Antimicrobial prophylaxis for 1 day versus 3 days in liver cancer surgery: a randomized controlled non-inferiority trial.

PURPOSES: This study compared the effectiveness of 1-day vs 3-days antibiotic regimen to prevent surgical site infection (SSI) in open liver resection. METHOD: We performed a randomized controlled non-inferiority trial in 480 patients at 39 hospitals across Japan (registered as UMIN000002852). Patients with hepatocellular carcinoma scheduled to undergo resection were randomly assigned to receive either a 1-day regimen for antimicrobial prophylaxis, or a 3-day regimen. The primary endpoint was the incidence of SSI. RESULTS: Among 480 randomized patients, 232 assigned to the 1-day regimen and 235 to the 3-day regimen were included in the full analysis set. Baseline characteristics of the two groups were well balanced. SSI was diagnosed in 22 patients (9.5%) in the 1-day group vs 23 patients (9.8%) in the 3-day group (difference, - 0.30; 90% CI - 4.80 to 4.19% [95% CI - 5.66% to 5.05%]; one-sided P = 0.001 for non-inferiority), meeting the non-inferiority hypothesis. In both groups, remote site infection (16 [6.9%] vs 22 [9.4%], P ˂ 0.001 for non-inferiority) and drain-related infection (5 [2.2%] vs 4 [1.7%], P ˂ 0.001 for non-inferiority) were comparable. CONCLUSION: To prevent SSI in liver cancer surgery, a 1-day regimen of flomoxef sodium is recommended for antimicrobial prophylaxis because of confirming the non-inferiority to longer usage.

A three-tier classification system based on the depth of submucosal invasion and budding/sprouting can improve the treatment strategy for T1 colorectal cancer: a retrospective multicenter study.

More than 85% of patients with T1 colorectal cancer have no lymph node metastasis and can be cured by endoscopic resection. To avoid unnecessary surgery after complete endoscopic resection, accurate histologic methods for evaluating resected specimens are needed to discriminate those at high risk for lymph node metastasis. A retrospective multi-institutional, cross-sectional study of 806 T1 colorectal cancer patients was conducted. A budding/sprouting score was incorporated for predicting lymph node metastasis in addition to other parameters, including the depth of submucosal invasion, histologic grade, and lymphovascular invasion. Lymph node metastasis was detected in 97 patients. Independent predictors of lymph node metastasis by multivariate analysis were depth of submucosal invasion ≥1000 µm (odds ratio (95% confidence interval)=5.56 (2.14-19.10)) and high-grade budding/sprouting (3.14 (1.91-5.21)). Among lesions with a depth of submucosal invasion ≥1000 µm, lymph node metastasis was detected in 59 (29%) of 207 patients with high-grade budding/sprouting, and in 34 (9%) of 396 with low-grade budding/sprouting. Lymph node metastasis was detected in only 4 (2%) of 203 lesions with a depth of submucosal invasion <1000 µm. Of these four tumors, three invaded lymphatic and/or venous vessels. Thus, the risk for lymph node metastasis can be classified into three groups: high risk with a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting, intermediate-risk with a depth of submucosal invasion ≥1000 µm and low-grade budding/sprouting, and low-risk with a depth of submucosal invasion <1000 µm. These findings revealed that a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting are powerful predictive parameters for lymph node metastasis in T1 colorectal cancer. This three-tier risk classification system will facilitate the decision for additional major surgery for T1 colorectal cancer patients after successful endoscopic treatment.

Multicenter study evaluating the clinical performance of the OSNA assay for the molecular detection of lymph node metastases in gastric cancer patients.

