Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Appendiceal orifice inflammation is associated with proximal extension of disease in patients with ulcerative colitis.

AIM: Ulcerative colitis (UC) is considered to be a disease of continuous mucosal inflammation extending proximally from the rectum. However, appendiceal orifice inflammation (AOI) is a skip lesion with segments of continuous involvement from the rectum. The aim of this study was to examine the clinical characteristics and clinical course, particularly focused on proximal extension, of UC in patients with AOI. METHOD: A retrospective evaluation of patients with UC who underwent total colonoscopy at the Department of Surgical Oncology, The University of Tokyo, from 2004 to 2014. The degree of AOI was graded endoscopically as follows: 0 (no inflammation); 1 (slight oedema); 2 (moderate inflammation); and 3 (marked inflammation). A total of 189 patient records were reviewed retrospectively. The presence of AOI was analysed with regard to the clinical information of each patient, and its association with proximal extension of proctitis or left-sided colitis was evaluated. RESULTS: Of 189 patients with UC who underwent total colonoscopy at our institution, 92 were diagnosed with pancolitis, 50 with left-sided colitis and 47 with proctitis. Endoscopic findings of AOI were observed in 26 patients, including 11 (12.0%) with pancolitis, six (12.0%) with left-sided colitis and nine (19.1%) with proctitis. During follow up, proximal extension of the disease occurred in all nine patients with proctitis AOI. CONCLUSION: AOI is more frequently observed in patients with proctitis. Our results showed correlations between AOI and subsequent proximal extension of mucosal inflammation in patients with proctitis.

Clinical pattern and progression of ulcerative proctitis in the Japanese population: a retrospective study of incidence and risk factors influencing progression.

AIM: The rate of extension of proctitis in Western countries has been reported, but no data regarding long-term follow-up have been described for the Japanese population. Additionally, patients with long-standing or extensive ulcerative colitis have an increased risk for developing colorectal cancer. This study evaluated both the rate of extension of the disease and the development of neoplasia among patients with an initial diagnosis of ulcerative proctitis. METHOD: We retrospectively investigated the medical charts of patients with proctitis from 1979 to 2014. The primary focus of this research was the extension of the inflammatory area. The secondary focus included risk factors for disease extension and the development of neoplasia. RESULTS: Sixty-six patients satisfied the inclusion criteria. Proximal extension of the disease occurred in 34 patients: 19 patients had left-sided colitis and 15 had pancolitis. According to a multivariate analysis, disease extension was significantly higher in patients with disease onset before 25 years of age (P-value = 0.043). The cumulative rates of disease extension at 10 and 20 years were 33.8% and 52.2%, respectively. Three patients were diagnosed with dysplasia during follow-up, all of whom experienced disease extension before the development of dysplasia. CONCLUSION: The rate of extension of ulcerative colitis in the Japanese population was comparable to that in Western countries. A younger age of disease onset was associated with disease extension. Extension of proctitis may be associated with an increased risk of colorectal cancer.

Surgical stress response after colorectal resection: a comparison of robotic, laparoscopic, and open surgery.

BACKGROUND: The perioperative immune status of colorectal robotic surgery (RS), laparoscopic surgery (LS), and open surgery (OS) patients has not been compared. Our aim was to evaluate perioperative stress and immune response after RS, LS and OS. METHODS: This prospective study included 46 colorectal surgery patients from the Department of Surgical Oncology of the University of Tokyo Hospital. Peripheral venous blood samples were obtained preoperatively and on postoperative days 1, 3, and 6. We evaluated expression of HLA-DR (marker of immune competence), C-reactive protein (CRP) levels, and lymphocyte subset counts (natural killers, cytotoxic T cells and helper T cells). RESULTS: Fifteen, 23, and 8 patients underwent RS, LS and OS, respectively. HLA-DR expression was the lowest on day 1 and gradually increased on days 3 and 6 in all the groups. There was no significant difference in postoperative HLA-DR expression between the RS and LS group. However, on day 3, HLA-DR expression in the RS group was significantly higher than in the OS group (p = 0.04). On day 1, CRP levels in the LS group were significantly lower than in the RS group (p = 0.038). There were no significant perioperative changes in the lymphocyte subset cell count between the three groups. CONCLUSIONS: Perioperative surgical stress, as evaluated by immunological parameters, was comparable between robotic and laparoscopic surgery and higher with open surgery. Robotic surgery may be an alternative to laparoscopic surgery, as a minimally invasive surgery option for colorectal cancer.

