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.

Changes in apolipoprotein B and oxidized low-density lipoprotein levels in gingival crevicular fluids as a result of periodontal tissue conditions.

BACKGROUND AND OBJECTIVE: Periodontal disease is a chronic inflammatory disease caused by bacterial infection that can lead to tooth loss. Gingival crevicular fluid can be collected easily and noninvasively. We previously discovered the presence of apolipoprotein B (apoB), the main constituent of low-density lipoprotein, and oxidized low-density lipoprotein (oxLDL) in the gingival crevicular fluid of healthy subjects. In this study, we investigated whether periodontal conditions affect the levels of apoB and oxLDL in gingival crevicular fluid. MATERIAL AND METHODS: The study population comprised 11 patients with chronic periodontitis. A pair of gingival crevicular fluid samples was collected from each patient at a healthy site and at a site with periodontitis (baseline samples). Thereafter, gingival crevicular fluid samples were collected from the same patients again at 4 and 8 wk after scaling and root planing (SRP). The levels of apoB, oxLDL, protein and cytokines in gingival crevicular fluid, in addition to gingival crevicular fluid volume, were measured. RESULTS: At baseline, the levels of apoB and oxLDL in gingival crevicular fluid were higher at the sites with periodontitis than at the healthy sites. The levels of apoB and oxLDL at periodontal sites decreased after SRP. The level of oxLDL in gingival crevicular fluid correlated well with the probing pocket depth. The oxLDL : apoB ratio in gingival crevicular fluid was significantly higher than that in plasma. CONCLUSIONS: The levels of apoB and oxLDL in gingival crevicular fluid change according to the periodontal tissue conditions.

Randomized clinical trial of skin closure by subcuticular suture or skin stapling after elective colorectal cancer surgery.

BACKGROUND: The best suture method to prevent incisional surgical-site infection (SSI) after clean-contaminated surgery has not been clarified. METHODS: Patients undergoing elective colorectal cancer surgery at one of 16 centres were randomized to receive either subcuticular sutures or skin stapling for skin closure. The primary endpoint was the rate of incisional SSI. Secondary endpoints of interest included time required for wound closure, incidence of wound problems, postoperative length of stay, wound aesthetics and patient satisfaction. RESULTS: A total of 1264 patients were enrolled. The cumulative incidence of incisional SSI by day 30 after surgery was similar after subcuticular sutures and stapled closure (8·7 versus 9·8 per cent respectively; P = 0·576). Comparison of cumulative incidence curves revealed that SSI occurred later in the subcuticular suture group (P = 0·019) (hazard ratio 0·66, 95 per cent c.i. 0·45 to 0·97). Wound problems (P = 0·484), wound aesthetics (P = 0·182) and postoperative duration of hospital stay (P = 0·510) did not differ between the groups; subcuticular sutures took 5 min longer than staples (P < 0·001). Patients in the subcuticular suture group were significantly more satisfied with their wound (52·4 per cent versus 42·7 per cent in the staple group; P = 0·002). CONCLUSION: Compared with skin stapling, subcuticular sutures did not reduce the risk of incisional SSI after colorectal surgery. REGISTRATION NUMBER: UMIN000004001 (http://www.umin.ac.jp/ctr).

High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients.

BACKGROUND: Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as antitumour agents. The interaction between the Crk-like adaptor protein (CrkL), which is encoded by the CRKL gene, and non-receptor tyrosine kinase c-ABL is reported to transform many cells into malignant cells. We examined the effects of CC chemokine receptor 7 (CCR7), CCR7 ligands and CrkL and c-ABL in lung adenocarcinoma. METHODS: One hundred and twenty patients with lung adenocarcinoma were included in this historical cohort analysis. We examined CCR7 and CCR7 ligands and CrkL and c-ABL mRNA expressions in surgically resected lung adenocarcinoma specimens and evaluated their contribution to prognosis, and the relationship with epidermal growth factor receptor (EGFR) and TP53 mutations. RESULTS: High CCR7 mRNA expressions indicated better prognoses than those of the groups with low CCR7 mRNA expressions (P=0.007, HR=2.00, 95% CI of ratio: 1.22 -3.31). In lung adenocarcinoma, CrkL and c-ABL mRNAs were related to CCR7 mRNA expression (P<0.0001). CrkL and c-ABL mRNA expressions were influenced by EGFR mutations. A high expression of CCL19 was a good prognostic factor of lung adenocarcinoma. CONCLUSION: We propose that CCR7 and CCL19 are clinically good prognostic factors and that CCR7 is strongly related to CrkL and c-ABL kinase mRNA expression in lung adenocarcinoma.

