A multicenter long-term study of imatinib treatment for Japanese patients with unresectable or recurrent gastrointestinal stromal tumors.

BACKGROUND AND OBJECTIVES: This multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST). METHODS: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001-2011 were retrospectively reviewed. Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The median follow-up period was 4.0 years. RESULTS: After a median follow-up period of 4.0 years, the patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3%, 74.9%, and 53.8%, respectively. In univariate and multivariate analyses, imatinib dose reduction and achieving a complete or partial response were found to be associated with increased OS. CONCLUSIONS: Long-term imatinib treatment is recommended for patients with non-progressive disease. If patients experience significant toxicities, temporary dose reduction might be useful.

Hemodynamics of the reconstructed gastric tube during esophagectomy: assessment of outcomes with indocyanine green fluorescence.

BACKGROUND: Construction of a gastric tube that is well perfused with blood during esophagectomy is the most important factor in avoiding anastomotic leakage. We clarified the hemodynamics of the reconstructed gastric tube with indocyanine green (ICG) fluorescence. METHODS: In 20 patients undergoing gastric tube reconstruction during esophagectomy, we evaluated blood flow in the gastric tube with ICG fluorescence imaging. We divided the patients into two groups according to the quality of blood flow to the gastric tube-"good" (n = 9) and "sparse or absent" (n = 11)-based on visual assessment of the anastomosis of the right and left gastroepiploic vessels. We measured the time from initial enhancement of the root of the right gastroepiploic artery until enhancement of the most cranial branch of the left gastroepiploic artery and tip of the gastric tube. RESULTS: The gastric tube was divisible into three zones according to the dominant arteries present in the greater curvature under ICG fluorescence. The left gastroepiploic artery was enhanced in a direction opposite that of physiological blood flow in all cases. The median period from initial enhancement of the root of the right gastroepiploic artery to the most cranial branch of the left gastroepiploic artery until perfusion up to the tip of the gastric tube did not differ significantly between the "good" and the "sparse or absent" groups (P = 0.24, 0.68) CONCLUSIONS: It is essential to preserve the whole vessel arcade of the greater curvature to achieve good blood perfusion in the gastric tube. The ICG fluorescence method has potential usefulness for evaluation of blood flow in the gastric tube.

[The efficacy and safety of FOLFIRI or combined FOLFIRI and bevacizumab treatment as second-line chemotherapy for metastatic colorectal cancer patients aged 75 years and older].

The safety and efficacy of FOLFIRI as second-line chemotherapy for metastatic colorectal cancer patients ≥ 75 years was retrospectively evaluated. We analyzed 106 patients, who received FOLFIRI or a combination of FOLFIRI and bevacizumab following oxaliplatin-based first-line chemotherapy. The clinical characteristics and outcome in elderly patients ≥75 years(elderly[EP]group; n=18)were compared with those in patients aged<75 years(control group; n=88). The number of patients treated by a combination of FOLFIRI and bevacizumab in the EP group was lower than that in the control group (27.8% vs 55.7%; p=0.03). The comparison revealed no significant differences in response rate, progression-free survival, overall survival, and the frequency of overall adverse events after the start of second-line chemotherapy, although the frequency of anemia(Bgrade 3, p=0.07)and alopecia(grade 1/2, p=0.054)tended to be higher in the EP group than in the control group. Although this study retrospectively analyzed a limited number of patients, our results indicate that the safety and efficacy of FOLFIRI as second-line chemotherapy for metastatic colorectal cancer are almost equal in patients ≥ 75 years and those aged<75 years.

[Theoretical background of our original single-incision laparoscopic-assisted surgery technique for colon cancer via a periumbilical approach].

