an Oesophago-Gastric Junction Gastro-Intestinal Stromal Tumour

Abstract Introduction Oesophageal gastro-intestinal stromal tumours (GISTs) are rare, accounting for less than five percent of all GIST, with the majority of these occurring at the oesophago-gastric junction (OGJ). Due to the anatomical location and size of these tumours at presentation, surgical resection is often a major undertaking. Neoadjuvant treatment with tyrosine kinase inhibitors, such as Imatinib mesylate, have the potential to downstage such tumours, thereby limiting the extent of subsequent surgical resection. This may therefore reduce any potentially associated morbidity and mortality. Case Description We report the case of a 75-year-old gentleman who presented with a large OGJ GIST, which presented with dysphagia. The tumour was deemed too large for local excision due to the risk of compromising the lumen at the OGJ in attempting to obtain a clear resection margin. Given the patient’s co-morbidity, oesophagectomy or total gastrectomy was deemed too major an undertaking. Therefore, endoscopic biopsies were obtained with a view to possible neoadjuvant therapy. These confirmed DOG-1 and Exon-11 mutations, suggesting sensitivity to Imatinib mesylate. A standard dose regime of 400mg daily for a planned 36-month course was commenced. Subsequent imaging showed a substantial decrease in tumour bulk and the decision was made to perform a local excision. A local enucleation procedure was performed, and the patient made a sound recovery. Post-operative histology of resected tumour showed almost complete tumour regression. Discussion This significant response to neoadjuvant Imatinib mesylate therapy demonstrates clear potential for its use in similar cases, where radical resection would cause significant morbidity and risk mortality.

Clinicopathological features, clinical efficacy on 101 cases of rectal gastrointestinal stromal tumors, and the significance of neoadjuvant therapy

ObjectiveTo investigate the clinicopathological features and clinical efficacy among 101 cases of rectal gastrointestinal stromal tumors (GISTs) and to investigate the significance of imatinib mesylate (IM) neoadjuvant therapy.MethodsThe clinicopathological features, treatment methods, perioperative data, and prognosis of the patients were summarized and analysed in 101 patients with rectal GISTs who received treatment in the Gastrointestinal Surgery of West China Hospital of Sichuan University and the Affiliated Hospital of Guizhou Medical University from August 2002 to November 2020 in China.ResultsA total of 101 patients, including 64 males and 37 females, were aged from 22 to 79 years (55.4 ± 12.2 years). Among the 70 patients who underwent direct surgery, 8 were very low risk cases, 10 were low risk cases, 7 were intermediate risk cases, and 45 were high risk cases. Cox regression analysis showed that postoperative IM adjuvant treatment improved the disease-free survival (DFS) and overall survival (OS) of 52 intermediate and high risk patients. Among the 31 patients who received neoadjuvant therapy, the objective response rate (ORR) was 83.9% (26/31), and the disease control rate (DCR) reached 96.8% (30/31). Subgroup analysis was also conducted based on the tumour diameter. (1) Among the 36 patients with a diameter ≤ 5 cm, two patients received IM neoadjuvant therapy, while 34 patients received direct surgery. Neither univariate nor Cox regression analysis found that neoadjuvant therapy affected DFS and OS. (2) Among the 65 patients with a diameter > 5 cm, 29 received IM neoadjuvant therapy, and 36 received direct surgery. Patients who underwent neoadjuvant therapy had less blood loss (P = 0.022), shorter postoperative hospital stay (P = 0.001), increased anal retention rate (93.1% vs. 72.2%, P = 0.031), and decreased enterostomy rate (10.3% vs. 33.3%, P = 0.037) than those who underwent direct surgery. Cox regression analysis suggested that neoadjuvant therapy and postoperative IM adjuvant therapy improved DFS.ConclusionRectal GISTs are relatively rare and highly malignant tumors. Postoperative oral IM therapy can improve the DFS and OS of intermediate and high risk patients. In patients with rectal GISTs with diameters > 5 cm, IM neoadjuvant therapy can improve anal retention rate, preserve the structure and function of the organs, reduce enterostomy rate, and improve prognosis.

