Long-term follow-up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212).

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.

ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.

Randomized clinical trial comparing standard diet with perioperative oral immunonutrition in total gastrectomy for gastric cancer.

BACKGROUND: Total gastrectomy for gastric cancer is associated with excessive weight loss and decreased calorie intake. Nutritional support using eicosapentaenoic acid modulates immune function and limits catabolism in patients with advanced cancer, but its impact in the perioperative period is unclear. METHODS: This was a randomized phase III clinical trial of addition of eicosapentaenoic acid-rich nutrition to a standard diet in patients having total gastrectomy for gastric cancer. Patients were randomized to either a standard diet or standard diet with oral supplementation of an eicosapentaenoic acid (ProSure®), comprising 600 kcal with 2·2 g eicosapentaenoic acid, for 7 days before and 21 days after surgery. The primary endpoint was percentage bodyweight loss at 1 and 3 months after surgery. RESULTS: Of 127 eligible patients, 126 were randomized; 124 patients (61 standard diet, 63 supplemented diet) were analysed for safety and 123 (60 standard diet, 63 supplemented diet) for efficacy. Across both groups, all but three patients underwent total gastrectomy with Roux-en-Y reconstruction. Background factors were well balanced between the groups. Median compliance with the supplement in the immunonutrition group was 100 per cent before and 54 per cent after surgery. The surgical morbidity rate was 13 per cent in patients who received a standard diet and 14 per cent among those with a supplemented diet. Median bodyweight loss at 1 month after gastrectomy was 8·7 per cent without dietary supplementation and 8·5 per cent with eicosapentaenoic acid enrichment (P = 0·818, adjusted P = 1·000). Similarly, there was no difference between groups in percentage bodyweight loss at 3 months (P = 0·529, adjusted P = 1·000). CONCLUSION: Immunonutrition based on an eicosapentaenoic acid-enriched oral diet did not reduce bodyweight loss after total gastrectomy for gastric cancer compared with a standard diet. Registration number: UMIN000006380 ( http://www.umin.ac.jp/).

Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study.

OBJECTIVES: The purposes of this study were to investigate the prevalence and distribution of intervertebral disc degeneration (DD) over the entire spine using magnetic resonance imaging (MRI), and to examine the factors and symptoms potentially associated with DD. DESIGN: This study included 975 participants (324 men, mean age of 67.2 years; 651 women, mean age of 66.0 years) with an age range of 21-97 years in the Wakayama Spine Study. DD on MRI was classified into Pfirrmann's system (grades 4 and 5 indicating DD). We assessed the prevalence of DD at each level in the cervical, thoracic, and lumbar regions and the entire spine, and examined DD-associated factors and symptoms. RESULTS: The prevalence of DD over the entire spine was 71% in men and 77% in women aged <50 years, and >90% in both men and women aged >50 years. The prevalence of an intervertebral space with DD was highest at C5/6 (men: 51.5%, women: 46%), T6/7 (men: 32.4%, women: 37.7%), and L4/5 (men: 69.1%, women: 75.8%). Age and obesity were associated with the presence of DD in all regions. Low back pain was associated with the presence of DD in the lumbar region. CONCLUSION: The current study established the baseline data of DD over the entire spine in a large population of elderly individuals. These data provide the foundation for elucidating the causes and mechanisms of DD.

Associations between radiographic lumbar spinal stenosis and clinical symptoms in the general population: the Wakayama Spine Study.

OBJECTIVE: Many asymptomatic individuals have radiographic lumbar spinal stenosis (LSS), but the prevalence of symptoms among individuals with radiographic LSS has not yet been established. The purpose of this study was to clarify the association between radiographic LSS and clinical symptoms in the general population. METHODS: In this cross-sectional study, data from 938 participants (308 men, 630 women; mean age, 66.3 years; range, 40-93 years) were analyzed. The severity of radiographic LSS, including central stenosis, lateral stenosis, and foraminal stenosis, was assessed by mobile magnetic resonance imaging and rated qualitatively. Assessment of clinical symptoms was based on the definition of symptomatic LSS in the North American Spine Society guideline. RESULTS: We found that 77.9% of participants had more than moderate central stenosis and 30.4% had severe central stenosis. Logistic regression analysis after adjustment for age, sex, body mass index, and severity of radiographic LSS showed that severe central stenosis was related to clinical symptoms. However, only 17.5% of the participants with severe central stenosis were symptomatic. CONCLUSION: Although radiographic LSS was common in our cohort, which resembled the general Japanese population, symptomatic persons were relatively uncommon.