We assessed the theoretical background of our original single-incision laparoscopic-assisted surgery( SILS) technique involving a periumbilical approach. The subjects included 10 cases who underwent periumbilical SILS colectomy and had their surgical wounds photographed before and after skin incision between September 2009 and October 2010. Using an image analyzer, we estimated the theoretical oval area after a 3/4-circumferential periumbilical skin incision, the actual oval area after placement of the wound retractor, and the length of the skin incision. The mean oval area after the placement of the wound retractor was 2.9 times (range: 1.6-5.0 times) larger than that of the theoretical area. The square of the length of the skin incision positively correlated with the actual oval area created by placing the wound retractor( p=0.04, r=0.67). There were 5 patients, whose actual oval area was ≤700 mm2, and thus required additional radial skin incision( s)( 1 in 3 cases, 2 in 1 case and 3 in 1 case). When performing our original SILS via the periumbilical approach, the area of the actual surgical window can be predicted by measuring the distance from the center of the umbilicus to its edge.

[Efficacy of oxaliplatin-based chemotherapy in Stage IV colorectal cancer patients with peritoneal carcinomatosis].

PURPOSE: This retrospective study evaluated the outcome of oxaliplatin-based chemotherapy for peritoneal metastasis from colorectal cancer. PATIENTS AND METHODS: The study included 49 patients with peritoneal metastasis from colorectal cancer who underwent oxaliplatin-based chemotherapy between January 2006 and November 2012 and 25 patients who underwent systematic chemotherapy before oxaliplatin-based chemotherapy. Patient background characteristics, overall survival(l OS), and prognostic outcomes were examined. RESULTS: OS was significantly longer in patients treated with oxaliplatin -based chemotherapy than in those treated with prior chemotherapy( median, 20.5 months vs 11.7 months, p= 0.04). Multivariate analysis showed that treatment with oxaliplatin-based chemotherapy, age less than 70 years(p=0.03), and primary tumor resection( p=0.02) were significant independent factors affecting OS. CONCLUSION: Oxaliplatin-based chemotherapy improved the prognosis of patients with peritoneal metastasis from colorectal cancer. In the treatment of such patients, initiation of chemotherapy after primary tumor resection appears to be important, especially in patients aged <70 years.

[Analysis of KRAS status in cancer tissue with submucosal or deeper invasion in patients with familial adenomatous polyposis].

The KRAS status in cancer tissue with submucosal or deeper invasion was investigated in patients with familial adenomatous polyposis (FAP). Fifteen cancerous lesions in 10 FAP patients were subjected to analysis for KRAS status. The clinical features of FAP were the dense type in 2 patients and the sparse type in 8 patients. Of the 15 cancerous lesions, 6 (40%) were identified as having wild-type KRAS and the remaining 9 (60%), as having mutated KRAS. Of the 9 mutated lesions, the G13D mutation was recognized in 4 patients and was the most frequent pattern. With regard to the KRAS status in patients with multiple cancerous lesions, 1 patient had 3 cancerous lesions of which 2 were of the mutated type and 1 was of the wild type and another patient had 4 cancerous lesions of which 3 were of the mutated type and 1 was of the wild type. These results suggest that the frequency of wild-type KRAS in cancer associated with FAP was approximately 40%, although it was lower than that in sporadic cancer. Moreover, we need to analyze the KRAS status in all cancerous lesions in clinical practice when chemotherapy with anti-epidermal growth factor receptor (EGFR) antibody is required for the treatment of FAP patients with unresectable advanced multiple cancers.

[Effect of chemotherapy in primary tumor of MSI-H colon cancer aged 50 years or younger].

Microsatellite instability( MSI) in colorectal carcinoma is reportedly associated with resistance to 5-fluorouracil-based chemotherapy. Moreover, colorectal cancer patients aged ≤ 50 years could potentially have Lynch syndrome. In the present study, we examined 11 colorectal cancer patients with unresectable Stage IV disease who underwent resection of the primary tumor between January 2006 and December 2012. The relationship between the MSI status and the efficacy of first- line oxaliplatin-based chemotherapy was retrospectively examined. The MSI status included MSI-H in 1 patient, MSS-L in 2 patients, and MSS in 8 patients. The MSI-H in 1 patient was associated with familial adenomatous polyposis. Following chemotherapy, among 8 MSS patients, 3 showed stable disease (SD) and 1 showed partial response (PR). Moreover 2 MSH-L patients and 1 MSI-H patient showed progressive disease (PD) after chemotherapy. However, additional data collection is required to determine the effect of oxaliplatin-based chemotherapy for MSS-H or MSS-L colorectal patients aged ≤ 59 years.