Treatment of lateral pelvic nodes metastases from rectal cancer: the future prospective.

One feature of rectal cancer that remains controversial is the significance of lateral lymph node, because TME does not remove these nodes. We discussed the brief history of lateral nodes dissection and some problems in performing the extended surgery.In Japan, an ongoing prospective multicenter randomized trial comparing TME alone and TME with clearance of lateral node is progress. In the West, MERCURY study showed 11.7% of patients with rectal cancer had MRI-identified suspicious pelvic side wall nodes. Judging from incidence and prognosis, pelvic side wall nodes in the west are almost similar meaning as lateral nodes in Japan. There is long-standing controversy as to whether lateral lymph nodes metastasis represent systemic or localized disease. Though there has been reports suggesting effect of RT on lateral nodes metastases, the question remains whether preoperative CRT can fully sterilize lateral nodes deposits. Is it appropriate inspection assuming that positive CRM and bowel perforation is major cause of local recurrence after abdominoperineal resection? Some reports say that lateral node metastasis is major cause of local recurrence.We must share following views that the east and the west should join forces to improve selection criteria for lateral node dissection and neoadjuvant treatment to prevent overtreatment, and ultimately aim to improve quality of life and oncological outcome for patients with low rectal cancer.

The indications for a diverting stoma in low anterior resection for rectal cancer: a prospective multicentre study of 222 patients from Japanese cancer centers.

AIM: The aim of the study was to determine the present state of diverting stoma construction in Japanese cancer centres and to investigate the relationship between symptomatic leakage and diverting stoma after low anterior resection for rectal cancer. METHOD: Two hundred and twenty-two consecutive patients undergoing low anterior resection for rectal cancer located within 10 cm from the anal verge were investigated in a prospective, multicenter study. RESULTS: The overall leakage rate was 9.0% (20/222). Of 31 cases with an anastomosis within 2.0 cm from the anal verge, 22 (71%) had a diverting stoma. Of cases anastomosed within 5.0 cm, the absence of a diverting stoma and tumour size were significantly related to an increased rate of leakage [leakage in 13 (12.7%) of 102 cases without a diverting stoma; in three (3.8%) of 80 cases with a diverting stoma]. Among anastomoses within 2.0 cm from the anal verge, leakage occurred in four (44.4%) of nine cases without and in none (0%) of 22 cases with a diverting stoma. CONCLUSION: We recommend a diverting stoma for an anastomosis within 5.0 cm of the anal verge and strongly recommend it for a very low anastomosis within 2.0 cm.

Origin of presacral local recurrence after rectal cancer treatment.

BACKGROUND: The objective of this study was to obtain detailed anatomical information about the lateral lymph nodes, in order to determine whether they might play a role in presacral local recurrence of rectal cancer after total mesorectal excision without lateral lymph node dissection. METHODS: Ten serially sectioned human fetal pelvises were studied at high magnification and a three-dimensional reconstruction of the fetal pelvis was made. RESULTS: Examination of the histological sections and the three-dimensional reconstruction showed that lateral lymph node tissue comprises a major proportion of the pelvic tissue volume. There were no lymph nodes located in the presacral area. Connections between the mesorectal and extramesorectal lymph node system were found in all fetal pelvises, located below the peritoneal reflection on the anterolateral side of the fetal rectum. At this site middle rectal vessels passed to and from the mesorectum, and branches of the autonomic nervous system bridge to innervate the rectal wall. CONCLUSION: The findings of this study support the hypothesis that tumour recurrence might arise from lateral lymph nodes.

Patterns of local recurrence in rectal cancer: a single-center experience.

A cohort of patients operated at the National Cancer Center Hospital in Tokyo for rectal carcinoma, at or below the peritoneal reflection, was reviewed retrospectively. The purpose was to study the risk factors for local relapse and the patterns of local recurrence. Three hundred fifty-one patients operated between 1993 and 2002 for rectal carcinoma, at or below the peritoneal reflection, were analyzed. One hundred forty-five patients, with preoperatively staged T1 or T2 tumors without suspected lymph nodes, underwent total mesorectal excision (TME). Lateral lymph node dissection (LLND) was performed in suspected T3 or T4 disease, or when positive lymph nodes were seen; 73 patients received unilateral LLND and 133 patients received bilateral LLND. Of the 351 patients 6.6% developed local recurrence after 5 years. TME only resulted in 0.8% 5-year local recurrence. In lymph-node-positive patients, 33% of the unilateral LLND group had local relapse, significantly more (p = 0.04) than in the bilateral LLND group with 14% local recurrence. Local recurrence in the lateral, presacral, perineal, and anastomotic subsites was lower in the bilateral LLND group as compared with in the unilateral LLND group. We conclude that, in selected patients, surgery without LLND has a very low local recurrence rate. Bilateral LLND is more effective in reducing the chance of local recurrence than unilateral LLND. Either surgical approach, with or without LLND, requires reliable imaging during work-up.

