Ten-Year Survival of a Patient Treated with Stereotactic Gamma Knife Radiosurgery for Brain Metastases from Colon Cancer with Ovarian and Lymph Node Metastases: A Case Report.

Brain metastasis from colorectal cancer is infrequent and carries a poor prognosis. Herein, we present a patient alive 10 years after the identification of a first brain metastasis from sigmoid colon cancer. A 39-year-old woman underwent sigmoidectomy for sigmoid colon cancer during an emergency operation for pelvic peritonitis. The pathological finding was moderately differentiated adenocarcinoma. Eleven months after the sigmoidectomy, a metastatic lesion was identified in the left ovary. Despite local radiotherapy followed by chemotherapy, the left ovarian lesion grew, so resection of the uterus and bilateral ovaries was performed. Adjuvant chemotherapy with tegafur-uracil (UFT)/calcium folinate (leucovorin, LV) was initiated. Seven months after resection of the ovarian lesion, brain metastases appeared in the bilateral frontal lobes and were treated with stereotactic Gamma Knife radiosurgery. Cervical and mediastinal lymph node metastases were also diagnosed, and irradiation of these lesions was performed. After radiotherapy, 10 courses of oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX) were administered. During FOLFOX administration, recurrent left frontal lobe brain metastasis was diagnosed and treated with stereotactic Gamma Knife radiosurgery. In this case, the brain metastases were well treated with stereotactic Gamma Knife radiosurgery, and the systemic disease arising from sigmoid colon cancer has been kept under control with chemotherapies, surgical resection, and radiotherapy.

Identification of HLA-A2 or HLA-A24-restricted CTL epitopes for potential HSP105-targeted immunotherapy in colorectal cancer.

We previously reported that heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal, pancreatic and esophageal cancer and has proven to be a novel biomarker for the immunohistochemical detection of these cancers. In the present study, we used HLA-transgenic mice (Tgm) and the peripheral blood mononuclear cells (PBMCs) of colorectal cancer patients to identify HLA-A2 and HLA-A24-restricted HSP105 epitopes, as a means of expanding the application of HSP105-based immunotherapy to HLA-A2- or HLA-A24-positive cancer patients. In addition, we investigated by ex vivo IFN-γ ELISPOT assay whether the HSP105-derived peptide of cytotoxic T cells (CTLs) exists in PBMCs of pre-surgical colorectal cancer patients. We found that four peptides, HSP105 A2-7 (RLMNDMTAV), HSP105 A2-12 (KLMSSNSTDL), HSP105 A24-1 (NYGIYKQDL) and HSP105 A24-7 (EYVYEFRDKL), are potential HLA-A2 or HLA-A24-restricted CTL HSP105-derived epitopes. HSP105-specific IFN-γ-secreting T cells were detected in 14 of 21 pre-surgical patients with colorectal cancer in response to stimulation with these four peptides. Our study raises the possibility that these HSP105 peptides are applicable to cancer immunotherapy in patients with HSP105-expressing cancer, particularly colorectal cancer.

Analysis of clinical factors associated with anal function after intersphincteric resection for very low rectal cancer.

PURPOSE: The purpose of this study was to identify factors that have a negative impact on anal function after intersphincteric resection. METHODS: We evaluated postoperative anal function in 96 patients with very lower rectal cancer who underwent intersphincteric resection by having patients fill out detailed questionnaires at 3, 6, 12, and 24 months after surgery. Univariate and multivariate analysis based on the Wexner incontinence score were used to identify factors associated with poor anal function after intersphincteric resection. RESULTS: The mean Wexner score at 12 months after stoma closure was 10.0. Patients with frequent major soiling showed a Wexner score of >or=16, and this score was used as a cutoff value of poor anal function. In the univariate analysis, poor anal function was significantly associated with a greater extent of excision of the internal sphincter and with preoperative chemoradiotherapy. In the multivariate analysis, preoperative chemoradiotherapy was the only independent factor associated with poor anal function after intersphincteric resection (odds ratio=10.3; 95 percent confidence interval, 2.3-46.3, P < 0.01). CONCLUSIONS: Preoperative chemoradiotherapy was identified as the risk factor with the greatest negative impact on anal function after intersphincteric resection, regardless of extent of excision of the internal sphincter.

