Timing of relapse and outcome after curative resection for colorectal cancer: a Japanese multicenter study.

BACKGROUND: The aim of this multicenter study was to clarify the influence of timing of relapse after curative resection for colorectal cancer on prognosis. METHODS: We enrolled 5,230 consecutive patients who underwent curative resection for colorectal cancer at 14 hospitals from 1991 to 1996. All patients were intensively followed up. Time to relapse (TR) was classified into three groups as follows: group A, TR < or =1 year; group B, TR >1 year and < or =3 years, and group C, TR >3 years. The prognoses after relapse were compared among the three groups. RESULTS: Of the 5,230 patients, 906 experienced relapse (17.3%). The curative resection rates for recurrent tumors were 35.2% in group A, 46.6% in group B, and 45.1% in group C (p = 0.0045). There were significant differences in the prognoses after relapse among the three TR groups in patients with relapse to the liver (p = 0.0175) and in those with local relapses (p = 0.0021), but not in those with pulmonary or anastomotic recurrence. There were no differences in prognoses after relapse in any recurrence site among the three groups in patients who underwent curative resection for relapse. CONCLUSION: If patients can undergo curative resection for relapse, they receive a survival benefit regardless of the timing of relapse.

Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer.

The early detection of colorectal cancer originating from any part of the colorectum is desirable because this cancer can be cured surgically if diagnosed early. We searched for marker genes for a fecal RNA-based colorectal cancer screening method by comparison of genome-wide expression profiles among cancerous and non-cancerous tissues, and healthy volunteer- and cancer patient-derived colonocytes from the feces, and the peripheral blood. Of 14,564 genes, only 3 (PAP, REG1A, and DPEP1) were selectable as final candidates which were expressed frequently at any stage of this cancer and were suppressed in non-cancerous tissues and also in the peripheral blood and colonocytes of healthy volunteers. Next, we directly compared fecal RNA-expression profiles between colorectal cancer patients and healthy volunteers, and found that most of the genes (92%) expressed in the colonocytes of the cancer patients were not expressed in those of the healthy volunteers. Six genes (SEPP1, RPL27A, ATP1B1, EEF1A1, SFN, and RPS11) selected randomly from 85 cancer patient-derived colonocyte-specific genes were evaluated. In total, reverse transcription-polymerase chain reaction or focused microarray of all those 9 genes detected 18 (78%) of 23 curable colorectal cancers (Dukes stages A-C), 9 or 10 (64% or 71%) of 14 early cancers with no lymph node metastasis (Dukes stage A or B) and 4 (80%) of 5 right-sided cancers. Our extensive gene list provides other markers for fecal RNA-based colorectal cancer screening.

Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study.

BACKGROUND: The aim of this study was to clarify the characteristics of recurrence and the effectiveness of surveillance tools after curative resection for colorectal cancer. METHODS: We enrolled 5230 consecutive patients (stage I, 1367; stage II, 1912; stage III, 1951) who underwent curative resection at 14 hospitals from 1991 to 1996. All patients were followed up intensively, and their outcomes were investigated retrospectively. RESULTS: Of the 5230 patients, 906 developed recurrence. The recurrence rates of stage I, II, and III cancers were 3.7%, 13.3%, and 30.8%, respectively (P < .0001). The curves of the cumulative appearance rate of recurrence in stage II and III patients showed a rapid increase for the first 3 years. Recurrence after 5 years was less than 1% in each stage. Clinical visits combined with measurements of tumor markers detected the majority of recurrences except in the case of lung metastasis. In contrast, 43.4% of hepatic recurrences were detected by liver imaging, and 48.4% of pulmonary recurrences were noted by chest x-ray. The 5-year survival rates after primary colorectal surgery in patients who underwent resection for recurrence were better than in those without resection: 55% vs 11% in hepatic recurrence, 68% vs 13% in pulmonary recurrence, and 48% vs 22% in local recurrence (all P < .001). CONCLUSION: It is useful to take these characteristics of recurrence into account in the management of patients after curative resection for colorectal cancer and in the setting of clinical trial for follow-up after curative resection for colorectal cancer.

A rare case of repeated anastomotic recurrence due to tumor implantation after curative surgery for sigmoid colon cancer.

