Akiko Nishitani

Surgical strategy for gastric gastrointestinal stromal tumors: laparoscopic vs. open resection

BackgroundBecause wide resections and extensive lymphadenectomies are usually not required, the laparoscopic approach has been considered reasonable for gastrointestinal stromal tumors (GISTs) of gastric origin and has been reported with increased frequency. However, its long-term oncologic outcome has not been fully assessed.MethodsWe reviewed 67 consecutive patients who underwent laparoscopic (LAP) or traditional open (OPEN) resection of gastric GISTs from January 1993 to May 2004.ResultsThere were 39 LAP and 28 OPEN cases. One LAP case was converted to open (2.6%). Patients in both groups had comparable backgrounds. Tumor location, size, and risk classification were similar. There was no difference in operating time and blood loss. Five patients (one in LAP and four in OPEN) showed recurrence and/or metastases after a median followup period of 26 months. Tumor enucleation resulted in a higher recurrence rate in both groups: one after three enucleations in LAP and two after six in OPEN. In cases with tumors that were larger than 5 cm, laparoscopic manipulation became technically challenging, although no recurrence was noted in this subgroup. Overall recurrence rate was comparable in the two groups.ConclusionLaparoscopic surgery is oncologically justified for gastric GISTs, while its indication should be carefully discussed for cases with bulky and high-risk tumors. Tumor enucleations should be avoided whichever approach (open/laparoscopic) is selected.

An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors

BackgroundRecent breakthroughs regarding the oncogenesis of gastrointestinal stromal tumors (GISTs) have led to the wider use of imatinib mesylate in the treatment of advanced GISTs. However, the role of imatinib in an adjuvant setting has yet to be established, mainly owing to the lack of an accurate system to prognosticate recurrences and/or metastases. The aims of this study were to identify factors prognostic for an unfavorable postoperative outcome, and to enhance the current NIH-consensus risk-group stratification system (Fletchers system).MethodsA retrospective review was conducted in 303 consecutive patients who had undergone surgical resection of primary GISTs during the study period (1987–2003). In addition to Fletchers system, which is based on morphologic variables (tumor size and mitotic count), with four risk groups: very low risk, low risk, intermediate risk, and high risk, the predictive potential of any major preoperative, intraoperative, or postoperative clinical factor was statistically evaluated.ResultsIn addition to tumor size and mitosis, four operative variables were found to affect disease-free survival: peritoneal dissemination, metastasis, invasion, and tumor rupture. Patients presenting with at least one of these “clinically malignant factors” had an unfavorable outcome (i.e., they were potential candidates for adjuvant therapy). We therefore modified Fletchers system by adding a new patient group, termed the “clinically malignant group,” (patients having at least one of the “clinically malignant factors”). With this modification, the outcomes of patients in the “new” very-low-risk and low-risk groups remained favorable, but the outcomes of patients in the “clinically malignant group” and the “new” high-risk group bceame unfavorable.ConclusionThis modified Fletchers system, enhanced by the addition of “clinically malignant factors,” can distinguish patients with a possible unfavorable outcome from those who require no therapy other than surgery. Patients in the “clinically malignant group” could be potential candidates for adjuvant therapy using imatinib.

Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor.

Although imatinib showed high activity for advanced gastrointestinal stromal tumor (GIST) and improved the prognosis of GIST patients, resistance to the drug appears with prolonged use. Mechanisms of acquired resistance are still under investigation. In the present study, we carried out histologic and genetic analysis of 45 secondary resistant lesions obtained from 25 Japanese GIST patients treated with imatinib. All resistant lesions showed viable tumor cells expressing KIT protein, whereas imatinib‐sensitive lesions did not. All pre‐imatinib samples have KIT mutations either in exon 9 (n = 3) or exon 11 (n = 22), identified in the KIT gene of corresponding resistant tumors. In addition to primary mutations, 33 out of 45 tumors (73%) showed secondary KIT mutations in the kinase domain of the KIT gene. Secondary mutations are missense mutations and are mostly located in the kinase domains of the same allele to the primary mutations (cis‐position). Resistant lesions showed monoclonal development of tumor cells. Taken together, additional cis‐positioned mutations in the kinase domains are a major cause of secondary resistance to imatinib in Japanese GIST patients. (Cancer Sci 2008; 99: 799–804)

Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy.