BACKGROUND: The accurate diagnosis of lymph node (LN) metastasis is important for making treatment decisions for gastric cancer patients. This multicenter study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp.), an automated system that detects cytokeratin 19 (CK19) mRNA, in detecting LN metastases in gastric cancer patients. METHODS: LNs retrieved from patients who had undergone gastric cancer surgery at one of the four Japanese hospitals involved in this study were divided into blocks at 2-mm intervals. Alternate blocks were examined with the OSNA assay and the remaining blocks were assessed histologically. RESULTS: A total of 394 LNs from 61 patients were examined. The concordance rate between the OSNA assay and the histological examination was 0.942 (95 % CI, 0.914-0.963). Sensitivity and specificity of the OSNA assay compared to the histological examination were 0.833 (95 % CI, 0.707-0.921) and 0.959 (95 % CI, 0.932-0.977), respectively. Discordant results were observed in 23 LNs (5.8 %), and these were mainly the result of tissue allocation bias and/or low CK19 protein expression. CONCLUSION: The OSNA assay can detect lymph node metastases in gastric cancer patients as accurately as the histological examination of blocks sectioned at 2-mm intervals. The OSNA assay is a useful tool for the intraoperative diagnosis of LN metastasis in gastric cancer patients.

The rs6983267 SNP is associated with MYC transcription efficiency, which promotes progression and worsens prognosis of colorectal cancer.

BACKGROUND: The oncogenic single nucleotide polymorphism rs6983267, located on 8q24.21, may affect copy number aberrations and/or expression profiles in colorectal cancer (CRC). We investigated the role of this single nucleotide polymorphism in the clinical outcome of CRC. METHODS: Array comparative genomic hybridization (aCGH) and oligomicroarrays were performed on cancer cells from 157 primary CRC tissues. Expression profiles were analyzed by means of extraction expression module (EEM) analyses. Mutations in TP53, KRAS, and BRAF and microsatellite instability were also examined in 107 of the 157 cases. RESULTS: aCGH analysis revealed two clusters; more frequent genomic copy number alteration (CNA) was observed in the 89 cases in cluster B than in the 18 cases in cluster A. The average CNA was higher in samples containing the major allele (GT/TT) of rs6983267 than in those containing the minor allele (GG). Additionally, MYC expression was the highest in samples containing the GG allele (n = 18), followed by the GT and TT alleles (n = 41 and 48, respectively). EEM analysis revealed dominant up-regulation of MYC in samples containing the minor allele. Moreover, the presence of the minor allele in a MYC-positive, CNA-negative context predicted a poorer prognosis than the presence of the major allele in a MYC-negative, CNA-positive context in CRC. CONCLUSIONS: The presence of the minor allele of rs6983267 at 8q24.21 worsened the prognosis of CRC through up-regulation of MYC transcription. Furthermore, progression of CRC may require global CNA in the presence of the major allele and with lack of MYC transcription.

Initial stability of cementless acetabular cups using robotic-assisted total hip arthroplasty compared with the conventional manual technique: An in vitro biomechanical study.

BACKGROUND: The aim of this study is to determine whether the initial stability of a cementless cup with the Mako system is superior to that of a conventional manual technique using bone models. METHODS: The bone models were prepared using a polyurethane foam block. Two hemispherical cementless cups (highly porous titanium cup [Trident II Tritanium, Stryker] and hydroxyapatite-coated titanium cup [Trident HA, Stryker]) were implanted using the Mako system. The torque of the cups was measured by rotational and lever-out torque testing and compared with that of a conventional manual technique. RESULTS: The two types of cups that were implanted using the Mako system demonstrated significantly higher mean rotational torque than that of the manual technique (p < 0.01, p = 0.01, respectively). CONCLUSIONS: This study provides the advantage of the initial stability of a cementless hemispherical cup implanted by the Mako system compared with that of the conventional manual technique.

Multicenter study for optimal categorization of extramural tumor deposits for colorectal cancer staging.