BACKGROUND: Anastomotic recurrence is often experienced at colocolic or colorectal anastomoses. Tumor cell implantation has been reported as the mechanism of anastomotic recurrence. However, anastomotic recurrence occurring repeatedly after curative surgery is rare. We herein report a rare case of repeated anastomotic recurrence after curative surgery for sigmoid colon cancer. CASE PRESENTATION: A 51-year-old man underwent radical surgery for sigmoid colon cancer. However, anastomotic recurrence developed three times during three years and six months after the initial operation in spite of irrigation with 5% povidone-iodine before anastomosis. The serum carcinoembryonic antigen (CEA) level had been within normal limits after sigmoidectomy. Finally, the patient underwent abdominoperineal resection. The clinico-pathological findings revealed that possible tumor cell implantation caused these anastomotic recurrences. The patients survived without recurrence during the follow-up period of seven years and nine months. CONCLUSION: We experienced a rare case of repeated anastomotic recurrence due to possible tumor implantation after curative surgery for sigmoid colon cancer; however the prognosis was ultimately very good. CEA monitoring was insensitive for detection of anastomotic recurrence in this case.

[A case of gastric cancer with synchronous hepatic metastases which enforced the intra hepatic arterial chemotherapy showed a reduction of both tumors].

This is a case report of the intrahepatic arterial chemotherapy showing an effective reduction of tumors without an operation. The patient was a 68-year-old female. Instead of having an operation to gastric cancer with synchronous hepatic metastases, an intrahepatic arterial embolization of MMC and CPT-11 with DSM was enforced in the right-and-left hepatic arteries, and intrahepatic arterial infusions of 5-FU and CDDP were enforced after that. After intrahepatic infusion, the tumor size and marker of the gastric cancer and synchronous hepatic metastases decreased, and it was diagnosed as partial response (PR). Since the tumor marker showed an increase after thirteen times of the intrahepatic arterial infusions of 5-FU and CDDP, intrahepatic arterial embolization of CPT-11 and MMC with DSM was performed again and the intrahepatic arterial infusions of 5-FU and CDDP were enforced fourteen times after that. Although the tumor marker showed a small range of fluctuation, PR was kept observed and the patient has been stable for fifteen months since the chemotherapy began. She continuously received the combination chemotherapy as an outpatient.

[Transarterial chemoembolization with irinotecan (CPT-11) and degradable starch microspheres (DSM) in patients with liver metastases from colorectal cancer].

We report 27 cases of liver metastases treated with transarterial chemoembolization (TACE) with CPT-11, DSM, and mitomycin C (CPT-DSM therapy). In the 27 patients with liver metastases from colorectal cancer, CPT-DSM therapy was performed 47 times. All of these patients were a contra indication of hepatectomy. We compared a tumor marker before and after the treatment, and measured a serum level of SN-38, which is an active substance of CPT-11 and resolved from CPT-11. Although the level of CPT-11 was wearing off after CPT-DSM therapy, the peak of SN-38 level delayed 1 hour after the infusion. The CEA and CA19-9 levels were decreased to 54.2% and to 45.1% of the level before the treatment, respectively. Nine of the partial response and stable disease patients underwent surgery. The response rate was 59%. A 3-year survival rate was 20%. These results suggest that CPT-DSM therapy is one of the most effective anticancer agents. This TACE can be a feasible therapy for colorectal liver metastases as the first-line therapy.

Long-term assessment of anorectal function after extensive resection of the internal anal sphincter for treatment of low-lying rectal cancer near the anus.

OBJECTIVES: Intersphincteric resection (ISR) for low-lying rectal cancer (LRC) may induce major problems associated with anorectal function. In this study, we assessed the severity of ISR-induced impairment in anorectal function. METHODS: In total, 45 patients followed up regularly ≥2 years after diverting ileostoma closure were eligible. The patients underwent ISR (n=35) or conventional coloanal anastomosis without resection of the internal anal sphincter (IAS) (n=10) for treatment of LRC from January 2000 to December 2011. We retrospectively compared anorectal function [stool frequency, urgency, Wexner incontinence scale (WIS) score, and patient satisfaction with bowel movement habits on a visual analog scale (VAS) score] for ≥2 years after stoma closure between the two groups. RESULTS: The median follow-up period was 4.0 years (range, 2.0-6.5 years). Of the total, 17 (48.6%) patients who underwent ISR had poor anorectal function, including two with complete incontinence. Significant differences were found between the groups in the incidence of urgency (p=0.042), WIS score (p=0.024), and defecation disorder with a WIS score of ≥10 (p=0.034) but not in stool frequency. Based on the VAS score, 45.7% of patients who underwent ISR were dissatisfied with their bowel movement habits (p=0.041). CONCLUSIONS: Extensive resection of the IAS has negative short- and long-term effects on anorectal function.