Preservation of Organ Function in Locally Advanced Non-Metastatic Gastrointestinal Stromal Tumors (GIST) of the Stomach by Neoadjuvant Imatinib Therapy.

Simple SummaryThis study reports a single-center analysis of 55 patients with primary, locally advanced gastric GIST treated with imatinib mesylate (IM) preoperatively for a median of 10 months. The therapy yielded shrinkage of median tumor size from 113 mm to 62 mm. This facilitated 50 patients to undergo significantly less-extensive surgical procedures and resulted in a stomach preservation rate of 96%. The rate of R0 resections was 94% and was followed by a mean recurrence-free-survival time of 132 months with the median not reached. The approach was successful even for patients starting IM during an episode of upper gastrointestinal bleeding. Neoadjuvant IM therapy for locally advanced, non-metastatic gastrointestinal stromal tumors (GIST) of the stomach may play an important role in preserving organ function which might be important for IM plasma levels in an adjuvant or metastatic setting.Background: Neoadjuvant imatinib mesylate (IM) for advanced, non-metastatic gastrointestinal stromal tumors (GIST) of stomach is recommended to downsize the tumor prompting less-extensive operations and preservation of organ function. Methods: We analyzed the clinical-histopathological profile and oncological outcome of 55 patients (median age 58.2 years; range, 30–86 years) with biopsy-proven, cM0, gastric GIST who underwent IM therapy followed by surgery with a median follow-up of 82 months. Results: Initial median tumor size was 113 mm (range, 65–330 mm) and 10 patients started with acute upper GI bleeding. After a median 10 months (range, 2–21 months) of treatment, tumor size had shrunk to 62 mm (range, 22–200 mm). According to Response Evaluation Criteria In Solid Tumors version 1.0 and version 1.1 (RECIST 1.1), 39 (75%) patients had partial response and 14 patients had stable disease, with no progressive disease. At plateau response, 50 patients underwent surgery with an R0 resection rate of 94% and pathological complete response in 24%. In 12 cases (24%), downstaging allowed laparoscopic resection. The mean recurrence-free survival (RFS) was 123 months (95%CI; 99–147) and the estimated 5-year RFS was 84%. Conclusions: Neoadjuvant IM allowed stomach preservation in 96% of our patients with excellent long-term RFS, even when starting treatment during an episode of upper GI bleeding. Preservation of the stomach provides the physiological basis for the use of oral IM in the adjuvant or metastatic setting.

Open transanal resection of low rectal stromal tumor following neoadjuvant therapy of imatinib mesylate: Report of 11 cases and review of literature.

The global burden of rectal gastrointestinal stromal tumor (GIST) is increasing. However, a limited number of reports hinder our ability to reach a definitive conclusion regarding the current treatment and prognosis.In this study, we outline our experience with open transanal resection of rectal GIST following neoadjuvant therapy with imatinib mesylate (IM). We retrospectively analyzed 11 patients with rectal GISTs treated with neoadjuvant IM therapy and open transanal resection between April 2011 and April 2017 in Shanghai Changzheng Hospital. The patients had 400-600mg/day IM once daily for a median of 7 months (range: 3-9 months). Tumor size, distance from the lower margin of the tumor to the anal verge (AV), mitotic rates and mutation analysis were assessed on pretreatment biopsy. After reassessment, all 11 patients underwent transanal R0 resection. With median follow-up of 28 months (range: 8-80 months), there was no tumor recurrence or metastasis. Open transanal resection of rectal GIST after neoadjuvant treatment with IM has good surgical and survival outcomes.