BackgroundAlthough imatinib has shown high activity in the majority of patients with advanced gastrointestinal stromal tumors (GIST), it has become clear that secondary resistance appears during chronic therapy. The aim of this study was to retrospectively analyze the safety and prognostic effects of surgical interventions for focal progression during imatinib treatment.MethodsBetween January 2002 and May 2005, 16 patients who had focal lesions of secondary-resistant GIST to imatinib treatment (male/female, 12 : 4; median age, 62 years) underwent surgical interventions such as resection, radiofrequency ablation, and their combination.ResultsPostoperative complications, including liver abscess, bile leak, wound infection, and ileus were mostly mild, and the patients recovered with conservative therapy. There was no hospital death. The median time to progression (TTP) of all patients was 5.5 months, and only one patient died of the disease; the others are alive after a median follow up of 12.4 months. Patients with complete resections of resistant lesions (n = 7) showed significantly better median TTP than those with incomplete resections (n = 9; P = 0.014). The impact of curability on focal lesions with secondary resistance was mainly significant in patients with tumors of stomach origin (P = 0.013), and a smaller number (P = 0.014) and smaller size (P = 0.018) of resistant lesions. Overall survival was 100% at 1 year and 75% at 2 years.ConclusionOur study indicates that surgical interventions in patients with GIST resistant to imatinib therapy are efficacious when complete resections are performed, when the lesions are of gastric origin, when the number of lesions is lower, and when the lesions are a smaller size.

A mouse model of a human multiple GIST family with KIT-Asp820Tyr mutation generated by a knock-in strategy

Several families exhibiting multiple gastrointestinal stromal tumours (GISTs) and germline c‐kit gene mutations at exons 8, 11, 13, or 17 have been reported. These patients also exhibit diffuse hyperplasia of the interstitial cells of Cajal (ICCs) as a pre‐existing lesion of multiple GISTs. We generated a mouse model of a family with germline c‐kit gene mutation at exon 17, and compared the phenotypes between the mice and humans. The mouse counterpart (KIT‐Asp818Tyr) of the human KIT‐Asp820Tyr mutation was transmitted into germline by a knock‐in strategy. Mating of male and female heterozygotes (KIT‐Asp818Tyr/+) resulted in the generation of homozygotes (KIT‐Asp818Tyr/KIT‐Asp818Tyr). Histological examination revealed that all heterozygotes had both a small KIT‐positive mesenchymal tumour at the caecum, consistent with GIST, and KIT‐positive diffuse spindle‐shaped cell proliferation in the distal oesophagus, stomach, proximal duodenum, and colon consistent with ICC hyperplasia. All homozygotes exhibited a larger caecal tumour and more prominent spindle‐shaped cell proliferation compared with the heterozygous mice, and they usually died within 10 weeks after birth, likely due to ileus. The small intestine of both genotypes showed no apparent morphological abnormality, and autonomous contraction of the ileal segments appeared normal. Western blotting demonstrated that the caecal tumours expressed phosphorylated KIT, MAPK, Stat1, and Stat5. These mutant mice are considered to be useful for further investigation of the mechanism of GIST development as a result of ICC hyperplasia and for assessment of the in vivo effects of drugs against molecular targets. Copyright

Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene

BackgroundAlthough sunitinib malate has shown significant clinical effect on imatinib-resistant gastrointestinal stromal tumors, with acceptable tolerability and improved prognosis for the patients, the mechanism of resistance to the drug is still under investigation.MethodsWe analyzed findings in 8 patients (seven men and one woman, median age, 59 years) out of 17 patients with imatinib-resistant gastrointestinal stromal tumors who had been treated with sunitinib. Sunitinib was orally administered once a day at a starting dose of 37.5 mg/day, 50 mg/day, or 75 mg/day, with 4 weeks on and 2 weeks off.ResultsAll imatinib- as well as sunitinib-resistant lesions showed viable tumor cells strongly re-expressing the KIT protein. Pre-imatinib samples had heterogeneous KIT mutations either in exon 9 (n = 1) or exon 11 (n = 7), and seven imatinib-resistant tumors carried a secondary mutation either in the ATP-binding domain or in the activation loop in the same allele as the primary mutation. Most patients with imatinib-resistant tumors carrying secondary mutations in the ATP-binding domain obtained clinical benefits from sunitinib, whereas some tumors with mutations in the activation loop showed resistance to the drug. A tumor with mutations in exon 11 and 13 of the KIT gene, and showing partial response to sunitinib, harbored a third mutation in the activation loop when sunitinib resistance was shown. All additional secondary and tertiary mutations were located on the same allele as the primary mutation (cis-mutation).ConclusionThese findings indicate that an additional cis-mutation in the activation loop of the KIT gene could be a potential cause of sunitinib resistance in gastrointestinal stromal tumors.

Intra-abdominal textiloma. A retained surgical sponge mimicking a gastric gastrointestinal stromal tumor: Report of a case

We describe a unique case of intra-abdominal textiloma (granuloma due to a retained foreign body), which mimicked a gastric tumor on preoperative imaging studies. A 78-year-old asymptomatic patient with a past history of a gastrectomy was referred for evaluation of an intra-abdominal mass lesion, which was incidentally observed on a computed tomography (CT) scan. Repeated CT with a higher resolution demonstrated a 5-cm heterogeneously enhanced mass with a distinct feeding artery. These findings were all compatible with a tumorous lesion originating in the gastric remnant, most likely gastric gastrointestinal stromal tumor. A diagnosis of textiloma was immediately made during surgery, and it was confirmed pathologically postoperatively. The feeding artery that appeared on CT images, which was a major reason for the false diagnosis, was considered to have resulted from a slow but continuous inflammation reaction around the retained surgical sponge. Surgeons should therefore always take the possibility of textilomas into consideration even with typical tumorous characteristics on preoperative imaging studies, especially in patients with a history of prior abdominal surgery.