Prevalence of symptomatic lumbar spinal stenosis and its association with physical performance in a population-based cohort in Japan: the Wakayama Spine Study.

OBJECTIVE: The purpose of this study was to investigate the prevalence of symptomatic lumbar spinal stenosis (LSS) and to clarify the association between symptomatic LSS and physical performance using magnetic resonance imaging (MRI) in a population-based cohort. DESIGN: This cross-sectional study was performed as a part of the research on osteoarthritis/osteoporosis against disability (ROAD) in Japan and 1,009 subjects (335 men, 674 women, mean age 66.3 years, age range 21-97 years) were analyzed. An experienced orthopedic surgeon obtained the medical history and performed the physical testing for all participants. Symptomatic LSS diagnostic criteria required the presence of both symptoms and radiographic LSS findings. A 6-m walking time, chair standing time, and one-leg standing time were obtained from all participants. RESULTS: The prevalence of symptomatic LSS was 9.3% (95% confidence interval [CI]: 7.7-11.3) overall, 10.1% (CI: 7.4-13.8) in men and 8.9% (CI: 7.0-11.3) in women. There was a difference in the prevalence with increasing age by gender. The LSS prevalence showed little difference with age greater than 70 years for men, but the LSS prevalence for women was higher with increasing age. Among physical performance measures, 6-m walking time at a maximal pace was significantly associated with symptomatic LSS (P = 0.03). CONCLUSION: The prevalence of symptomatic LSS was approximately 10% in a cohort resembling the general Japanese population. A 6-m walking time at a maximal pace was a more sensitive index than walking at a usual pace in assessing decreased physical performance associated with symptomatic LSS.

Role of inorganic polyphosphate in promoting ribosomal protein degradation by the Lon protease in E. coli.

Inorganic polyphosphate (polyP), a polymer of hundreds of phosphate (Pi) residues, accumulates in Escherichia coli in response to stresses, including amino acid starvation. Here we show that the adenosine 5'-triphosphate-dependent protease Lon formed a complex with polyP and degraded most of the ribosomal proteins, including S2, L9, and L13. Purified S2 also bound to polyP and formed a complex with Lon in the presence of polyP. Thus, polyP may promote ribosomal protein degradation by the Lon protease, thereby supplying the amino acids needed to respond to starvation.

Laparoscopy-assisted hepatic lobectomy using hilar Glissonean pedicle transection.

Although many reports have described laparoscopic minor liver resections, major hepatic resection, including right or left lobectomy, has not been widely developed because of technical difficulties. This article describes a new technique for performing laparoscopy-assisted right or left hepatic lobectomy using hilar Glissonean pedicle transection. Laparoscopic mobilization of the right or left hepatic lobe is performed, including dissection of the round, faliciform, triangular, and coronary ligaments. The right or left Glissonean pedicle is encircled and divided laparoscopically. A parenchymal dissection is then performed though the upper median or right subcostal incision, through which the resected liver is removed. We successfully performed this procedure in 6 patients without blood transfusion or serious complications. Laparoscopy-assisted hepatic lobectomy using hilar Glissonean pedicle transection can be feasible and safe in highly selected patients.

Inorganic polyphosphate stimulates lon-mediated proteolysis of nucleoid proteins in Escherichia coli.

Inorganic polyphosphate (polyP) accumulates in response to amino acid starvation in Escherichia coli. Previously, we found that the complex formation of Lon with polyP stimulates proteolysis of free ribosomal proteins. In the current studies, we examined the effects of polyP on the degradation of major nucleoid proteins. Fusions of green fluorescent protein with HimA, Fis, HupA, and HupB were clearly associated with polyP in vivo. Lon degraded His-tagged HimA protein only in the presence of polyP in vitro as well as in vivo. Whereas, when HimA and HimD formed a heterodimer, Lon could not degrade it even in the presence of polyP. In addition, Lon degraded His-tagged Fis protein in the presence of polyP. However, in vivo, Lon did not efficiently degrade the Fis protein even when cells accumulated polyP in response to amino acid starvation. It appears that this is due to tighter binding of Fis to DNA than to polyP and resistance of the DNA-Fis to Lon-mediated proteolysis. Indeed, we found that at least a five-fold excess of polyP was necessary to displace DNA from the DNA-Fis complex. Furthermore, Lon degraded His-tagged HupA protein efficiently in the presence of polyP. We also showed that degradation of the translational initiation factor InfC depends on polyP.