Neoadjuvant Chemotherapy for Duodenal GIST: A Case Report

The principal treatment for gastrointestinal stromal tumors (GISTs) is surgical; and complete excision is important, but cannot always be achieved. For such cases, neoadjuvant chemotherapy (NAC) with imatinib mesylate (IM) has been recommended. A case of a GIST of the second portion of the duodenum for which pancreatoduodenectomy was indicated, and for which partial resection was made possible as a result of cytoreduction by IM NAC, is reported. A 64-year-old man with pancytopenia due to hepatic cirrhosis caused by hepatitis C infection received repeated blood transfusions because of anemia of unknown origin starting 2 years earlier. Most recently, the patient had melena with hemoglobin of 5.1 mg/dL. Diagnostic imaging showed a solid tumor, 55 × 48 × 65 mm3, in the second portion of the duodenum showing mainly extramural development. Endoscopic aspiration biopsy showed proliferation of KIT-positive spindle-shaped heterotypic cells. GIST was diagnosed, and an exon 11 KIT mutation was found. Because of the exon 11 mutation, neoadjuvant IM was started at 400 mg/day and then eventually maintained at 300 mg/day for 10 months. Regular CT examinations showed gradual tumor shrinkage. At surgery, a tumor with strong extramural growth was found on the outer side of the duodenum that invaded the retroperitoneum. The tumor was excised as a mass, and the duodenum was resected partially. There has been no recurrence at 9 years postoperatively. Evaluating KIT exon mutations and predicting the effectiveness of NAC appear useful for determining the treatment policy for advanced GISTs.

Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment.

This report aims to investigate the feasibility and outcomes of neoadjuvant imatinib mesylate (IM) administration followed by organ-preserving surgery (OPS) for patients with locally advanced duodenal gastrointestinal stromal tumor (GIST). Between 2012 and 2015, 10 consecutive patients with locally advanced duodenal GISTs were treated in Peking University Cancer Hospital. Multidisciplinary assessment was implemented, and pancreaticoduodenectomy (PD) was initially indicated as the most probable surgical procedure for all 10 patients. To attempt to create opportunities of less-invasive OPS for patients, neoadjuvant IM was administered followed by radical resection. All data were prospectively collected, and the short- and long-term outcomes of the treatment strategy were analyzed. The median treatment duration of neoadjuvant IM administration was 5 mo (range 2-18 mo). Significant tumor shrinkage (from 9.2 to 5.9 cm on average) was observed in all patients, and partial response was achieved in eight patients (80.0%) according to the Response Evaluation Criteria in Solid Tumors 1.1. No tumor perforation occurred, and nine patients (90.0%) underwent successful OPS with four different operation types. Postoperative morbidity rate of OPS was 55.6% (5/9), and no mortality occurred. After a median follow-up of 36 mo, one patient developed multiple distant metastases, but no local recurrence was observed. For long-term follow-up, patients who underwent OPS did not show any degradation in quality of life, whereas the patient who underwent PD suffered weight loss of ~10 kg. In conclusion, in patients with locally advanced duodenal GISTs, neoadjuvant IM administration followed by OPS is a feasible treatment strategy which leads to favorable short- and long-term outcomes.

Neoadjuvant imatinib: longer the better, need to modify risk stratification for adjuvant imatinib.

Multimodality treatment of gastrointestinal stromal tumor (GIST) with surgery and adjuvant imatinib mesylate (IM), along with an emerging role for neoadjuvant IM prior to evaluation for resectability has resulted in high survival rates. We conducted a retrospective analysis of prospectively collected data of patients who underwent surgery for GIST, prior to or followed by IM therapy. A total of 112 patients underwent surgery between January 2009 and March 2015 at our centre. This included 27 patients with upfront resectable disease, 76 patients with locally advanced GIST who received neoadjuvant IM followed by surgery and 9 patients with metastatic disease who had excellent response to IM and were taken for surgery. The primary tumor in the non metastatic patients was in the stomach (53%), duodenum (16%), rectum (12%), jejunum (11%), ileum (7%), and others (2%). Median duration of neoadjuvant IM was 5 months with 4 patients showing disease progression during neoadjuvant IM. Ninety-three percent of all patients had R0 resections, while 7% had R+ resections. The estimated 3- and 5-year DFS in non-metastatic patients was 86.1% and 67% respectively with a 3- and 5-year median OS of 95.4% and 91.7% respectively. Five-year PFS and OS for the metastatic patients was 88.8% and 100% respectively. Lack of adjuvant IM was the only factor related to inferior PFS and OS. Longer duration of neoadjuvant IM should be considered in locally advanced GIST prior to surgery and resection may be considered in responding metastatic patients.