[Liver metastasis from sigmoid colon cancer with peritoneal dissemination showed a complete response to TS-1].

A 64-year-old man with unresectable sigmoid adenocarcinoma due to peritoneal dissemination (P3) and liver metastasis (H2) treated with TS-1, showed a complete response. TS-1 is an oral anticancer drug that produces biochemical modulation. It is composed of tegafur, gimestat and ostat potassium in a molar ratio of 1:0.4:1 to increase the effect of 5-FU and to decrease toxicity in the digestive canal. Treatment with TS-1 requires no hospitalization and can enhance the quality of life of the patient. TS-1 is expected to be an effective agent for the treatment of colon cancer with liver metastasis and peritoneal dissemination.

[Case report of a liver metastasis from rectal cancer achieving complete response (CR) by a combination of intra-hepatic arterial infusion of irinotecan (CPT-11) with degradable starch microspheres (DSM) and weekly high-dose intra-hepatic arterial chemotherapy with 5-FU].

A 67-year-old woman, who was diagnosed with rectal cancer and liver metastasis, underwent a low anterior resection of the rectum in May 2004. Two months later, the level of tumor markers increased and a CT scan revealed a 45 x 35 mm liver metastasis in the S(8) segment. She was referred to our hospital for treatment of the liver tumor. Intra-hepatic arterial infusion of irinotecan (CPT-11) and mitomycin C (MMC) with degradable starch microspheres (DSM) was given in July 2004. Following this, a 34-week course of weekly high-dose intra-hepatic arterial 5-FU infusion (5-FU 1,000 mg/m(2)) was performed. In April 2005, the size of the liver metastasis decreased, and the level of serum tumor marker normalized. A CT and echo scan revealed a calcified tumor, and therefore all chemotherapy was stopped. She was followed in the outpatient clinic, with no evidence of recurrence for 12 months. This case suggests that the use of intra-hepatic arterial infusion of CPT-11 and MMC with DSM is useful for the treatment of liver metastases in colorectal cancer.

Disappearance of HCV after cessation of immunosuppression in a patient with ulcerative colitis and renal transplantation.

We report a patient, a 45-year-old Japanese woman, who underwent living-related donor renal transplantation in 1986 and 1988, with the second procedure being successful. Ulcerative colitis (UC) was diagnosed in 1987 while she was receiving immunosuppressive therapy after the renal transplantation. She became positive for serum anti-hepatitis C virus (HCV) in November 1990, although her serum aminotransferase levels were normal. In June 2001, she had frequent episodes of melena with abdominal pain, as control of her UC deteriorated. In July 2001, she was admitted to the Department of Surgery at our hospital, and her daily dose of prednisolone was increased from 40 mg to 80 mg. After 2 weeks of high-dose prednisolone therapy, there was a significant increase of serum aminotransferases, and serum HCV-RNA rose above 850 KIU/ml (by reverse transcription-polymerase chain reaction [RT-PCR]). Control of UC was still poor, so cyclosporine A (CyA) was added at a dose that maintained a high serum concentration. The daily dose of prednisolone was tapered and leukapheresis was performed three times weekly. As result, serum aminotransferases decreased to the normal range. However, total colectomy and colostomy were required because the UC could not be controlled by these therapies. Serum aminotransferase levels increased transiently 2 months after the cessation of immunosuppressive therapy (prednisolone, azathioprine [AZP], and CyA). Subsequently, serum aminotransferases rapidly declined below normal, and the serum level of HCV-RNA (by RT-PCR) fell from 480 KIU/ml to less than 0.5 KIU/ml. She was discharged on April 25, 2002. During follow-up as an outpatient, serum HCV-RNA became negative and remained negative for 7 months. To confirm clearance of HCV, liver biopsy was performed, and no HCV-RNA was detected in the liver tissue by RT-PCR. These findings suggested that HCV was cleared by the cessation of immunosuppressive therapy, as a rebound effect.