Receptor-type protein tyrosine phosphatase κ directly dephosphorylates CD133 and regulates downstream AKT activation.

Although CD133 has been considered to be a molecular marker for cancer stem cells, its functional roles in tumorigenesis remain unclear. We here examined the molecular basis behind CD133-mediated signaling. Knockdown of CD133 resulted in the retardation of xenograft tumor growth of colon cancer-derived HT-29 and LoVo cells accompanied by hypophosphorylation of AKT, which diminished ß-catenin/T-cell factor-mediated CD44 expression. As tyrosine residues of CD133 at positions 828 and 852 were phosphorylated in HT-29 and SW480 cells, we further addressed the significance of this phosphorylation in the tumorigenesis of SW480 cells expressing mutant CD133, with substitution of these tyrosine residues by glutamate (CD133-EE) or phenylalanine (CD133-FF). Forced expression of CD133-EE promoted much more aggressive xenograft tumor growth relative to wild-type CD133-expressing cells accompanied by hyperphosphorylation of AKT; however, CD133-FF expression had negligible effects on AKT phosphorylation and xenograft tumor formation. Intriguingly, the tyrosine phosphorylation status of CD133 was closely linked to the growth of SW480-derived spheroids. Using yeast two-hybrid screening, we finally identified receptor-type protein tyrosine phosphatase κ (PTPRK) as a binding partner of CD133. In vitro studies demonstrated that PTPRK associates with the carboxyl-terminal region of CD133 through its intracellular phosphatase domains and also catalyzes dephosphorylation of CD133 at tyrosine-828/tyrosine-852. Silencing of PTPRK elevated the tyrosine phosphorylation of CD133, whereas forced expression of PTPRK reduced its phosphorylation level markedly and abrogated CD133-mediated AKT phosphorylation. Endogenous CD133 expression was also closely associated with higher AKT phosphorylation in primary colon cancer cells, and ectopic expression of CD133 enhanced AKT phosphorylation. Furthermore, lower PTPRK expression significantly correlated with the poor prognosis of colon cancer patients with high expression of CD133. Thus, our present findings strongly indicate that the tyrosine phosphorylation of CD133, which is dephosphorylated by PTPRK, regulates AKT signaling and has a critical role in colon cancer progression.

A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer.

To investigate the usefulness of oral doxifluridine (5'-DFUR), an active intermediate metabolite of capecitabine (XELODA), in gastric cancer patients after curative resection, we conducted a phase III randomized controlled study to compare oral 5'-DFUR and oral 5-fluorouracil (5-FU). 485 gastric cancer patients with Stage II or III operative findings at curative resection were registered and administered 5'-DFUR (460 mg/m2/day, daily, for two years) or 5-FU (115 mg/m2/day, daily, for the same period). Although no differences in overall survival or disease-free survival were detected, subset analysis showed 5'-DFUR was more effective in reducing peritoneal recurrence than 5-FU (p = 0.047), and in patients with Stage III or stage IIIb (histologic findings) in the 5'-DFUR group had more favorable disease-free survival curves and survival curves than the 5-FU group with similar stages.

Thymidine phosphorylase expression is useful in selecting adjuvant chemotherapy for stage III gastric cancer.

Thymidine phosphorylase (TP) is an enzyme which converts doxifluridine (5'-DFUR) to 5-fluorouracil (5-FU). To assess whether TP expression is useful for selecting adjuvant chemotherapy in advanced gastric cancer, we compared effects of oral 5'-DFUR and 5-FU and assessed correlation between drug efficacy and TP expression level. We examined TP expression in 286 patients. TP expression was assessed with immunohistochemical staining. When we compared prognosis in two chemotherapy groups with high TP expression, better survival was observed in 5'-DFUR than in 5-FU group (p=0.0413). Especially in stage III, patients with high TP had better survival in 5'-DFUR than in 5-FU group.

Use of 5-FU plus hyperbaric oxygen for treating malignant tumors: evaluation of antitumor effect and measurement of 5-FU in individual organs.