Clinicopathological significance of fibrous tissue around fixed recurrent rectal cancer in the pelvis.

BACKGROUND: Fibrous tissue around a locally recurrent rectal tumour is an interesting histological feature, but its clinicopathological significance has not been investigated. METHODS: This retrospective study examined clinicopathological findings in 48 patients who underwent curative total pelvic exenteration with distal sacrectomy (TPES) between 1992 and 2004. Data were analysed with respect to fibrosis around the recurrent tumour, categorized into one of three groups: no fibrosis (f0), partial fibrosis (f1) or circumferential fibrosis (f2). RESULTS: Ten, 17 and 21 patients had f0, f1 and f2 fibrosis respectively, with 5-year survival of none, four and eight patients respectively. The overall survival of patients with circumferential fibrosis was significantly better than that in patients with no fibrosis (P = 0.003). Univariable analysis showed that a high level of sacrectomy (P = 0.036), absence of lymphatic invasion (P = 0.031) and circumferential fibrosis (P = 0.039) were significantly associated with better overall survival. In multivariable analysis, circumferential fibrosis (P = 0.031) and low serum carcinoembryonic antigen levels (P = 0.044) were independent factors for a favourable outcome. CONCLUSION: The outcome of patients with locally recurrent rectal cancer after curative TPES appears to be better when circumferential fibrosis is present around the tumour.

Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs.

The non-clinical pharmacokinetics (PK) of TAK-357, a highly lipophilic (clogP>6) potential agent for the amelioration of Alzheimer's disease, was investigated in rats and dogs. A long half-life (t1/2) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t1/2. The absorption, distribution, metabolism and excretion (ADME) studies using radiolabeled TAK-357 revealed that the total radioactivity was highly distributed to the adipose tissues and sustained with high concentration for over 4 weeks after oral administration. The metabolite analysis also revealed that the main component in the plasma and adipose tissues was unchanged TAK-357. The major elimination route of absorbed TAK-357 was suggested to be by metabolism. An ADME study indicated that the adipose tissue is the main depot of remaining TAK-357 in the body and slow release from the adipose tissues contributes to the long t1/2. The PK of highly lipophilic compounds have a tendency to be affected by body weight changes especially changes in the adipose tissues. Therefore, it is considered that the relationship between the plasma levels of TAK-357 and the body weight should be evaluated carefully during the clinical trials.

Reduction of prolonged postoperative hospital stay after laparoscopic surgery for colorectal carcinoma.

BACKGROUND: In evaluating the quality of laparoscopic surgery (LS) for colorectal carcinoma, many previous reports have used median or range values to assess the length of postoperative hospital stay and to show the complication and conversion rates separately. However, with this method, it is impossible to assess the proportion of patients who required prolonged postoperative hospital stay because of perioperative morbidities. This study investigated the proportion of patients who benefited from LS as minimally invasive surgery by assessing the percentage of patients who required prolonged postoperative hospital stay because of major perioperative morbidities. METHODS: A review of 202 patients who underwent LS for colorectal carcinoma at the authors' hospital between January 2002 and December 2004 was performed. Short-term outcomes were compared among the patients who underwent LS in 2002, 2003, and 2004. RESULTS: No significant differences were observed in baseline characteristics among the groups, and all the procedures in this study were completed laparoscopically. There were no significant differences in the operative times and intraoperative blood losses among the groups. Most of the patients resumed liquid intake on postoperative day 1 and solid food on day 3. However, there was a significant difference in the rate of postoperative prolonged hospital stays by year of surgery. In 2004, 97.3% of the patients (72/74) undergoing LS could be discharged to home within 8 days postoperatively. Major complications occurred at a low rate of 1.4% (1/74) in 2004. Regarding the reasons for prolonged postoperative hospital stay, inappropriate judgment of the physician in charge, based primarily on requests from patients without medical necessity, disappeared in 2004. CONCLUSIONS: When LS is performed properly by specialists who have accumulated sufficient experience in both LS and conventional open surgery for colorectal carcinoma, up to 97% of patients undergoing LS can benefit from minimally invasive surgery.