Laparoscopic Heller myotomy with Dor fundoplication for esophageal achalasia treatment after distal gastrectomy and Billroth-II reconstruction.

Laparoscopic Heller myotomy with Dor fundoplication is the standard surgical treatment for esophageal achalasia. However, there are few reports on the use of this method after gastric surgery. We report a case of a 78-year-old man who underwent laparoscopic Heller myotomy with Dor fundoplication for achalasia after distal gastrectomy and Billroth-II reconstruction. After the intraabdominal adhesion was sharply dissected using an ultrasonic coagulation incision device (UCID), Heller myotomy was performed 5 cm above and 2 cm below the esophagogastric junction using the UCID. To prevent postoperative gastroesophageal reflux (GER), Dor fundoplication was performed without cutting the short gastric artery and vein. The postoperative course was uneventful, and the patient is in good health without symptoms of dysphagia or GER. Although per-oral endoscopic myotomy is becoming the mainstay of treatment for achalasia after gastric surgery, laparoscopic Heller myotomy with Dor fundoplication is also an effective strategy.

Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases.

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.

Prediction of lateral lymph node metastasis in lower rectal cancer: analysis of paraffin-embedded sections.

OBJECTIVE: In the surgical treatment for lower rectal cancer, preoperative selection of patients at high risk for lateral lymph node metastasis is important, since lateral lymph node dissection might impair genitourinary functions. We examined whether the status of lateral lymph node metastasis can be predicted from the lymph node size. METHODS: The subjects were 533 (35 positive and 498 negative) lateral lymph nodes from 47 patients with lower rectal cancer who underwent curative resection with lateral lymph node dissection. The sizes of the lateral lymph nodes immediately after removal and those in paraffin-embedded sections were compared for 108 lateral lymph nodes from 13 patients. In addition, receiver-operating characteristic curves were generated for the 533 paraffin-embedded lateral lymph nodes from the 47 patients to determine the optimal cut-off size for discriminating between positive and negative lateral lymph nodes. RESULTS: Irrespective of the presence/absence of metastasis and the long-/short-axis diameter, a positive relationship was noted between the sizes of the lateral lymph nodes measured immediately after removal and those measured on paraffin-embedded sections (P< 0.01). The area under the curve for the short-axis diameter differed little from that for the long-axis diameter (0.77 vs. 0.76, P =0.80). The optimal cut-off values of the short- and long-axis diameter extrapolated to the living body were 5.4 and 8.4 mm, respectively, with an accuracy of 72.8% for the short-axis diameter and 71.9% for the long-axis diameter. CONCLUSIONS: Prediction of the status of lateral lymph node metastasis from the lymph node size (long-/short-axis diameter) may be a simple and reliable method. The optimal cut-off diameter should be validated in prospective imaging studies.

[Evaluation of chemoradiotherapy for Stage II and III( non-T4) esophageal cancer].

AIM: We retrospectively evaluated the clinical efficacy of chemoradiotherapy for surgically resectable Stage II and III (non-T4) esophageal cancer. MATERIALS AND METHODS: 93 patients were diagnosed with esophageal cancer of clinical stage II and III(non-T4) from April 2005 to December 2010. Among them, 20 patients who were treated with 5-fluorouracil(5-FU) and cisplatin(CDDP) plus 60 Gy extra beam radiation were enrolled in this study. RESULTS: 13 patients(65%) had a complete response (CR), 3 patients had a partial response (PR), and the overall response rate was 80%. Significant statistical differences in lymph node metastasis ratio and clinical stage before chemoradiotherapy were revealed between CR patients and non-CR patients. No statistical differences were observed between surgically-treated cases and chemoradiotherapy cases in overall five-year survival rate and disease-free survival rate. The five-year survival rate of the CR patients (71.6%) was significantly better than that of the non-CR patients(22.2%)( p=0.04). CONCLUSION: Chemoradiotherapy for Stage II and III esophageal cancer appeared to be by no means inferior to esophagectomy and must be a choice during treatment planning.