術前補助療法後に腹腔鏡下ISRを施行した直腸GISTの1例

術前補助療法後に腹腔鏡下ISRを施行した直腸GISTの1例

A Targeted Approach to a Giant Gastrointestinal Stromal Tumor of the Esophagus

Sir, Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, accounting for 0.1 %–3.0 % of all gastrointestinal malignancies. GISTs can arise anywhere in the gastrointestinal tract: 50–70 % in the stomach, 20–40 % in the small bowel, 5–15 % in the colon and rectum and rarely in the mesentery or retroperitoneum. Esophageal GISTs are extremely uncommon, representing approximately 5 % of GISTs with a majority occurring at the esophagogastric junction (GEJ). [1, 2] We report a case of a borderline resectable GIST of the lower esophagus, treated with neoadjuvant imatinib mesylate (IM) which ultimately resulted in a successful R0 resection. A 50-year-old lady with no co-morbid conditions was referred to us for progressively worsening dysphagia of 6 months. An upper gastrointestinal endoscopy revealed a circumferential ulcerated growth in the lower end of the esophagus, from 30 to 36 cm, which was seen extending to the GEJ. An endoscopic biopsy was suggestive of a spindle cell neoplasm, which on immunohistochemistry correlation (CD117 and CD34 positive, Ki-67–30 %) was suggestive of a high grade GIST. Computerized tomography (CT) scan of the chest and abdomen revealed a large lobulated, hetero-dense, poorly enhancing mass (10.9 × 7.4 × 16 cm) in the thoraco-abdominal region, involving the lower end of the esophagus, GEJ, posterior stomach and extending along the retroperitoneum to infiltrate the body and tail of pancreas, causing a mass effect on the left kidney. (Figures 1a and ​and2a2a) Fig. 1 a- Axial CT scan at presentation (Maximal diameter-10.9 cm). b- Axial CT scan following 6 months of Imatinib Mesylate (Maximal diameter-4.2 cm) Fig. 2 a- Coronal CT scan at presentation. b- Coronal CT scan following 6 months of Imatinib Mesylate After thorough discussion of the issues of borderline resectability/unresectability, the patient consented to attempt to downstage the tumor by neoadjuvant treatment with IM. (400 mg/day) An interim CT scan at two months revealed a regression of the tumor diameter, IM was hence continued for another 4 months. A follow-up CT at 6 months revealed a regression of the tumor diameter from 10.2 cm to 4.2 cm. (Figures 1b and ​and2b)2b) Resection of the residual tumor was deemed feasible and the patient was taken up for an exploratory laprotomy. The residual tumor was found to be densely adherent to a portion of the distal body of the pancreas; a distal pancreatico-spleenectomy had to be combined with an esophago-gastrectomy via a transhiatal approach to attain a R0 resection. (Figures 3 and ​and4)4) The bowel continuity was restored using a gastric tube conduit through the posterior mediastinum. Histopathological examination of the resection specimen confirmed a GIST with extensive post treatment changes and clear margins. The postoperative course was uneventful, after recovery the patient continued adjuvant therapy with IM for 6 more months, she is currently disease free. Fig. 3 Specimen photograph (Esophago-gastrectomy along with distal pancreatico spleenectomy) Fig. 4 a- H& Ex 40- Shows tumor composed of fascicles and sheets of spindle cells with dark staining nuclei in a myxoid background. b- IHCX40- Tumor cells showing immunopositivity to CD-117. c- IHCX40- Tumor cells showing immunopositivity to CD-34. ... GISTs are thought to arise from the intestinal cells of Cajal, which are intestinal pacemaker cells that regulate peristalsis. Considerable progress has been made recently in our understanding of the natural history, risk stratification, and molecular biology of GIST. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor-A gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. Despite the efficacy of targeted therapy, surgery remains the only curative primary treatment and cures >50 % of GIST patients who present with localized disease. Many authors agree that loco regionally advanced tumors or those poorly positioned which require an extended/multi-organ resection should be considered for neoadjuvant treatment with IM and should be re-evaluated for a possible curative resection. [3–5] This approach has been proven to be safe and feasible even in the management GIST of the esophagus as was also seen in our patient. In conclusion a multimodal approach with neoadjuvant administration of IM is emerging as a viable treatment strategy for borderline resectable esophageal GIST, although the dose and duration have not been clearly established. The long-term impact of this approach on survival is presently under investigation in multicenter prospective randomized trials.