OBJECTIVE: This study aimed to determine the optimal categorization of extramural tumor deposits lacking residual lymph node (LN) structure (EX) in colorectal cancer staging. BACKGROUND: The TNM classification system categorizes EX on the basis of their contour characteristics (the contour rule). METHODS: We conducted a multicenter, retrospective, pathological review of 1716 patients with stage I to III curatively resected colorectal cancer who were treated at 11 institutions (1994-1998). In addition, 2242 patients from 9 institutions (1999-2003) were enrolled as a second cohort for validating results. EX were classified as isolated foci confined to vascular or perineural spaces (ie, lymphatic, venous, or perineural invasion) or as tumor nodules (ND). N- and T-staging systems employing different categories for staging were compared in terms of their prognostic power. In addition, the diagnoses of extramural, discontinuously spreading lesions made by 11 observers from different institutions were assessed for interobserver agreement. RESULTS: EX were observed in 18.2% of patients in the first cohort. The method of categorization of EX in tumor staging has a stronger impact on N than T staging. The N-staging system in which all ND types were classified as N factor (the ND rule) could more effectively stratify the survival outcome than the contour rule (Akaike information criterion, 3040.8 vs 3059.5; the Harrell C-index, 0.7255 vs 0.7103). EX were observed in 16.9% of patients in the second cohort. Statistically, the ND rule was more informative than the contour rule for N staging. The Fleiss kappa coefficient for distinguishing LN metastases from EX (0.74) was lower than expected for complete agreement, and it decreased further to 0.51 when calculated for the judgment of ND with smooth contours. CONCLUSIONS: Classifying all ND types as N factors irrespective of contours can simplify the tumor staging system by enhancing diagnostic objectivity, resulting in improved prognostic accuracy.

Impact of race/ethnicity on prognosis in patients who underwent surgery for colon cancer: analysis for white, African, and East Asian Americans.

PURPOSE: We retrospectively investigated the impact of race/ethnicity on prognosis in patients who underwent surgery for colon cancer. METHODS: Surveillance, Epidemiology, and End Results population-based data on 39,210 colon cancer patients without distant metastasis who underwent radical surgery were analyzed. Prognostic impact of race/ethnicity for non-Hispanic white, Hispanic white, African American, and East Asian (Japanese, Chinese, Korean) American patients, and confounding factors of age, sex, registry region, year of diagnosis, tumor, node, metastasis system stage, tumor grade, tumor site, and the number of lymph nodes examined were analyzed by the Cox proportional hazard model. The lymph node count was analyzed and adjusted means were calculated by a generalized multiple regression model with respect to race and other factors. RESULTS: Significant differences due to race/ethnicity were observed in crude hazard ratios with respect to overall and colon cancer-specific mortality, which persisted even after adjusting for confounding factors. Adjusted hazard ratios of colon cancer-specific mortality for non-Hispanic white, Hispanic white, African American, and East Asian American patients were 1 (reference), 1.01 (95% confidence interval 0.91-1.12), 1.40 (95% confidence interval 1.31-1.50), and 0.83 (95% confidence interval 0.74-0.94), respectively. There were significant differences in crude number of lymph nodes examined among races, which were no longer significant after adjusting for covariates. CONCLUSIONS: East Asian American patients had significantly better prognosis, while African American patients had worse prognosis than non-Hispanic white patients, despite the identical adjusted number of lymph nodes examined after surgery for colon cancer. This disparity in prognosis among races/ethnicities should be taken into consideration when deciding adjuvant chemotherapy for nonwhite patients.

Increased risk for CRC in diabetic patients with the nonrisk allele of SNPs at 8q24.

BACKGROUND: Colorectal cancer (CRC) oncogenesis was considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. METHODS: A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at 11 known single nucleotide polymorphisms (SNPs). TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. RESULTS: Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (odds ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.0015). Non-insulin-dependent diabetes mellitus (DM), a higher body mass index at age 20, and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and DM had a 1.66-fold higher risk ratio than the cohort of major allele patients without DM. CONCLUSIONS: We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G allele at the 8q24 rs6983267 SNP; however, a major T allele SNP could more clearly reveal a correlation with CRC specifically when DM is present.

Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer.

BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for "high-risk stage II" cancer, but this is not clearly defined and the efficacy has not been confirmed. METHODS/DESIGN: SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify "high-risk factors of recurrence/death" in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500-600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year). The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events. DISCUSSION: A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the therapeutic strategy for stage II colon cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00392899.