Modulation of cell growth, differentiation, and production of interleukin-3 by 1 alpha,25-dihydroxyvitamin D3 in the murine myelomonocytic leukemia cell line WEHI-3.

The effect of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], the active form of vitamin D3, on the relation between cell growth and differentiation was examined in a murine myelomonocytic leukemia cell line WEHI-3 which is known to produce high levels of interleukin-3. 1 alpha,25(OH)2D3 markedly inhibited proliferation of WEHI-3 cells in a time- and dose-dependent manner. Flow cytometric analysis of the cell cycle by a double staining method using fluorescein isothiocyanate-conjugated anti-bromodeoxyuridine and propidium iodide revealed that 1 alpha,25(OH2D3 increased the proportion and the number of cells accumulating in the G0-G1 phase and decreased those in the S phase. The phenotype of the surface antigens of the cells was of the T-cell lineage, but the cells became positive in macrophage-associated surface markers (Mac-1 and Ia) after treatment with 1 alpha,25(OH)2D3. The vitamin induced phagocytic activity, appearance of Fc receptors, nitroblue tetrazolium-reducing activity, and nonspecific esterase activity, indicating that the vitamin induces the cells to differentiate into macrophages. Furthermore, 1 alpha,25(OH)2D3 inhibited interleukin-3 production by the cells in a time- and dose-dependent manner. These results suggest that 1 alpha,25(OH)2D3 inhibits proliferation of WEHI-3 cells by blocking transition of the cells from the G0-G1 to the S phase, resulting in induction of the G0-G1-arrested cells to differentiate into macrophages. The relation between the suppression by 1 alpha,25(OH)2D3 of cell growth and interleukin-3 production remains to be elucidated in the future.

Adoptive immunotherapy by pantropic killer cells recovered from OK-432-injected tumor sites in mice.

A murine malignant ascites model with BAMC-1 tumors was established previously, which was cured completely by five consecutive i.p. injections of OK-432. We have found that peritoneal mononuclear cells from these animals contained antitumor effector cells which could destroy nonspecifically a variety of tumor cells in vitro. They were tentatively called pantropic killer cells (PKCs). The present study was essentially designed to show the antitumor effectiveness of the PKCs in vivo by the use of an adoptive immunotherapy model. The growth of BAMC-1 tumors transplanted s.c. 5 days earlier was significantly suppressed by passive transfer of 5 x 10(6) to 2 x 10(7) PKCs induced by injection of OK-432 into BAMC-1 bearing donor mice, while more than 1 x 10(8) immune spleen cells from the same donors treated with OK-432 were required to achieve the similar effects. Furthermore, if the tumor-bearing recipients were pretreated with 180 mg/kg of cyclophosphamide 1 h before the adoptive transfer, even 5 x 10(6) PKCs could induce complete regression of the tumors transplanted 5 days earlier. This protocol made it possible even to achieve the complete regression of larger tumors (9-10 mm in diameter) in recipients transplanted 12 days earlier. The PKCs were, as expected, able to cure not only BAMC-1-bearing animals but also Meth-A-bearing mice. As effector cells for adoptive immunotherapy, therefore, the PKCs induced by OK-432 seem to be as effective as, if not better than, lymphokine-activated killer cells expanded in vitro by culturing tumor infiltrating lymphocytes with interleukin-2. Although the study on surface markers of PKCs did not unequivocally discriminate these from lymphokine-activated killer cells, the present findings are considered significant indicating that a potent biological response modifier such as OK-432 can induce pantropic killer cells which are extremely effective in destroying various tumor cells in vivo. One of the advantages of OK-432 therapy over lymphokine-activated killer cell therapy, therefore, is that the former does not require the tedious and time-consuming in vitro procedures which are essential for the latter.

Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.

Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.

Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.

TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 µmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 µmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors.

Male sexual dysfunction after rectal cancer surgery: Results of a randomized trial comparing mesorectal excision with and without lateral lymph node dissection for patients with lower rectal cancer: Japan Clinical Oncology Group Study JCOG0212.