[Clinical significance and problems of sentinel node identification for individualization of rectal cancer therapy].

In the surgical treatment of advanced rectal cancer, wide lymphadenectomy has been replaced by autonomic nerve preservation because of serious problems such as postoperative urinary and sexual dysfunction. This may offer a considerable clue to as whether metastasis of lateral lymph node can be diagnosed by a new technique in order to provide more benefits to many patients with advanced rectal cancer. Moreover the sentinel lymph node (SLN) concept has lately attracted attention as a new technique. We studied SLN in 40 patients with advanced lower rectal cancer using 99mTc-Sn colloid as a tracer. SLN was successfully identified in 35 (87.5%) of 40 patients, and the mean number of SLNs identified per patient was 5.6 lymph nodes (range 1-14). In this study overall accuracy was 86%, and it was suggested that lateral lymphadenectomy was excluded in 91%, thanks to application of the SLN technique. Although the role this technique plays in the individualization of the therapy for rectal cancer will be large in the near future, many problems remain to be solved in the exact identification of SLN.

[Cryotherapy of the resection edge after hepatectomy of colorectal liver metastases].

Obtaining a one-centimeter negative margin is an important factor in preventing disease recurrence after surgery for hepatic tumors. Cryotherapy of the resected edge has been used to achieve optimal margin clearance in cases in which the alternative would be an extended high-risk liver resection. As a concrete method, cryotherapy was delivered with a liquid nitrogen based compact system (CRY-AC, Brymill Co., USA). The resection edge with involved or inadequate resection margins was ablated directly by using the flat probe for 3 minutes per 1 place. Between 2002 and present, a total of 14 patients with colorectal liver metastases underwent edge cryotherapy. Although there was no hemorrhage from the stump, postoperative leak of the bile and stump recurrence were recognized in each patient. Since cryotherapy has features that make the vascular difficult to be damaged, the complication was not recognized in the patient with exposed vascular in the resected edge. By extending the follow-up period, we want to examine whether the edge recurrence could be controlled or not.

Morphologies of the interfaces between the levator ani muscle and pelvic viscera, with special reference to muscle insertion into the anorectum in elderly Japanese.

A specific, smooth muscle-mediated interface between the levator ani muscle (LA) and the pelvic viscera has been reported. Using 110 sagittally trimmed anorectal tissue strips (80 lateral, 15 anterior and 15 dorsal specimens) obtained from the donated cadavers of 46 elderly subjects, we examined variations in the interface between the LA and the rectal muscularis propria, including the so-called conjoined longitudinal muscles. In type A (9/46), little or no tissue connected the LA to the external rectal muscularis propria, but the LA and external sphincteric mass formed a definite complex. In type B (26/46), the covering fascia of the LA changed abruptly into smooth muscles, which merged into the external rectal muscularis propria. In type C (11/46), most of the LA-associated connective tissues, composed of smooth muscles, were tightly connected to the internal and external rectal muscularis propria. These variations seemed to depend on the morphology of the recto-urethralis, the lateral extension of which reinforced the LA-associated smooth muscles sufficiently to form type B and C insertions. We also demonstrated differences in the interfacial tissues between the LA and other pelvic viscera. We hypothesize that, to avoid injury of the LA and its interfaces during strong movement of the pelvic viscera, for example during childbirth, coitus or squeezed evacuation, the pelvic connective tissue-like smooth muscles play an important role as an autonomic buffer and/or modulator of pelvic floor function. Digital examination and transrectal or transvaginal sonography may be useful for evaluating interindividual variation in these interfacial tissues in elderly patients.

Pyrimidine nucleoside phosphorylase and dihydropyrimidine dehydrogenase indicate chemosensitivity of human colon cancer specimens to doxifluridine and 5-fluorouracil, respectively.