Genomic copy number of a carcinogenic single nucleotide polymorphism at 8q24 in non-risk allele colorectal cancer associated with insulin growth factor 2 receptor expression.

BACKGROUND AND AIM: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC. METHODS: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype. RESULTS: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P = 0.012). There was neither a diabetes- nor a fat metabolism-related gene that was significantly associated with CRC cases with the risk allele at 8q24. CONCLUSIONS: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC.

One-step nucleic acid amplification (OSNA) for the application of sentinel node concept in gastric cancer.

PURPOSE: This study was designed to apply safely the sentinel node navigation surgery (SNNS) to the malignancies, an accurate and prompt intraoperative diagnosis of SN is essential, and micrometastasis has been frequently missed by conventional frozen sections. Recently, a novel molecular-based rapid diagnosis for the lymph node (LN) metastases has been developed using (OSNA) in breast cancer, which takes approximately 30 min to obtain a final result. We evaluated the efficacy of OSNA in terms of the intraoperative diagnosis of LN metastasis in patients with gastric cancer. METHODS: A total of 162 LNs dissected from 32 patients with gastric cancer was included in this study; 45 LNs were pathologically diagnosed as metastatic LNs and 117 LNs were negative. The LNs were bisected; halves were examined with H&E stain, and the opposite halves were subjected to OSNA analyses of CK19 mRNA. The CK19 mRNA expression was examined in the positive or negative metastatic LNs, and the correlation between the tumor volume and CK19 mRNA expression in the metastatic LNs was examined. RESULTS: The CK19 mRNA expressions in the positive metastatic LNs were significantly higher than those of negative LNs. When 250 copies/µl was set as a cutoff value, the concordance rate was 94.4%, the sensitivity was 88.9%, and the specificity was 96.6%. The OSNA expression was significantly correlated with the estimated tumor volumes in the metastatic LNs. CONCLUSIONS: The OSNA method is feasible and acceptable for detecting LN metastases in patients with gastric cancer. This should be applied for the intraoperative diagnosis in the SN-navigation surgery in gastric cancer.

Pretreatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients.

BACKGROUND: CD133 confers chemoradioresistance properties to cells and has recently been used to identify cancer-initiating cells. OBJECTIVE: We investigated whether the overexpression of CD133 and cyclooxygenase-2 can be used as predictive markers of tumor response to preoperative chemoradiotherapy in patients with rectal cancer. SETTING: The study was conducted at the National Defense Medical College Hospital in Japan. PATIENTS: We recruited 96 patients who underwent a single regimen of preoperative short-term chemoradiotherapy (20 Gy in 5 fractions with 400 mg/day Tegafur/Uracil for 1 week) and radical resection. DESIGN: This was a retrospective study. We obtained pretreatment biopsy specimens of these patients and immunostained these specimens with antibodies for CD133, cyclooxygenase-2, p53, p27, p21, and epidermal growth factor receptor. The resected primary tumor was evaluated according to 2 different tumor regression grading systems that were based on the degrees of fibrosis and cytological alterations. RESULTS: Positivity for CD133 or cyclooxygenase-2 expression was associated with chemoradioresistance, which was determined by the degree of fibrosis, in both univariate (P = .02 and P = .0003) and multivariate (P = .03 and P = .001) analyses. Univariate and multivariate analyses of the degree of cytological alterations also revealed a significant association between chemoradioresistance and the expression of CD133 (P = .005 and P = .003) and cyclooxygenase-2 (P = .005 and P = .03), whereas other markers failed to associate. LIMITATIONS: The information on patients' outcome was not available. CONCLUSIONS: Our study revealed the independent predictive values of CD133 and cyclooxygenase-2 expressions in histological tumor regression after preoperative chemoradiotherapy.

High-risk stage II colon cancer after curative resection.