Nomograms for predicting the prognosis of stage IV colorectal cancer after curative resection: a multicenter retrospective study.

PURPOSE: Although stage IV colorectal cancer (CRC) encompasses a wide variety of clinical conditions with diverse prognoses, no statistical model for predicting the postoperative prognosis of stage IV CRC has been established. Thus, we here aimed to construct a predictive model for disease-free survival (DFS) and overall survival (OS) after curative surgery for stage IV CRC using nomograms. METHODS: The study included 1133 stage IV CRC patients who underwent curative surgical resection in 19 institutions. Patients were divided into derivation (n = 586) and validation (n = 547) groups. Nomograms to predict the 1- and 3-year DFS rates and the 3- and 5-year OS rates were constructed using the derivation set. Calibration plots were constructed, and concordance indices (c-indices) were calculated. The predictive utility of the nomogram was validated in the validation set. RESULTS: The postoperative carcinoembryonic antigen (CEA) level, depth of tumor invasion (T factor), lymph node metastasis (N factor), and number of metastatic organs were adopted as variables for the DFS-predicting nomogram, whereas the postoperative CEA level, T factor, N factor, and peritoneal dissemination were adopted for the nomogram to predict OS. The nomograms showed moderate calibration, with c-indices of 0.629 and 0.640 in the derivation set and 0.604 and 0.637 in the validation set for DFS and OS, respectively. CONCLUSIONS: The nomograms developed were capable of estimating the probability of DFS and OS on the basis of only 4 variables, and may represent useful tools for postoperative surveillance of stage IV CRC patients in routine practice.

E-selectin can mediate the arrest type of adhesion of colon cancer cells under physiological shear flow.

The aim of this study was to determine whether colon cancer cells flowing in blood exhibit the same adhesion pattern to the vascular bed as leucocytes using a flow adhesion system. In shear flow conditions, five colon cancer cell lines showed less tethering to E-selectin substrates than polymorphonuclear cells (PMN). However, some of the Colo201 cells formed complete arrest on E-selectin in continuous shear flow which was never observed in PMN cells. Colo201 cells expressed both sialyl Le-x and sialyl Le-a at similar levels in flow cytometry. However, the staining pattern showed marked contrast under the fluorescein microscope. The cell membrane of Colo201 cells was uniformly stained with anti-sialyl Le-a MAb, whereas anti-sialyl Le-x MAb only stained in the patchy areas. Pretreatment of Colo201 cells with anti-sLe-a decreased tethering, while anti-sLe-x significantly inhibited the arrest formation. Our data suggest that E-selectin alone can mediate colon cancer cell lodgement and subsequent metastasis without the contribution of integrin molecules and that the different distribution of E-selectin ligands may affect the adhesion behaviour of colon cancer cells in flow conditions.

Carney's complex in association with right atrial myxoma.

The association between myxomas, spotty pigmentation, and endocrine overactivity is referred to as Carney's complex. This report describes the case of a 24-year-old woman with right atrial myxoma who presented with this association. The patient had a previously excised myxoid tumor of the breast and uneven facial pigmentation was observed, but no evidence of endocrinopathy was detected. The myxoma originated from the right atrial wall adjacent to the junction of the inferior vena cava and right atrium, and was successfully excised. A brief review of Carney's complex is provided after discussion of this rare case.

Gasless laparoscopically assisted colonic surgery.

BACKGROUND: Laparoscopic technique has been applied to a variety of colonic and rectal operations, generally using carbon dioxide insufflation (CDI). However, CDI is inevitably associated with cardiopulmonary loading and can cause complications. The objective of this study was to determine the feasibility of gasless laparoscopic colonic surgery. METHODS: The abdominal wall was lifted up using an originally designed retractor. A small incision, 3 to 5 cm in length, was made at the start of the operation. The surgeon operated through this incision using both conventional and laparoscopic instruments. RESULTS: Operations were undertaken in 67 patients. In 6 patients (9%), conversion to open surgery was necessitated. In the remaining 61 patients, operations were completed with gasless laparoscopically assisted technique. Four reoperations (7%) were performed because of postoperative bleeding, anastomotic rotation, anastomotic stricture, and transmesenteric hernia. Fifty-three patients with colonic cancer were operated on with potentially curative intent. Of these, 1 (2%) developed hepatic recurrence during the mean follow-up period of 23.8 months. There was no port site recurrence. CONCLUSIONS: Gasless laparoscopic colonic surgery is technically feasible. CDI is not necessary to perform minimal access surgery.