[The efficacy of postoperative adjuvant chemotherapy for esophageal cancer with lymph node metastasis].

The clinical significance of postoperative 5-fluorouracil+cisplatin(FP) therapy for esophageal cancer with lymph node metastasis was retrospectively investigated. Overall, 37 patients who underwent curative resection of esophageal squamous cell cancer with lymph node metastasis were investigated. Clinical background and prognosis were compared between patients treated with FP therapy(FP group, 13 patients) and patients treated without FP therapy(non-FP group, 24 patients). In the FP group, the completion rate and adverse events were also analyzed. No significant difference was found between the FP and non-FP group in terms of age, gender, tumor location, number of dissected lymph nodes, and number of lymph node metastases. However, the frequency of 3-field lymph node dissection in the FP group was higher than that in the non-FP group(p=0.04), and the risk for operation in the FP group tended to be lower than that in the non-FP group(p=0.06). There was no significant difference in disease-free survival between these groups(p=0.46). Overall survival time in the FP group tended to be longer than that in the non-FP group (p=0.06). In the FP group, 2 patients with Grade 3 adverse events were recognized, and the completion rate of FP therapy was 77%. Although we analyzed a small number of patients in this study, postoperative adjuvant chemotherapy using FP does not contribute to the prevention of recurrence in esophageal cancer patients with lymph node metastasis.

[Clinical significance of serum anti-p53 antibody measurement for colorectal cancer].

We investigated the usefulness of serum anti-p53 antibody (anti-p53) measurement for the diagnosis of colon cancer. carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and anti-p53 were measured by enzyme-linked immunosorbent assay in 375 colorectal cancer patients and 115 healthy volunteers(control group). When the cut-off level of the serum anti-p53 antibody was set to 1.3 U/mL, 114 (30.4%) of the colorectal cancer patients tested positive. Twelve positive cases(10.4%) were recognized in the control group. The median levels of anti-p53 were 0.69 U/mL(0.69- 10,610) and 0.69 U/mL (0.69-19.5) in the colorectal cancer patients and control group, respectively. The positive rates of CEA level (cut-off value 6.7 ng/mL) and CA19-9 level (cut-off value 37 U/mL) were 40.0% and 18.9%, respectively. Of these tumor markers, positive cases with only anti-p53 were observed in 60 patients (16%). The positive rate of all markers examined was 61.6%. No significant correlation was observed between the level of anti-p53 and other markers. The positive rates of anti-p53 in each stage of the colon cancer patients were as follows: stage 0 and I, 19.4%; stage II, 27.0%; stage III,36.1%; and stage IV,61.0%. The positive rate of anti-p53 was higher than that of CEA and CA19-9 in the early stages of colorectal cancer. Furthermore, a combination of these markers improved the diagnosis of colorectal cancer by approximately 60%. These results suggest that the measurement of anti-p53 is useful for diagnosis of colorectal cancer in clinical practice.

[Colon cancer with portal vein tumor thrombosis-a case report and review of the literature].