OBJECTIVES: This study was designed to clarify which attributes of stage II colon cancer are associated with tumor recurrence and survival after curative resection, and the effects of adjuvant chemotherapy (ACT). METHODS: We retrospectively reviewed outcomes and clinicopathological characteristics of 1476 patients with stage II colon cancer who underwent curative resection. RESULTS: Of 1476 patients, 204 (13.8%) developed recurrence. Macroscopic type, serum CA19-9 levels, venous invasion, emergency operation, and postoperative ileus were independently associated with overall recurrence. Carbohydrate antigen (CA)19-9 levels, the number of dissected lymph nodes (LN), sex, age, ACT, emergency operation, venous invasion, and macroscopic type were independently associated with poor prognosis. Prognosis was significantly better in patients who received ACT than in those who did not. Among patients with extensive venous invasion, those with fewer than 13 dissected LNs, male patients, and patients >50 years old, the prognosis was significantly better in patients who received ACT than in those who did not. CONCLUSIONS: ACT for stage II colon cancer is recommended to improve the prognosis of patients with extensive venous invasion, patients with fewer than 13 dissected LNs, patients >50 years old, and male patients, particularly patients with more than two of these risk factors.

Lymph node ratio is a powerful prognostic index in patients with stage III distal rectal cancer: a Japanese multicenter study.

PURPOSE: The present study aims to define the prognostic impact of the lymph node ratio (LNR) in patients with stage III distal rectal cancer. METHODS: We analyzed data from 501 patients who underwent curative resection (total mesorectal excision, TME) for stage III distal rectal cancer at 12 institutions between 1991 and 1998. Patients were divided into four groups according to quartiles based on LNR. RESULTS: Among the 501 patients, 381 underwent TME with pelvic sidewall dissection (PSD). The median numbers of lymph nodes retrieved with and without PSD were 45 and 17, respectively (P < 0.0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P = 0.0059), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0003), and number of positive nodes (P < 0.0001) and LNR (P < 0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P = 0.014), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0002), and LNR (group 3, P = 0.0012; group 4, P < 0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P < 0.0001) and LNR (P < 0.0001) were independent prognostic factors. CONCLUSIONS: Adding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.

[A case of long-term survival after resection of advanced undifferentiated rectal cancer treated by short-term preoperative chemoradiotherapy and postoperative adjuvant chemotherapy].

A 75-year-old man with advanced undifferentiated rectal cancer, diagnosed by endoscopic biopsy, underwent preoperative short-term chemoradiotherapy (whole pelvis, 4 Gy × 5 day with UFT 400 mg/day × 7 day). Tumor size and lymph node swellings were reduced after radiation therapy. Down-staging was achieved from cT3, cN2, cStage III b to cT3, cN1, cStage III a. A curative low anterior resection with D3 lymphadenectomy including lateral lymph node dissection, was performed 4 weeks after the completion of chemoradiotherapy. Pathological findings of resected specimen showed undifferentiated carcinoma with regional lymph node involvement (pT2, pN1, pStage III a). The histological change in response to chemoradiation was evaluated as Grade 2. The postoperative course was uneventful and postoperative adjuvant chemotherapy (UFT+Uzel) was performed for six months (5 courses). No sign of recurrence has been found until 51 months after the operation. Undifferentiated rectal cancer is a rare condition with extremely poor prognosis according to the Japanese literature. Nine cases have been reported so far with only one long-term survivor. This combination of preoperative short-term chemoradiotherapy and adjuvant chemotherapy, which is one of the standard strategies for advanced rectal cancer in Western countries, but not common in Japan, may be a promising option for treatment of undifferentiated rectal cancer.

[Chemoradiation combined with total mesorectal excision for patients with locally advanced rectal cancer].