PURPOSE: Hyperbaric oxygen (HBO) has been shown to increase tumor radiosensitivity. Several reports indicate that it also increases sensitivity to alkylating agents, but other reports suggest that it may speed angiogenesis and tumor growth. To throw light on these questions, we investigated the effects of HBO and 5-fluorouracil (5-FU), individually and in combination, on Sarcoma 180 implants in mice. METHODS: We administered 5-FU at a dose of 0.75 mg/mouse six times per week and HBO at 2 atm absolute pressure for 90 min six times per week, both 17 times in total. In combination treatment, HBO was administered immediately after 5-FU injection. RESULTS: Over the treatment period, tumor diameter increased 277.8% in the untreated control group, 244.1% in the group receiving HBO monotherapy, 182.7% in the group receiving 5-FU monotherapy, and 138.5% in the group receiving combination therapy. Concomitant HBO increased accumulation of 5-FU in the tumors, liver, and kidneys, but not in the brain, of recipient animals. CONCLUSIONS: Based on the above results, we conclude that concomitant HBO enhances the effects of 5-FU.

Ileocolic intussusception in adult due to malignant lymphoma in the cecum with intramural metastasis.

A rare adult case of intussusception caused by malignant lymphoma of the cecum with intramural metastasis is reported. The patient was a 24-year-old man. Ileocolic intussusception was diagnosed by characteristic findings on abdominal computed tomography. Endoscopic examination revealed a massive protuberant tumor, 3 cm in diameter, and a semipedunculated polyp, 1 cm in diameter, in the cecum, which had caused the ileocolic intussusception. Endoscopic biopsy specimens failed to yield a definitive diagnosis histologically, but right hemicolectomy with lymph node dissection was performed. On histologic examination of the surgical specimens, both the tumor and the polyp were diagnosed as diffuse lymphoma of medium-sized cell type, and no lymph node involvement was found. The patient responded well to surgical and chemotherapeutic treatment, and has had no recurrence of malignant lymphoma in the 2 years since the surgical treatment. This was a very rare case of an intussusception in an adult patient due to malignant lymphoma in the cecum with intramural metastasis and without lymph node involvement.

Clinical evaluation of nerve-sparing surgery combined with preoperative radiotherapy in advanced rectal cancer patients.

BACKGROUND: Since 1984, we have studied nerve-sparing surgery (NSS) combined with preoperative radiotherapy (XRT) in patients with advanced rectal cancer to preserve the genitourinary function without compromising radicality. The present aim was to evaluate the prognosis and the postoperative genitourinary function. METHODS: A total of 167 patients with advanced rectal cancer underwent curative nerve-sparing surgery. Among them, 60 underwent the preoperative therapy using irradiation (42.6 Gy) and tegafur suppository. Survival, local recurrence, and postoperative genitourinary function were investigated in these patients. RESULTS: The 5-year survival rate was 80.9% and the local recurrence rate was 6.7% in the NSS+XRT group. Almost all of the patients receiving NSS could micturate spontaneously, but preservation of sexual function was not as successful. CONCLUSIONS: Better local control and preservation of urinary function were possible in advanced rectal cancer patients by NSS+XRT.

Evaluation of phosphate removal from water by immobilized phosphate-binding protein PstS.

The phosphate (P(i))-binding protein PstS is a member of a family of periplasmic proteins that act as high-affinity receptors for active transport systems in bacteria. PstS protein purified from Pseudomonas aeruginosa was immobilized to N-hydroxysuccinimide-activated Sepharose, packed into a plastic column (5 x 70 mm), and examined for its potential ability to remove P(i) from water. The PstS-Sepharose column completely removed P(i) from 32P-labeled pond water containing about 0.5 microM P(i) (0.015 mg P per liter). More than 90% of 32P-P(i) that was retained in the column could be eluted by washing with low-pH water.

Cloning and characterization of Pseudomonas putida genes encoding the phosphate-specific transport system.

The pstSCAB genes of Pseudomonas putida PRS2000, encoding the phosphate (Pi)-specific transport (Pst) system, were cloned. The pstS gene of Pseudomonas aeruginosa PAO1, of which the pstCAB genes had been cloned previously, was also cloned (Nikata, T. et al., Mol. Gen. Genet., 250, 692-698, 1996). The predicted translation products of the P. putida pstSCAB genes showed 83, 75, 78 and 88% amino acid identity with their P. aeruginosa counterparts. Two well-conserved Pho box sequences were found in the region upstream of the pstS gene (15/18 base identity with the consensus Pho box sequence) and in the intercistronic region between the pstS and pstC genes (11/18 base identity) of P. putida PRS2000. To investigate the functions of PstSCAB, the pstSC genes were inactivated by inserting a kanamycin resistance gene cassette into the chromosome of P. putida PRS2000. The resultant mutant, designated PNT1, failed to take up 32Pi even under conditions of Pi limitation. Strain PNT1 was also constitutive for alkaline phosphatase synthesis, as well as chemotaxis toward Pi, indicating that the Pst system is involved in the negative regulation of the pho regulon in P. putida. Although overexpression of the pstSCAB genes in P. putida PRS2000 resulted in decreased cell growth, this recombinant strain could remove Pi at a rate similar to that seen with the control strain.