ACRIN 6665/RTOG 0132 Phase II Trial of Neoadjuvant Imatinib Mesylate for Operable Malignant Gastrointestinal Stromal Tumor: Monitoring with 18F-FDG PET and Correlation with Genotype and GLUT4 Expression

We investigated the correlation between metabolic response by (18)F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy. (18)F-FDG PET was performed at baseline, 1-7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery. (18)F-FDG PET showed high baseline tumor glycolytic activity (mean SUV(max), 14.2; range, 1.3-53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, -0.5-47.7, P < 0.001, n = 44), and again before surgery (mean, 3.0; range, -0.5-36.1, P < 0.001, n = 40). At week 1, there were 3 patients with complete metabolic response (CMR), 33 with partial metabolic response (PMR), 6 with stable metabolic disease (SMD), and 2 with progressive metabolic disease (PMD). Before surgery, there were 3 with CMR, 33 with PMR, 4 with SMD, and none with PMD. The best response according to RECIST was 2 with partial response, 36 with stable disease, and 1 with progressive disease (n = 39). Of the patients with a posttreatment decrease in GLUT4 expression, 1 had CMR, 15 had PMR, 2 had SMD, and 1 had PMD at week 1, whereas before surgery 1 patient had CMR, 16 had PMR, 2 had SMD, and none had PMD. Among 27 patients with KIT exon 11 mutations, 1 had CMR, 22 had PMR, 3 had SMD, and 1 had PMD at week 1, whereas 1 had CMR, 22 had PMR, 2 had SMD, and 2 were unknown before surgery; among 4 patients with a wild-type genotype, 2 had PMR and 2 SMD at week 1, whereas 1 had CMR, 2 had PMR, and 1 had SMD before surgery. After imatinib mesylate initiation, metabolic response by (18)F-FDG PET was documented earlier (1-7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in (18)F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1-7 in patients with exon 11 mutations.

Clinicopathologic change of gastrointestinal stromal tumor after neoadjuvant imatinib followed by surgical resection

A 53-year-old woman was diagnosed with gastrointestinal stromal tumor (GIST) of the stomach. Computed tomography (CT) revealed a huge mass (12 cm in diameter), likely to invade pancreas and spleen. In the operation field, the tumor was in an unresectable state. The patient was then started on imatinib therapy for 4 months. On follow-up imaging studies, the tumor almost disappeared. We performed total gastrectomy and splenectomy upon which two small-sized residual tumors were found on microscopy. In this paper, we describe a case of clinicopathologic change in unresectable GIST after neoadjuvant imatinib mesylate.

The Role of Neoadjuvant Imatinib Mesylate Therapy in Sphincter-Preserving Procedures for Anorectal Gastrointestinal Stromal Tumor

To explore the role of neoadjuvant imatinib mesylate (IM) therapy in sphincter-preserving procedures for anorectal gastrointestinal stromal tumor (GIST). Between January and December of 2007, 3 patients with primary anorectal GIST who declined recommendations to receive abdominoperineal resection of the rectum, were treated with IM at a single institution. Tumor size, distance to anal edge, and the number of mitoses were compared before and after the treatment. After 12 weeks of IM therapy, conservative surgical procedures were performed. After IM therapy for the 3 patients, computed tomography scan, colonoscopy, and biopsy showed a decrease in size of the rectal mass, an extension in the distance to anal edge, and a reduction in mitotic count. During this treatment regimen, the patients did not experience any side effects. A sphincter-preserving transsacral excision with direct coloanal anastomosis was performed and the resection margins were uninvolved on all sides. During 22 to 28 months postoperatively, the function of anal sphincter was satisfactory and no recurrence occurred among all 3 patients. Neoadjuvant IM therapy for anorectal GIST is safe and effective. Tumor shrinkage and an extension of the distance to anal edge have a clear benefit for the local excision, in terms of feasibility, function preservation, and safety.

