[A Case of Conversion Surgery after Nivolumab Monotherapy as Third-Line Therapy for Advanced Gastric Cancer].

A 79-year-old man with unresectable advanced gastric cancer due to invasion to the pancreas and positive lavage cytology( T4b, N+, M1, CY1, cStage ⅣB; Japanese classification of gastric carcinoma, 15th edition)received standard chemotherapy, including 6 courses of S-1 plus cisplatin as first-line therapy and 2 courses of paclitaxel plus ramucirumab followed by 6 courses of paclitaxel monotherapy as second-line therapy. The primary lesion became PD with these treatments. Subsequently, nivolumab monotherapy was introduced as third-line therapy. After 9 courses, the primary tumor shrunk, and lavage cytology turned to negative on diagnostic laparoscopy. We judged that the tumor was resectable, and the patient underwent radical total gastrectomy and D2 lymphadenectomy as conversion surgery. The pathological stage was ypT3(SS), N0, M0, CY0, and the therapeutic effect was Grade 1b. R0 resection was accomplished. He has been alive without recurrence for 18 months after resection without adjuvant chemotherapy.

Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.

BACKGROUND: In our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies. METHODS: We enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines. RESULTS: Patient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival. CONCLUSIONS: Concurrent chemotherapy is effective and safe for treating cancer patients with active MTB.

[Long-term survival of a case of advanced cancer of the esophagogastric junction with complete response to low-dose 5-fluorouracil and cisplatin chemotherapy].

A 58-year-old man was admitted to the author's institution with complaints of dysphagia and tarry stool. An advanced squamous cell carcinoma of the esophagogastric junction was revealed by endoscopy. The clinical stage was GE, T4, N1, H0, M0, cStageIVa, according to the Japanese Classification of Esophageal Cancer. Low-dose FP chemotherapy(continuous 5-FU div of 500mg/day with intermittent CDDP div of 10mg/day)was used. The tumor size was remarkably reduced while the side effects were trivial. A clinically complete response was recognized with CT and with pathological findings from endoscopic biopsy. As a recurrence was diagnosed in the off-treatment period, the same regimen was resumed. Soon, a complete response was again. The patient is doing well with no reoccurrence after almost 10 years, with a low-dose FP chemotherapy.

Treatment for gastric carcinoma in the oldest old patients.

BACKGROUND: The strategy for treating extremely aged patients with gastric carcinoma is controversial. This study reviews the prognoses of patients aged 85 years and older who were diagnosed with gastric carcinoma. METHODS: One hundred seventeen patients aged 85 years and older were diagnosed as having gastric carcinoma after 1969 in our institution. After excluding those at stage IV, 36 cases underwent curative resection and 30 cases received best supportive care (BSC), which we reviewed retrospectively. RESULTS: Surgical methods included distal gastrectomy for 28 cases, total gastrectomy for five cases, and other procedures for three cases. Postoperatively, pneumonia developed in four cases, anastomotic leakage in two cases, and pancreatic fistula in one case. Two patients died of pneumonia within 1 month of surgery. Univariate analysis demonstrated that age, surgery, performance status, and sodium level were statistically significant prognostic factors. Multivariate analysis demonstrated that surgery was the only independent prognostic factor. When patients with a performance status of 4 were excluded, the clinical characteristics of the surgery group (n = 36) and BSC group (n = 20) were statistically identical, and the overall survival was significantly better in the surgery group (p = 0.0078). CONCLUSIONS: Postoperative outcomes were relatively acceptable. Surgery may be feasible and beneficial even for extremely aged patients 85 years and older, except for those with a performance status of 4.

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.

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

BACKGROUND: Because 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. METHODS: We reviewed 67 consecutive patients who underwent laparoscopic (LAP) or traditional open (OPEN) resection of gastric GISTs from January 1993 to May 2004. RESULTS: There 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. CONCLUSION: Laparoscopic 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.

Pancreatic desmoid-type fibromatosis with beta-catenin gene mutation-Report of a case and review of the literature.