BACKGROUND: We conducted a randomized controlled trial (JCOG0212) to determine whether the outcome of mesorectal excision (ME) alone for rectal cancer is not inferior to that of ME with lateral lymph node dissection (LLND). The present study focused on male sexual dysfunction after surgery. METHODOLOGY: Eligibility criteria included clinical stage II/III rectal cancer, the lower margin of the lesion below the peritoneal reflection, the absence of lateral pelvic lymph node enlargement, and no preoperative radiotherapy. After confirmation of R0 resection by ME, patients were intraoperatively randomized. Questionnaires using the International Index of Erectile Function (IIEF-5) about the sexual function of men were collected before and 1 year after surgery. Sexual dysfunction incidence was defined as the ratio of patients showing sexual dysfunction after surgery relative to the number who had no erectile dysfunction before surgery. RESULTS: Among 701 patients enrolled between June 2003 and August 2010, 472 males were included. Among them, 343 (73%) completed preoperative and postoperative questionnaires. According to the study protocol, the incidences of sexual dysfunction in patients who underwent ME alone and ME with LLND were 68% (17/25; 95%CI, 47-85%) and 79% (23/29; 95%CI, 60-92%), respectively (p = 0.37). Incidences of sexual dysfunction in patients with no or only mild erectile dysfunction before surgery who underwent ME alone and ME with LLND were 59% (48/81) and 71% (67/95), respectively (p = 0.15). Multivariate analysis identified age as the only risk factor for sexual dysfunction after surgery (p = 0.02). CONCLUSIONS: LLND may not increase sexual dysfunction incidence after rectal cancer surgery. This incidence is associated with increased age. This trial is registered with ClinicalTrials.gov, number NCT00190541 and University Hospital Medical Information Network Clinical Trials Registry, number C000000034.

Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.

Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.

Nerve-sparing surgery with lateral node dissection for advanced lower rectal cancer.

133 patients who underwent nerve-sparing surgery with lateral dissection for lower rectal cancer were analysed for survival and functional results, operative burdens, and modes of recurrence. In 84% of patients an acceptable urinary function was preserved. Operative time averaged 334 min, and blood loss averaged 935 ml. The 5-year survival rate was 67% in all patients, and 88% for Dukes' A, 74% for Dukes' B and 59% for Dukes' C. According to the number of positive nodes, the 5-year survival rate comprised 83% of patients with up to three nodes, and 34% of those with more than four nodes. Local recurrent rates were 2.7% in patients with Dukes' B and 13% with Dukes' C. At present, pelvic nerve-sparing procedures with lateral dissection is the most promising surgery, guaranteeing both adequate lymphadenectomy and preservation of urinary function.

Patterns of lymphatic spread in rectal cancer. A topographical analysis on lymph node metastases.

The presence of lymph node (LN) metastases is the most important prognostic factor in rectal cancer. The exact LN status can only be known when an extended lymph node dissection (LND) has been performed, a process not routinely performed. If the likelihood of LN metastases can be more accurately assessed preoperatively, then an optimal multimodality treatment plan can be established. 605 patients with primary rectal cancer operated upon with wide LND (D3 level) were analysed for LN metastases combining topographical localisation and morphological features of the tumour. More distal rectal tumours tend to more LN metastases and more lateral lymphatic spread. Tumours >or=3 cm show more LN metastases compared with those smaller than 3 cm. Depth of bowel wall invasion is strongly related to the presence of LN metastases. The peritoneal reflection has no discriminating role in the mode of spread. Intra-operative assessment by the surgeon for presence of LN metastases is not reliable. When localisation, depth of bowel wall invasion and diameter of a rectal tumour are known, a likelihood of LN metastases can be assessed pre-operatively, not intra-operatively.

Hemolysis of sheep erythrocytes with the cell membrane of liquid paraffin-induced guinea pig macrophages.

As reported previously, the lysate of liquid paraffin-induced guinea pig peritoneal macrophages contains a hemolytic factor which is composed of two components: the soluble (S) and membrane-bound (M) components. To investigate the mechanism whereby the factor hemolysis sheep erythrocytes, an attempt was made to identify the S and M components. The fractionation of the cytosol of macrophages by DEAE-cellulose chromatography and the failure of the lysate from L-ascorbate-depleted macrophages to lyse erythrocytes demonstrated that the S component was L-ascorbate. In addition, L-ascorbate was found to be replaced by NADPH, a substrate of the membrane-bound NADPH oxidase, showing that L-ascorbate acts as a donor of active oxygen. When L-ascorbate was combined with the phospholipids isolated from the membrane fraction by extraction with chloroform-methanol and thin layer chromatography, it became able to lyse erythrocytes. The results so far obtained indicate that the hemolysis by the macrophage lysate is dependent on the formation of peroxidized phospholipids in the membrane fraction with certain active oxygen species produced either from L-ascorbate or by the NADPH oxidase.