Colon cancer with portal vein tumor thrombosis has a poor prognosis. However, little is known about the clinicopathological characteristics of these patients. In this study, we attempted to clarify the clinicopathological characteristics of such patients reported in the Japanese literature, including our own case. This case concerns a 48-year-old female patient diagnosed as having transverse colon cancer with severe portal vein tumor thrombosis. Despite curative resection, the patient was found to have multiple liver metastases six months later, and chemotherapy did not prove to be adequately effective; she died 18 months after surgery. A search of the relevant literature revealed 9 reports of similar patients. The patients consisted of 4 males and 6 synchronous cases, with a median age of 70 years. Portal vein tumor thrombosis was observed in 6 patients. While the portal vein was the most frequent site of thrombosis, other patients showed tumor thrombosis of the superior and inferior mesenteric veins. Despite curative resection, 3 patients eventually developed liver metastases after the operation. The median disease-free survival of the patients who had undergone curative resection was 300 days, and the overall median survival of the patients was 420 days. Thus, for the portal vein tumor thrombosis, we need to adopt adjuvant chemotherapy in consideration of a high risk for the liver metastases.

[A long-term survivor of colorectal cancer associated with multiple liver metastases and peritoneal carcinomatosis treated through a multidisciplinary approach].

Even in the era of new anticancer drugs, an optimal treatment strategy for colorectal cancer associated with liver metastasis and peritoneal carcinomatosis has yet to be established. Here we report the case of a long-term survivor with very advanced colon cancer who underwent repeated resective surgery and chemotherapy. This 69-year-old man underwent a Hartmann's procedure and the resection of peritoneal metastases of cancer of the rectosigmoid, which had infiltrated the retroperitoneum giving rise to multiple liver metastases and peritoneal carcinomatosis. The resection margin was positive for cancer. After 14 courses of a modified FOLFOX6 (mFOLFOX6) regimen, a partial response with no development of new lesions was obtained. Multiple partial hepatectomies were subsequently performed. After the completion of an additional 6 courses of mFOLFOX6, a positron-emission tomography (PET)/computed tomography (CT) examination demonstrated a hot spot in segment 4. This hot deposit disappeared after a further 8 courses of mFOLFOX6. The patient then underwent a left lateral segmentectomy for a newly developed lesion in segment 3, which was detected 2 years and 7 months after the first operation. The patient has remained free from recurrence for 2 years since his last operation.

[Clinicopathological characteristics and treatment outcome of retroperitoneal liposarcoma].

Six patients with retroperitoneal liposarcoma were referred to our institution and retrospectively analyzed. Clinicopathological factors, initial treatment, postoperative recurrence, treatment, disease-free survival, and overall survival were investigated. Median age was 67 years and the male to female ratio was 0.5. Every patient underwent a surgical procedure as an initial treatment. Maximum tumor diameter was 190 mm (range, 100-250 mm). Three patients had local excisions, whereas the remaining 3 had extended surgery. Histological classification included well-differentiated type in 3, dedifferentiated type in 2, and mucinous type in 1. Three patients developed recurrence (local, n=3; hematogeneous, n=2). Local recurrence was excised but the disease relapsed in 2 patients. Median disease-free survival period was 21 months and 3-year survival rate was 62.5%. Since surgical resection remains the only promising treatment for liposarcoma, total removal of the tumor with negative surgical margins is mandatory. Wide resection, including the neighboring organs, should be performed without hesitation in selected cases.

[A case of multiple hepatic epithelioid hemangioendothelioma mimicking metastatic hepatic tumor].

We report a case of multiple hepatic epithelioid hemangioendothelioma( EHE) mimicking hepatic metastasis of colon cancer. A 71-year-old man was referred to our hospital for further evaluation of multiple hepatic tumors. Enhanced CT scan was not performed because of renal dysfunction. Total colonoscopy revealed a type 1 cancer at the rectosigmoid junction. We therefore diagnosed the hepatic tumors as metastases from rectal cancer. Anterior resection was performed and postoperative chemotherapy targeting the hepatic tumors was carried out. Unfortunately, the size of the hepatic tumors increased. We therefore performed lateral segmentectomy and partial hepatectomies (11 lesions). The macroscopic findings indicated basically localized tumor without diffuse infiltration. Microscopically, spindle and oval-shaped cells with abundant eosinophilic cytoplasm were observed; immunohistochemical staining was positive for factor VIII and CD34. These data were conclusive for EHE. EHE of the liver is a rare neoplasm of which little is currently known. We herein report a case of EHE in the liver, misdiagnosed as colorectal metastatic tumor.