Differential expression of connexin 43 in gastrointestinal stromal tumours of gastric and small intestinal origin

Gastrointestinal stromal tumours (GISTs) are considered to originate from interstitial cells of Cajal (ICCs). ICCs are classified into several subtypes according to their location or roles. Several reports indicate that GISTs of the small intestine appear to have different clinical and pathological characteristics from gastric GISTs. We previously found using a cDNA expression chip that connexin 43, a component of gap junctions, is expressed specifically in small intestinal GISTs but not in gastric GISTs. To confirm the specificity of connexin 43 expression, we analysed 10 small intestinal GISTs and 15 gastric GISTs by northern blotting, western blotting and immunohistochemistry in this study. Northern blotting was performed in five small intestinal GISTs and five gastric GISTs, and revealed connexin 43 mRNA expression in all of the five small intestinal GISTs, but in none of the gastric GISTs. By western blotting, bands corresponding to connexin 43 were easily detected in all of the five small intestinal GISTs studied but were absent in all five gastric GISTs analysed. Immunohistochemistry showed that all of the 10 small intestinal GISTs were positive for connexin 43 but only one of 15 gastric GISTs, which exhibited a mutation in exon 9 of the KIT gene, was connexin 43‐positive. We also examined the localization of connexin 43 in the normal stomach and small intestine. Immunoreactivity for connexin 43 was present in both normal gastric and small intestinal circular muscle layers, but it was unclear which cell type was positive. These results suggest that GISTs are divided into at least two groups, namely the gastric subtype and the small intestinal subtype, through phenotype but not location. Furthermore, these data indicate that the gastric and the small intestinal subtypes of GIST may originate from different subtypes of ICC. Copyright

A versatile dual-channel carbon dioxide (CO2) insufflator for various CO2)applications. The prototype.

BackgroundCarbon dioxide (CO2), with its rapid absorptive nature, has been proven superior to atmospheric air as an insufflating agent in various clinical settings. However, CO2 insufflation has not gained wide clinical acceptance, mainly because there has been no suitable feeding system. The authors therefore have developed a versatile “dual-channel” CO2 insufflator that facilitates wider use of CO2. The objectives of this study were to introduce the authors’ prototype insufflator, to evaluate its safety and performance, and to validate CO2 application using the prototype.MethodsThe prototype insufflator provides one CO2 inlet connected to a regular CO2 gas cylinder and two CO2 outlets positioned on the front and back of the device, respectively. The CO2 gas fed from the cylinder is pressure-regulated and divided into two independent conduits inside the device. The front outlet feeds CO2 gas for pneumoperitoneum at an electronically controlled pressure and flow rate. The back channel supplies CO2 gas at a fixed flow rate, allowing manual control of insufflation for various purposes. The device was evaluated with canine models.ResultsThe prototype was safe and performed well. The CO2 application (colonoscopy in this series) using the back channel was feasible while intact CO2 pneumoperitoneum was simultaneously maintained via the front channel. There were no device malfunctions. The serial abdominal x-rays indicated that intraluminal CO2 insufflation such as that used for CO2 colonoscopy caused less residual intestinal gas than conventional air insufflation.ConclusionsThe dual-channel CO2 insufflator enabled two different modes of CO2 insufflation at the same time from a single CO2 cylinder. The authors are now improving the prototype to allow safer and wider usage of CO2 in the operating room.

Large and Asymptomatic Pancreatic Islet Cell Tumor in a Patient with Multiple Endocrine Neoplasia Type 1

The major phenotypes of multiple endocrine neoplasia type 1 (MEN 1) consist of three lesions characterized by hyperparathyroidism, pituitary tumors, and endocrine pancreatic tumors. The endocrine pancreatic tumors are a significant cause of disease-related mortality in MEN 1. Although symptomatic pancreatic tumors such as insulinoma and gastrinoma should be resected, the management of asymptomatic pancreatic tumors is not established. In asymptomatic pancreatic tumors, the most important factor is the propensity for malignant transformation of the tumors. Although there are no means to foresee it, the size of the pancreatic tumors might be predictive of malignant development in MEN 1. We report here a patient with MEN 1 who had a large asymptomatic pancreatic tumor. The patient (72-yr-old man) was diagnosed with primary hyperparathyroidism and underwent a total parathyroidectomy. Genetic examination showed a germline mutation of the MEN1 gene (E45G). Abdominal magnetic resonance imaging revealed a large (>6 cm) tumor with a heterogeneous pattern in the tail of the pancreas. No metastases of the tumor were evident. Serum levels of insulin, gastrin, and glucagon were normal, and the patient had no symptoms. Operative resection was performed, and microscopic examination revealed that the tumor was an islet cell tumor stained with multiple hormones. This is a case indicating that asymptomatic pancreatic tumors associated with MEN 1 might be indolent independent of their size.