Influence of learning curve on short-term results after laparoscopic resection for rectal cancer.

BACKGROUND: Technical difficulties have been encountered in laparoscopic surgery for the treatment of rectal cancer. There are fewer studies about the learning curve for laparoscopic rectal resection. METHODS: Between June 1995 and August 2007, 200 patients who were scheduled to undergo laparoscopic rectal resection for rectal cancer were enrolled in the study. Each surgeon's operative experience was divided into three groups: 1-20 cases, 21-40 cases, and 41 or more cases. Furthermore, patients were divided chronologically into four groups of 50 patients each. This report describes the association between the learning curves (surgeon's experience and team's experience) and short-term outcomes such as operating time, complication rate, and hospital stay in the case of laparoscopic resection for rectal cancer. We also analyzed how the learning curve influences several postoperative outcomes compared with other clinical factors. RESULTS: The team's experience was not associated with short-term results except for surgical site infection (SSI). On the other hand, surgeon's experience was associated with mean operating time and SSI rate. The endpoints of the learning curve for reducing mean operating time and SSI rate were defined as 40 and 20 cases of laparoscopic rectal resection. In contrast, anastomotic leakage was not associated with surgeon's experience and showed the greatest correlation with total mesorectal excision (TME). CONCLUSION: Surgeon's learning improved operating time and SSI. On the other hand, low level of anastomosis accompanied with TME was strongly related with leakage, and the association between leakage and surgeon's learning was not clearly demonstrated.

Improvement of the diagnostic accuracy of lymph node metastases of colorectal cancer in 18F-FDG-PET/CT by optimizing the iteration number for the image reconstruction.

OBJECTIVE: Improvement in the diagnostic accuracy of lymph node (LN) metastases of colorectal cancer by optimizing the reconstruction parameters was studied, including a phantom study and clinical studies. METHODS: In the experimental study, the contrast ratio was evaluated using a standard image quality phantom, changing the iteration number of ordered subsets expectation maximization algorithm from 2 to 6. In the clinical study, 89 patients with preoperative colorectal cancer who received 18F-2-deoxy-2-fluoro-D: -glucose positron emission tomography/computed tomography (PET/CT) were studied. Their LN metastases were visually assessed when systematically changing the iteration number, and the optimal iteration number was determined. After the appropriate cut-off value of maximum standardized uptake value was determined, the improvement of the diagnostic accuracy of LN metastases was evaluated for the proximal nodes and the distal ones using the reconstructed images with the optimal iteration number. This was compared with the conventional method that had an iteration number of 2. RESULTS: In the phantom study, it was confirmed that the contrast ratio improved when the iteration number increased. In clinical evaluation, the optimal iteration number was determined to be 5 by visual assessment. When the cut-off value of 1.5 was used, which happened to be the best number, the sensitivity/specificity/accuracy improved from 52%/91%/72% to 77%/89%/83% for the proximal nodes, and from 63%/90%/84% to 91%85%/87% for the distal nodes, respectively. CONCLUSIONS: When the iteration number of the reconstruction algorithm was optimized, the sensitivity of LN metastasis improved by more than 20%, and the accuracy exceeded 80%. Optimization of the image reconstruction parameters in the diagnosis of LN metastases using PET/CT is clinically important.

Preoperative diagnosis of lymph node metastases of colorectal cancer by FDG-PET/CT.

PURPOSE: The purpose of this study was to assess the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for lymph node (LN) metastasis of colorectal cancer. METHODS: FDG-PET/CT was used to preoperatively evaluate 88 patients with colorectal cancer. In this study, LN sites were divided into proximal and distant according to their distance from the primary tumor. The FDG-PET/CT images were evaluated by three criteria; nodal diameter, abnormal uptake and maximum standardized uptake value (SUV). We compared the diagnostic ability of these methods for LN metastasis at proximal and distant sites. RESULTS: The mean SUV of the malignant LNs was significantly higher than that of the benign LNs. The sensitivity, specificity and accuracy of diagnosis by abnormal uptake were 28.6, 92.9 and 75.0%, those by nodal diameter using cutoff value of 10 mm were 30.6, 95.3 and 74.4% and those by SUV using cutoff value of 1.5 were 53.1, 90.6 and 80.1%, respectively. The sensitivity, specificity and accuracy of diagnosis based on optimal SUV were 51.2, 85.1 and 69.3% in the proximal site and 62.5, 92.5 and 89.7%, respectively, in the distant site. CONCLUSIONS: FDG-PET/CT is useful for preoperative diagnosis of distant LN metastases of colorectal cancers.