Rectal cancer is characterized by a high rate of local recurrence. Although it is widely believed that local control results in improved patient outcome, its strategy is still controversial. In Japan, total mesorectal excision (TME) or tumor-specific mesorectal excision (TSME) with pelvic sidewall dissection is regarded as the standard procedure, while TME or TSME with preoperative chemoradiotherapy (CRT) is common in Western countries. Most clinical data have indicated that preoperative CRT is not associated with improved long-term survival but with a lower incidence of local recurrence. In addition, CRT is known to enhance the severity of impaired sphincter function. Currently, trials using CRT regimens with newly developed chemotherapy agents are ongoing to elucidate the effect on the control of distant metastasis. According to clinical reports, the prognosis of Japanese patients undergoing surgery alone is as favorable as that in patients undergoing surgery plus CRT in the West, which implies that CRT is not a necessary treatment but a selective option. The precise prediction of tumor response and advances in CRT regimens resulting in better survival may improve the treatment of rectal cancer in the future.

Prognostic significance of the number of lymph nodes examined in colon cancer surgery: clinical application beyond simple measurement.

OBJECTIVE: To identify an optimal cutoff value for the number of lymph node examined (NLNE) to distinguish the prognoses in patients following a curative resection for advanced colon cancer, to clarify the mechanism of the difference, and to suggest the integration of NLNE to colon cancer staging. PATIENTS AND METHODS: A total of 859 patients who had undergone surgical treatment for localized colon cancer from 1980 to 2000 were reviewed. This was a cohort from a single institution with mean NLNE of 20.7 and more than 12 NLNE in 77% of the patients. The optimal breakpoint for NLNE was calculated by a receiver operating characteristic curve (ROC) analysis. The patients were stratified into groups based on various parameters and underwent univariate and multivariate analyses with respect to survival. RESULTS: The ROC analysis identified NLNE as a significant prognostic factor with cutoff value of 18 for node-negative and 20 for node-positive patients. A multivariate analysis with these cutoff values identified NLNE as a significant prognostic factor independent of tumor depth and the number of lymph nodes involved. The 5-year cause-specific survival of stage IIB patients was 96.5% with 18 or more NLNE and 67.5% with NLNE less than 18 (P[r]=0.0067). Similarly, a cutoff value of 20 NLNE for node-positive patients separated the 5-year cause-specific survival of stage IIIB patients into 79.3% with 20 or more NLNE and 63.3% with less than 20 NLNE (P=0.0052). CONCLUSIONS: The clinical significance of NLNE is not limited to being a benchmark for quality care, but has a definite benefit as a prognostic indicator across the stages. Patients could be stratified more efficiently by the integration of NLNE to TNM staging.

Arginine-enriched total parenteral nutrition improves survival in peritonitis by normalizing NFkappaB activation in peritoneal resident and exudative leukocytes.

BACKGROUND: Enteral nutrition maintains peritoneal defense more effectively than parenteral nutrition, at least partly by preserving NFkappaB activation in peritoneal cells. We hypothesized that arginine (ARG)-enriched parenteral nutrition would normalize NFkappaB activation in peritoneal leukocytes, thereby improving the survival of peritonitis models. METHODS: A total of 105 ICR mice were randomized to chow (n=33), IV feeding of a standard (STD) total parenteral nutrition (STD-TPN) solution (ARG 0.3%) (n=35), or 1% ARG-TPN solution (n=37), and fed accordingly for 5 days.Experiment 1: Thirty mice were used for intranuclear NFkappaB measurement in peritoneal resident cells (PRCs). After incubation with lipopolysaccharide (LPS: 0, 1, 10 microg/mL) for 30 minutes, intranuclear NFkappaB activity was examined by laser scanning cytometry.Experiment 2: Fifty-one mice were injected with 2 mL of 1% glycogen intraperitoneally. Peritoneal exudative cells (PECs) were obtained at 2 or 4 hours after glycogen administration for NFkappaB measurement. Cytokine (TNFalpha, IL-10) levels in peritoneal lavage fluid were also determined by ELISA.Experiment 3: After 5 days of feeding, 24 mice underwent cecal ligation and puncture. Survival was observed up to 5 days. RESULTS: Experiment 1: Intranuclear NFkappaB levels in the ARG-TPN and chow groups increased dose-dependently after LPS stimulation, while the level in the STD-TPN group was unchanged.Experiment 2: Intranuclear NFkappaB level was significantly higher at 2 hours in the chow than in the STD-TPN group, whereas in the ARG-TPN mice the level was midway between those of the chow and STD-TPN groups. TNFalpha and IL-10 levels of the chow group were significantly higher than those of STD-TPN mice at 2 hours. TNFalpha was significantly higher in the ARG-TPN group than in the STD-TPN group, but the IL-10 level showed no recovery.Experiment 3: Survival times were significantly reduced in the STD-TPN as compared with the chow group, though ARG-TPN improved survival. CONCLUSION: ARG-enriched TPN is a surrogate for enteral feeding which maintains peritoneal defense by preserving NFkappaB activation in peritoneal resident and exudative leukocytes.