We experienced a rare case of pancreatic desmoid-type fibromatosis (DTF) in a 75-year-old Japanese woman. She was asymptomatic but routine examination including ultrasonography revealed a mass in the abdomen. For precise examination, she was referred to the regional hospital. Computed tomography showed that the mass was protruding anteriorly from the left-sided pancreas. Because of the enlargement of the mass lesion, distal pancreatectomy with splenectomy was performed after about 3 months. Macroscopically, the mass was encapsulated and approximately 8cm in diameter. Histological examination revealed that spindle or blunt stellate cells were proliferating in parallel or storiform fashion with myxoid and fibrous background. The tumor cells did not show prominent atypia and mitoses were rarely seen, suggesting that the tumor was low grade or borderline. Immunohistochemistry showed obvious nuclear staining of beta-catenin. Furthermore, analysis of beta-catenin gene revealed that the tumor had a typical missense mutation of threonine to alanine at colon 41 (T41A) in exon 3. These findings confirmed the pathological diagnosis of DTF of the pancreas. To the best of our knowledge, 18 cases of pancreatic DTF have been reported in the English literature and beta-catenin gene mutation had been examined in only one case among them. Thus, our case is the 19th pancreatic DTF and the second case with confirmed beta-catenin gene mutation.

Splenic artery embolization using contour emboli before laparoscopic or laparoscopically assisted splenectomy.

The present study assessed preoperative splenic artery embolization using spherical embolic material, super absorbent polymer microspheres (SAP-MS), before laparoscopic or laparoscopically assisted splenectomy. Distal splenic artery embolization using 250 to 400 microm SAP-MS was performed in nine cases with ITP and in seven cases with the other diseases with splenomegaly. Laparoscopic or laparoscopically assisted splenectomies, including a hand-assisted procedure and the procedure involving left upper minilaparotomy, were done 2 to 4 hours after embolization. Conversion to traditional laparotomy was not required in any of the 16 cases, while conversion to 12-cm laparotomy was required in one case with massive splenomegaly. Mean operating time was 161 minutes, and mean intraoperative blood loss was 290 mL. No major postoperative complications were identified, and only one patient reported postembolic pain before surgery. Preoperative splenic artery embolization using painless embolic material, SAP-MS, would be effective for easy and safe laparoscopic or laparoscopically assisted splenectomy.

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

BACKGROUND: Although 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. METHODS: We 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. RESULTS: All 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). CONCLUSION: These 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.

Aberrant expression of glycosylation in juvenile gastrointestinal stromal tumors.

Most adult gastrointestinal stromal tumors (GIST) are thought to be caused by activating mutations in the KIT or PDGFRA gene. However, many juvenile GIST lack either mutation and are considered to develop with a different pathogenesis. To investigate the molecular characteristics of juvenile GIST, we analyzed the proteome difference in phosphorylated protein between adult and juvenile GIST. Eleven GIST samples (seven adult cases and four juvenile cases lacking either mutation) were analyzed by using immunostaining and LC-MS/MS. Comparative analysis of tyrosine-phosphorylated protein levels showed that juvenile GIST possessed phosphorylated KIT in spite of lacking mutation in the KIT gene. Moreover, downstream signals of KIT were also activated as in adult GIST. Although, SDS-PAGE gels showed that there was a difference of each KIT bands between adult and juvenile GIST, they became the same after removal of N-glycans or sialic acids. Moreover, one of the most typical enzymes, ST6Gal1, which transfers Neu5Ac residues in α2-6 linkage to Gal ß1-4GlcNAc units on N-glycans, is significantly less expressed in juvenile GIST. This suggests that the difference in KIT is generated by post-translational modification and may play a role in the progression of juvenile GIST.

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

BACKGROUND: Recent 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 (Fletcher's system). METHODS: A 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 Fletcher's 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. RESULTS: In 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 Fletcher's 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. CONCLUSION: This modified Fletcher's 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.

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

BACKGROUND: Although 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. METHODS: Between 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. RESULTS: Postoperative 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. CONCLUSION: Our 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.

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.