Relationship between multiple numbers of stapler firings during rectal division and anastomotic leakage after laparoscopic rectal resection.

BACKGROUND: We experienced some technical difficulty in dividing the middle and lower rectum through the right-lower quadrant intracorporeally. The aim of this study was to determine whether multiple stapler firings during rectal division are associated with anastomotic leakage after laparoscopic rectal resection. METHODS: Laparoscopic anterior resection with double-stapling technique anastomosis was performed in 180 consecutive rectal cancer patients. We often used vertical rectal division through a suprapubic site instead of the standard transverse rectal division for laparoscopic total mesorectal excision (LapTME). We attempted to determine whether there was an association between the number of stapler firings and procedures in rectal division. Moreover, we identified risk factors for anastomotic leakage after laparoscopic rectal resection by multivariate analysis. RESULTS: Anastomotic leakage occurred in 5% of the subjects of this study. Vertical rectal division through the suprapubic site after Lap TME required fewer staples than transverse division through the right-lower port and a smaller percentage of patients required three or more staples for vertical rectal division than for transverse division (15% vs. 45%, p=0.03). In the multivariate analysis, TME and the number of staplers used for rectal division were the factors found to be associated with a significantly greater risk of subsequent leakage (odd's ratio=5.3; 95% CI 1.2-22.7 and odd's ratio=4.6; 95% CI 1.1-19.2). CONCLUSION: TME and multiple stapler firings during distal rectal division were associated with anastomotic leakage after laparoscopic rectal resection. Vertical rectal division through a suprapubic site was a useful method of avoiding multiple stapler firings during laparoscopic TME.

HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice.

We previously reported that glypican-3 (GPC3) is uniquely overexpressed in human hepatocellular carcinoma and melanoma and that it is an ideal tumor antigen for immunotherapy in mouse models. We recently identified both HLA-A24 (A*2402) and H-2Kd-restricted GPC3298-306 (EYILSLEEL) and HLA-A2 (A*0201)-restricted GPC3144-152 (FVGEFFTDV), both of which can induce GPC3-reactive cytotoxic T cells (CTLs). The present study was a preclinical study in a mouse model that was conducted in order to design an optimal schedule for clinical trial of GPC3-derived peptide vaccine. When BALB/c mice were intradermally vaccinated at the base of the tail with Kd-restricted GPC3298-306 peptide mixed with incomplete Freund's adjuvant (IFA), the peptide-specific CTLs were induced. But the peptide alone could not induce peptide-specific CD8+ T cells. Furthermore, proteomic analyses showed that IFA protected the peptide against degradation in the human serum. Peptide-reactive CTLs were induced by peptide vaccine in a dose-dependent manner. In addition, at least two vaccinations with a single dose >10 microg were needed for the induction of GPC3298-306-specific CTLs. But repeated vaccination with a lower dose of GPC3298-306 did not induce peptide-specific CTLs. Similarly, induction of an Ag-specific immune response by HLA-A2 GPC3144-152 depended on the dose administered. The results of this study suggested that IFA is one of the indispensable adjuvants for peptide-based immunotherapy, and that the immunological effect of peptide vaccines depends on the dose of peptide injected.

Diagnosis supporting algorithm for lymph node metastases from colorectal carcinoma on 18F-FDG PET/CT.