Chemotaxis of the nematode Caenorhabditis elegans toward cycloheximide and quinine hydrochloride.

We investigated the chemotaxis of the nematode Caenorhabditis elegans toward cycloheximide, denatonium benzoate, 6-n-propyl-2-thiouracil, and quinine hydrochloride. Interestingly, C. elegans was strongly attracted to cycloheximide, while avoiding quinine hydrochloride. This is the first report thus far to describe the chemotactic responses of C. elegans toward bitter tastants for humans.

Colliding malignant lymphoma and adenocarcinoma of the stomach: case report.

We report a case of malignant lymphoma presenting as the superior vena cava syndrome. This case is very interesting since both adenocarcinoma mucocellulare scirrhosum, Borrman type IV, and lymphoma were present in the stomach, forming colliding neoplasms. Rather than systemically disseminated, the lymphoma cells were localized in the stomach, the intestine, a few perigastric lymph nodes and in a mediastinal mass, which may have constituted a neoplastic thymus invaded by lymphoma cells from the stomach. The unique occurrence of the histological combination as gastric colliding neoplasms is discussed.

Ovo-testis and disturbed reproductive cycle in the giant abalone, Haliotis madaka: possible linkage with organotin contamination in a site of population decline.

Histological examination of gonads as well as chemical analysis of organotin compounds in tissues of the giant abalone, Haliotis madaka, was conducted to evaluate possible endocrine disruption and to consider the causal factors for the decline of abalone stocks in Japan. Abalone specimens were collected from two different areas, Tsushima as a reference site and Jogashima as a site representative of declining abalone populations, each month from September 1995 to November 1996. Scores were given to the development stages of reproductive cells in the ovary and testis. The degree of sexual maturation was evaluated by calculating the mean value of a histogram of these scores for the reproductive cells of each abalone. The temporal variations in degree of sexual maturation showed that female and male abalone from Tsushima matured synchronously, while those from Jogashima did not. The observed maximum reproductive developmental score in abalone from Jogashima was much lower than that from Tsushima, because immature females were present at the former site throughout the spawing season. Approximately 20% of the abalone from Jogashima were masculinized females with an ovo-testis. The masculinization of female abalone was similar to the imposex, typically induced in other gastropod molluscs by tributyltin (TBT) and triphenyltin (TPhT) from antifouling paints. Concentrations of TBT and TPhT in the muscles of abalone from Jogashima (n = 83) of 4.9 +/- 4.4 ng/g wet wt and 6.3 +/- 6.6 ng/g wet wt, respectively, were significantly higher than those from Tsushima (n = 125) (P < 0.01) of 0.8 +/- 0.8 ng/g wet wt and 0.6 +/- 1.3 ng/g wet wt, respectively. In situ exposure of abalone from Tsushima caged near a dockyard in Jogashima for 7 months (from the immature to the mature stage) resulted in spermatogenesis in the ovary of approximately 90% of females. Endocrine disruption may be caused in the giant abalone by organotin compounds from antifouling paints, which are possibly one of the causal factors for the decline of Japanese abalone stocks.

Preoperative natural killer cell activity: correlation with distant metastases in curatively research colorectal carcinomas.

The authors investigated whether host immunity contributes to the development of asynchronous distant metastases in colorectal carcinomas. The host immunity was examined 8 times, pre- and postoperatively during a one year period in 77 curatively operated cases. A prospective study was performed using obtained personal data. During the mean follow-up period of 920 days, 13 patients developed distant metastases. Among the immunological parameters, the preoperative natural killer (NK) cell activity differed significantly between the metastases positive and negative groups. On univariate analysis, dichotomous NK activity, presence of nodal metastases, and venous invasion correlated with metastases. The hazard ratios on multivariate analysis were 4.53, 3.82, and 4.81, respectively. No correlation was noted between NK activity and the progression stages of colorectal carcinomas. These data suggested that attenuated preoperative NK activity is an important background factor for the development of asynchronous distant metastases following curative resection of colorectal carcinomas.