Is total mesorectal excision always necessary for T1-T2 lower rectal cancer?

BACKGROUND: The goal of this multicenter study was to clarify the determinants of local excision for patients with T1-T2 lower rectal cancer. METHODS: Data from 567 consecutive patients who underwent radical resection for T1-T2 lower rectal cancer at 12 institutions between 1991 and 1998 were reviewed. Rates of lymph node metastasis were investigated using a tree analysis, which was hierarchized using independent risk factors for nodal involvement. RESULTS: The independent risk factors for lymph node metastasis were female gender, depth of tumor invasion, histology other than well-differentiated adenocarcinoma, and lymphatic invasion. According to the first three parameters that can be obtained preoperatively, only 0.99% of the patients without risk factors had lymph node metastasis. On the other hand, even if the lower rectal cancer was at stage T1, women with histological types other than well-differentiated adenocarcinoma had an approximately 30% probability of having lymph node metastasis. Lymphatic invasion was most useful to predict nodal involvement among patients with T2 lower rectal cancer. The rates of lymph node metastasis in T2 patients with and without lymphatic invasion were 32.9% and 9.1%, respectively. CONCLUSIONS: Gender is one of the most important predictors for lymph node metastasis in patients with early distal rectal cancer. Three parameters, including depth of tumor invasion, histology, and gender, are useful determinants for local excision. Additional studies are required to establish the minimum optimal treatment for T2 lower rectal cancer.

Risk factors of nodal involvement in T2 colorectal cancer.

PURPOSE: Because of the adverse consequences of radical resection of T2 colorectal cancer, criteria are needed for selection of patients who can safely undergo local excision without requiring additional radical surgery. We therefore conducted a retrospective study of patients with T2 colorectal cancer to identify risk factors for nodal involvement that might be used in selecting patients for local excision. METHODS: We reviewed records from consecutive patients who had undergone curative resection of T2 colorectal cancer at the Department of Surgery, National Defense Medical College, Saitama, Japan, between 1985 and 2005. Data on conventional clinicopathologic variables were retrieved from pathology reports at the time of surgery, and archived slides were evaluated regarding potential risk factors such as extent of poorly differentiated component (grade I-III), myxoid cancer stroma, tumor budding, and growth pattern and invasion depth in the muscularis propria. RESULTS: A total of 244 patients (139 men and 105 women) treated for T2 colorectal cancer were included. Nodal involvement was found in 7 (8.4%) of 83 patients classified as grade I on the poorly differentiated component vs. 47 (29.2%) of 161 patients classified as grade II or III (P < .001). Of 148 patients negative for myxoid cancer stroma, 30 (16.9%) had nodal involvement vs. 24 (36.4%) of 42 patients who were positive for myxoid cancer stroma (P = .0011). According to multiple variable logistic analysis, significant independent risk factors for nodal involvement included poorly differentiated component (P = .002), myxoid cancer stroma (P = .032), and lymphovascular invasion (P = .022). CONCLUSIONS: Poorly differentiated component, myxoid cancer stroma, and lymphovascular invasion are significant independent risk factors for nodal involvement in T2 colorectal cancer. We need further study to validate these results on another data set, especially in patients with rectal cancer, and to confirm whether local resection of T2 rectal cancer is able to predict the nodal involvement before laparotomy.