OBJECTIVE: We studied the improvement of the detect-ability of lymph node (LN) metastases from colorectal cancer in (18)F-fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT) by analyzing the acquired counts with a statistical method. METHODS: Thirty-nine metastatic LNs from 32 cases with colorectal cancer were included in this study. "Uptake region" was defined as the site where counts were higher than the average plus 3 standard deviations (SDs) on each transaxial image of FDG PET. After the initial uptake regions were selected, these high accumulation areas were automatically excluded from consideration thereafter. This method was repeated and new uptake regions were identified. This method was repeated up to five times. After that, the stacked-up uptake regions were compared with computed tomography (CT) images, and the high accumulation areas that were superimposed on the normal structures, such as intestine, vessels, and ureters, were excluded from the consideration. The remaining uptake regions were diagnosed as metastatic LNs, and the detectability of LN metastases was calculated. We then compared these statistical results with the results obtained on the basis of visual assessments by radiologists. RESULTS: Our proposed method showed the best results when the procedures were repeated three times in the light of detectability. After being repeated three times, this method detected 15/23 (65.2%) metastatic LNs in the first LN group, 16/16 (100%) in the second-third LN groups and 31/39 (79.4%) in the total LNs, whereas the radiologists diagnosed 8/23 (34.8%) of metastatic first LNs, 12/16 (75.0%) in the second-third LNs and 20/39 (51.3%) in the total LNs. A statistically significant difference was observed between the result of iteration number 3 and that by radiologists as for the second-third LNs and the total LNs. CONCLUSIONS: This study suggests that our proposed statistical method could improve the detectability of LN metastases from colorectal cancer. Our method will help radiologists to detect small metastatic lesions such as LN metastases.

Bladder-sparing extended resection of locally advanced rectal cancer involving the prostate and seminal vesicles.

PURPOSE: Total pelvic exenteration (TPE) is the standard procedure for locally advanced rectal cancer involving the prostate and seminal vesicles. We evaluated the feasibility of bladder-sparing surgery as an alternative to TPE. METHODS: Eleven patients with advanced primary or recurrent rectal cancer involving the prostate or seminal vesicles, or both, underwent bladder-sparing extended colorectal resection with radical prostatectomy. The procedures performed were abdominoperineal resection (APR) with prostatectomy (n = 6), colorectal resection using intersphincteric resection combined with prostatectomy (n = 4), and abdominoperineal tumor resection with prostatectomy (n = 1). Local control and urinary and anal function were evaluated postoperatively. RESULTS: Cysto-urethral anastomosis (CUA) was performed in seven patients and catheter-cystostomy was performed in four patients. Coloanal or colo-anal canal anastomosis was also performed in four patients. There was no mortality, and the morbidity rate was 38%. All patients underwent complete resection with negative surgical margins. After a median follow-up period of 26 months there was no sign of local recurrence, and ten patients were alive without disease, although distant metastases were found in three patients. Five patients had satisfactory voiding function after CUA, and three had satisfactory evacuation after intersphincteric resection (ISR). CONCLUSION: These bladder-sparing procedures allow conservative surgery to be performed in selected patients with advanced rectal cancer involving the prostate or seminal vesicles, without compromising local control.

Clinical factors influencing CT findings in patients with acute appendicitis.

BACKGROUND/AIMS: CT has proven useful in diagnosing appendicitis, but it also has some disadvantages. In this study we investigated clinical factors influencing CT findings of acute appendicitis and identified the most appropriate patients for preoperative CT. METHODOLOGY: Enhanced helical CT scans were obtained preoperatively in 95 patients who underwent appendectomy. They were gangrenous in 52 (55%), phlegmonous in 38 (40%) and catarrhal in 5 (5%) and we usually indicated emergent surgery for phlegmonous or gangrenous appendicitis patients. 62 (69%) of 90 phlegmonous or gangrenous cases had both an enlarged appendix (> or = 6mm) and periappendiceal fat strand in CT, which strongly suggested the need for emergent operation (Positive group). We compared clinical factors in the positive group with those in the other 28 patients (Equivocal group). RESULTS: There was no significant difference between the positive and equivocal groups in age, gender, or white blood cell count. The depth of subcutaneous fat (SCF) at the umbilicus level in CT and the number of patients with gangrenous appendicitis were significantly increased in the positive group compared with the equivocal group by both univariate and multilogistic regression analysis. CONCLUSIONS: These indicated that the degree of inflammation and SCF were significantly associated with CT findings of appendicitis and CT should be routinely done in obese patients.