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.

Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial

BackgroundThe role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial.MethodsThe database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria.ResultsFifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients who underwent surgical resection versus those who did not (median not reached vs 23.6 months, p = 0.0318 for PFS and median not reached vs 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by IM, the 3-year PFS and OS rates were 67% and 89% respectivelyConclusionsFollowing neoadjuvant IM for non metastatic locally advanced GIST 9 of 25 patients (36%) were selected for resection of the primary tumor. OS and PFS figures were close to those of localised intermediate or high risk GIST (70% at 5 years) in the subgroup of operated patients, while the outcome of the non-operated subgroup was similar to that of metastatic GIST.

An unusual and potentially misleading phenotypic change in a primary gastrointestinal stromal tumour (GIST) under imatinib mesylate therapy

We present a unique case of a 62-year-old female who was diagnosed with a huge gastric gastrointestinal stromal tumour (GIST). Core needle biopsy revealed a cellular spindle cell GIST with diffuse expression of CD117 and CD34. Four mitotic figures were counted in ten available HPFs, indicating a high-risk tumour. Computed tomography scan, performed after 8months of neoadjuvant imatinib mesylate treatment (Glivec, 400mg/day), revealed a partial response with reduction of tumour size from 20 × 15 × 15cm to 13.3 × 8 × 7.6cm. The patient underwent complete tumour resection. The tumour revealed extensive cystic changes and hyalinisation in 90% of the tumour mass. Multiple viable tumour clones, measuring up to 1cm, showed highly anaplastic, large epithelioid cells with vesicular nuclei and prominent, centrally located nucleoli, strikingly mimicking the appearance of proximal-type epithelioid sarcoma, anaplastic carcinoma, melanoma or epithelioid angiosarcoma. These anaplastic tumour cells expressed pankeratin (KL-1) and vimentin, but they were completely negative for CD117, DOG-1, CD34, S100, desmin, α-smooth muscle actin, HMB45, CD30, CD45, CK7, CK20 and 34βE-12. Sufficient tissue for molecular analysis was available from the resected tumour. No mutations were detected in KIT exons 9, 11, 13, 17, PDGFRA exons 12, 14, 18, KRAS and BRAF. The patient was alive with no evidence of recurrence 28months later. To our knowledge, this represents the first report on this unusual type of trans-differentiation in GIST under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-treatment resections from GISTs.

Using Imatinib as Neoadjuvant Therapy in Dermatofibrosarcoma Protuberans: Potential Pluses and Minuses

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, low grade soft-tissue malignancy associated with a high risk for local recurrence and widespread subclinical extension. Imatinib, a selective tyrosine kinase inhibitor, has been a beneficial adjuvant therapy in patients with unresectable, recurrent, or metastatic DFSP. Because of its characteristic infiltrative growth, effective surgical excision of DFSP may be limited by the risk for disfigurement or functional impairment. In recent cases, neoadjuvant imatinib mesylate therapy has been shown to reduce preoperative tumor size and lessen surgical morbidity associated with the removal of residual DFSP. Use of neoadjuvant imatinib before surgery, however, requires appropriate patient selection and careful weighing of the potential risks and benefits of this treatment.

Neoadjuvant Imatinib Therapy for Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma protuberans (DFSP) is an unusual soft-tissue tumor with a propensity for subclinical extension and local recurrence. Surgical excision, even with tissue-sparing techniques, may cause significant deformity or disability because of the infiltrative nature of DFSP. In this study, we evaluate retrospective data obtained from 4 patients with locally advanced or recurrent DFSP who received neoadjuvant imatinib mesylate therapy before undergoing Mohs micrographic surgery. Patients treated with neoadjuvant imatinib therapy had an average tumor size reduction of 36.9%. This clinical response was paralleled by histopathologic changes, including decreased cellularity in 100% of the total area as well as significant hyalinization. Imatinib therapy for DFSP before Mohs micrographic surgery was associated with 100% local control at a maximum follow-up of 4 years. Neoadjuvant imatinib therapy is a well-tolerated, novel approach to DFSP that reduces tumor burden and facilitates resection. Larger prospective studies are needed to confirm and expand on these results.

ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate (IM) for primary and recurrent operable malignant GIST: Imaging findings and correlation with genotype and GLUT4 expression

10552 Background: IM has improved the treatment of GIST patients (pts), but few achieve objective response despite significant clinical benefit. Imaging of tumor metabolism may provide earlier assessment of therapeutic response. In this study, FDG-PET metabolic response (MR) was compared with RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Methods: FDG-PET was done at baseline, 1–7 days, and 4 or 8 weeks (wk) after IM initiation. Best objective response was defined by RECIST. Immunohistochemical (IHC) tumor GLUT4 expression and mutation analyses were done at baseline and/or surgery. Background-subtracted SUVmax was measured in all lesions and summed; MR based on EORTC criteria was compared to RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Results: FDG-PET showed high tumor glycolytic activity at baseline (mean SUVmax = 14.2, range: 1.3–53.2), decreasing after 1 wk of IM (5.5, range: 0.5–47.7, p &lt; 0.001, n = 44), and again prior to surgery (3.0, range: 0.5–36.1, p &lt; 0.001, n = 40). FDG-PET response at wk 1 was 3 complete MR (CMR), 33 partial MR (PMR), 6 stable metabolic disease (SMD), and 2 progressive metabolic disease (PMD). Prior to surgery, FDG-PET response was 3 CMR, 33 PMR, 4 SMD, and no PMD. For 39 pts, RECIST best response was 2 PR, 36 SD, and 1 PD. GLUT4 expression decreased in 19 pts with PMR, and 3 with SMD. Among 12 pts with exon 11 mutation, 11 had PMR, 1 SMD; among 5 pts with wild-type genotype, 4 had PMR, and 1 SMD. Conclusions: After IM initiation, MR by FDG-PET was documented earlier (1–7 days), and was of much greater magnitude (36/40) than that documented by RECIST (2/39). IHC data suggest that: (1) GLUT4 plays a role in FDG uptake in GIST; (2) GLUT4 decreases in most pts with PMR; and, (3) the biologic action of IM interacts with glycolysis and GLUT4 expression. No difference in PMR was seen in pts with exon 11 vs. wild type mutations. [Table: see text]

Correlation of gastrointestinal stromal tumor (GIST) gene expression signatures and response to imatinib mesylate in the Radiation Therapy Oncology Group phase II clinical trial S-0132

10533 Background: Despite the known efficacy of imatinib mesylate (IM) in metastatic GIST, both primary and secondary drug resistance remain a clinical problem. Therefore, future management of GIST may benefit from further molecular characterization associated with IM treatment. Methods: A recently completed prospective phase II trial of neoadjuvant/adjuvant IM treatment for advanced primary and recurrent operable GISTs included gene expression profiling using oligonucleotide microarrays on tumor samples obtained before and after neoadjuvant IM therapy for 8 to 12 weeks. Fifty-two analyzable patients were classified according to changes in tumor size after IM based on CT scan measurements. A response was defined as &gt;25% tumor reduction. Gene profiling data were then evaluated with SAM analysis (FDR = 10%) to identify differentially expressed genes (in pre-treatment GIST samples). In addition, a custom siRNA library was designed targeting these genes and a mid-throughput siRNA synthetic lethal screening approach was used to evaluate the ability of each to sensitize GIST cells to IM. Results: Thirty-eight genes were expressed at significantly lower levels in the pre-treatment samples of tumors that rapidly responded to IM. Eighteen of these genes encoded KRAB domain containing zinc finger (KRAB-ZNF) transcriptional repressors. Importantly, ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset of these predicted likely response to IM-based therapy in a naïve panel of GISTs. Further evaluation revealed that modifying in vitroexpression of genes via RNAi approaches within this predictive response signature enhanced the sensitivity of GIST cells to IM. Conclusions: Using clinical samples from a prospective neoadjuvant/adjuvant phase II trial we have identified a genetic signature which includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely rapid response to short-term IM treatment and which may provide a prognostic biomarker identifying patients who will benefit from it. [Table: see text]