We have assessed pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) activity to compare the chemosensitivity of 5-fluorouracil (5-FU) and doxifluridine (5'-DFUR). Tumor samples were prepared from fresh surgical specimens of 28 patients with advanced colon carcinoma. The activity levels of the two enzymes were assessed as indicators of chemosensitivity to 5'-DFUR and 5-FU. PyNPase activity was analyzed using the HPLC method, and DPD activity was assessed according to the methods of Naguib et al. (1985). A histoculture drug response assay (HDRA) was conducted according to the methods described by Furukawa et al. (1992). The mean and standard deviation of PyNPase activity in the tumor tissue was 110 +/- 48.6 &mgr;g 5-FU/mg protein/h, which was statistically higher than the corresponding value obtained in normal tissue (60 +/- 43.1 &mgr;g 5-FU/mg protein/h) (P < 0.005). When chemosensitivity to the two drug forms was compared in 16 samples obtained from 16 cases with colon cancer, 1 specimen was sensitive to both drug forms, 3 specimens were exclusively sensitive to 5'-DFUR, 5 specimens were exclusively sensitive to 5-FU, and the other 7 specimens were insensitive to both drugs, without significance. High PyNPase activity was associated with a high chemosensitivity to 5'-DFUR, and high DPD activity correlated with a low chemosensitivity to 5-FU. However, the converse relationship was not found. We suggest that the activity of PyNPase and DPD represents a reliable indicator for the chemosensitivity of colon cancer to 5'-DFUR and 5-FU, respectively.

[The results of liver cryosurgery for synchronized liver metastasis from colorectal cancer].

We examined our results of liver cryosurgery for synchronized liver metastasis from colorectal cancer. Twelve patients whose prognosis after the cryosurgery was clear were eligible. All of the patients received not only a resection of the colorectal primary lesion, but they also received a cryosurgery for liver metastases under the same laparotomy. These patients had been treated in this manner from 1981 to 1987. Ten of the 12 patients died from recurrent cancer. The range in survival time of 12 cases was from 6 months to 117 months, and the average survival length was 25.4 months. The examination of the results suggested that there were no cryosurgery induced anti-immunological response observed among the patients. The survival lengths of the patients with untreated cancer were good.

[A case of metastatic liver tumor of colorectal cancer responding to low-dose CPT-11 chemotherapy].

We report a case in which low-dose CPT-11 chemotherapy was effective for metastatic liver tumor of sigmoid colon cancer. A 49-year-old male with metastatic liver tumor, who had undergone sigmoidectomy with D2 lymphadenectomy, was treated by low-dose CPT-11 chemotherapy (CPT-11 30 mg/m2 x 3 days, every 2 weeks). After 7 courses of this chemotherapy, CT and ultrasound examinations showed a reduction of tumor size in the liver. This chemotherapy also showed no high grade toxicities. Therefore, low-dose CPT-11 chemotherapy seems to be effective for metastatic colorectal cancer, and safe in view of toxicities.

[Clinical significance of TS and DPD activities in colorectal carcinoma as a predictive factor of UFT sensitivity].

We measured TS and DPD activities in 40 patients with colorectal cancer who had undergone surgical reduction in our department between May 1997 and April 1998, including 26 patients with preoperative UFT (450 mg/body/day) chemotherapy for 2 weeks, and evaluated the clinical significance of TS and DPD activities as predictive factors of UFT sensitivity. TS activity was collated with histological type from a clinical pathological examination (p = 0.0103). Also, the tendency for TS activity to become high with the stage was observed. According to the evaluation of pathological response, histological effectiveness greater than grade 2 was noted in 7.7%. The apoptosis index (AI) in tumors with preoperative UFT chemotherapy was higher than those without such treatment, which showed a higher correlation with DPD activity of tumor tissue than TS activity (p = 0.0465). Recurrence was seen in 7 cases (lung metastasis: 2, liver metastasis: 4, and local recurrence: 1) in the preoperative chemotherapy group. TS activity was high in all patients with recurrence. TS showed significantly high activity in patients with recurrence compared with the non-recurrence (p = 0.0034) patients. Therefore, these results suggested that activity of both TS and DPD was a key factor for anti-tumor effectiveness of UFT. In particular, TS activity was an important predictive factor for effectiveness of UFT in recurrences.