[Clinical outcome of Stage IV colorectal cancer on the basis of the seventh edition of the TNM classification].

Recent advances in chemotherapy for stage IV colorectal cancer have improved clinical outcome. According to the seventh edition of the TNM classification of colorectal cancer, stage IV is classified into stage IVA and stage IVB. In this study, we assessed the clinical validity of this classification as a prognostic factor. The subjects were 170 patients with stage IV colorectal cancer(stage IVA, n=78; stage IVB, n=92)treated between January 2006 and December 2011 at our institute. Of 92 patients with stage IVB, peritoneal carcinomatosis alone was recognized in 21 patients. The median survival periods for patients with stage IVA and IVB were 29.2 and 16.1 months, respectively( p=0.13). The median survival period for patients with peritoneal carcinomatosis alone was 37.6 months, and there was no difference between survival in patients with stage IVA and those with peritoneal carcinomatosis alone. Our present results suggest that it may be reasonable and useful to classify peritoneal carcinomatosis alone into stage IVA instead of stage IVB in clinical practice.

[The clinical significance of serum anti-p53 antibody as a monitoring marker in colorectal cancer].

We examined alterations in the level of serum anti-p53 antibody(S-p53 Ab) in colorectal cancer patients who underwent curative resection and analyzed the usefulness of S-p53 Ab as a monitoring marker for postoperative observation. The measurement of S-p53 Ab was performed preoperatively and postoperatively in 16 stage II/III colorectal cancer patients with a high level of S-p53 Ab. A time course analysis of both S-p53 Ab and CEA levels was performed in 6 of these patients who were carcinoembryonic antigen (CEA) positive. The median S-p53 Ab level was 29.9 U/mL and the half-life of the S-p53 Ab level was 40.3 days. In 4(25%) cases, the level of S-p53 Ab recovered to within normal limits by 79-142 days. When the half-lives of S-p53 Ab and CEA were analyzed in 6 patients who were both S-p53 Ab and CEA positive, the half-lives of S-p53 Ab and CEA were 32.3 and 13.2 days, respectively. In the case of recurrence with liver metastasis after resection of ascending colon cancer, the S-p53 Ab level did not respond quickly while the CEA level increased. Therefore, it is difficult to use the level of S-p53 Ab as a marker for monitoring treatment, and priority should be given to the examination of CEA and imaging modality.

[Predictive value of Köhne's index on the efficacy of FOLFIRI regimen in the treatment of unresectable liver metastatsis of colorectal cancer].

The aim of this retrospective study was to analyze the predictive value of Köhne's index on the efficacy of FOLFIRI regimen in the treatment of unresectable liver metastasis of colorectal cancer. The subjects were 44 patients with unresectable liver metastasis from colorectal cancer treated with FOLFIRI regimen as second-line, for all of whom oxaliplatin-based regimen had previously failed. Bevacizumab was concomitantly used in 23 patients. Classification of the Köhne's index revealed high risk in 22 patients, intermediate risk in 7 patients, and low risk in 15 patients. The response rate was 13.6% in the patients with high risk(H group) and 27.3% in the patients with intermediate or low risk(non-H group)(p=0.45). The disease control rate was 50% in the H group and 68.2% in the non-H group (p=0.36). In the H group, the median progression -free survival time was 4.1 months and in the non-H group it was 7.1 months (p=0.33). Compared with the H group, the non-H group showed significantly better overall survival (10.8 months vs 23.9 months, p=0.03). None of the patients has received hepatectomy (conversion therapy). These results suggest that the predictive value of Köhne's index is limited in terms of the effect of shrinkage of liver metastases, including conversion therapy.