Appleby operation for carcinoma of the body and tail of the pancreas.

Long-term survival of carcinomas in the body and tail of the pancreas after surgery is still rare. One of the major reasons for unresectability is cancerous invasion to major vessels, such as the common hepatic and splenic arteries. Resection of the involved arteries can increase resectability and thus might increase post-operative survival. The aim of this study was to clarify the importance of the Appleby operation for carcinoma of the body and tail of the pancreas. A Case Report was carried out with a 54 year-old man, had suffered back pain and loss of body weight for six months. Imaging procedures such as US, CT or angiography showed a carcinoma in the body of the pancreas, about 3 cm in size, and both the common hepatic and splenic arteries were invaded by the tumor. The Appleby operation was used for this patient, since firstly there was no invasion to the head of the pancreas, secondly neither the proper hepatic artery nor the SMA was involved, thirdly the root of the CA was free of carcinoma, and finally because clear pulsation of the proper hepatic artery could be felt one or two minutes after occlusion of the CHA, which indicated that resection of the CHA would not lead to hepatic ischemia. The postoperative course was uneventful. His appetite recovered well and his body weight increased to the level before the disease. The patient was relieved from back pain and has returned to work 18 months after the operation, although he had a local recurrence eight months after the operation. In addition, eleven cases with carcinoma of the body and tail of the pancreas were used for a literature review. The average survival time after the Appleby operation is 6.6 months, and four patients are still alive. One patient has survived 13 years after the operation. It was concluded that although the prognosis after Appleby procedure is still not satisfactory that this operation can at least offer patients a better quality of life.

Primary intestinal obstruction complicated by persistent descending mesocolon.

Persistent descending mesocolon is an uncommon developmental anomaly which results from failure of fusion of the descending mesocolon with the posterior parietal peritoneum. It is asymptomatic in most cases and rarely causes intestinal obstruction. We report here a case of primary intestinal obstruction complicated by a persistent descending mesocolon. A 66-year-old man without prior laparotomy was admitted with a diagnosis of small bowel obstruction. Pre-operative investigation demonstrated a segmental jejunal stenosis and a persistent descending mesocolon as possible causes of the obstruction. Laparotomy showed that the cause of the obstruction was the jejunal stenosis, not the persistent descending mesocolon. The stenosis was resected, but correction of the anomaly was not performed. The patient made an uneventful recovery after the operation. From our limited experience, persistent descending mesocolon need not be surgically corrected when it is not considered to be the cause of obstruction and another definite cause co-exists.

Transmesenteric hernia after laparoscopic-assisted sigmoid colectomy.

BACKGROUND AND OBJECTIVES: Laparoscopic-assisted surgery has been applied for a variety of colonic surgery. The objective of this paper is to demonstrate a possible and avoidable complication of laparoscopic colonic surgery. CASE PRESENTATION: A 47-year-old woman underwent gasless laparoscopic-assisted sigmoid colectomy. On the 20th postoperative day, she developed bowel obstruction. Decompression with a long tube failed to resolve the bowel obstruction. Open laparotomy was performed. Abdominal exploration revealed a loop of the small bowel incarcerated in the mesenteric defect caused by the previous operation. Adhesiolysis was performed, and the postoperative course was uneventful. DISCUSSION: Despite technical difficulty, complete closure of the mesentery after bowel resection is strongly recommended for prevention of transmesenteric incarcerated hernia after laparoscopic surgery.

[Long-term complete response in a case of unresectable rectal cancer following chemoradiation].

We report a case of unresectable rectal cancer in a 53-year-old male treated with chemoradiation. Radiation therapy was delivered with a total pelvic dose of 45 Gy together with oral administration of 5'-DFUR (1,200 mg/day). The patient received one course of combination chemotherapy consisting of cisplatin, 100 mg/body x 1 day, and 5-FU, 1,000 mg/body x 5 days, followed by radiation therapy. Oral administration of tegafur-uracil (300 mg/day) was continued for five years following the chemoradiation. The patient is now disease-free 75 months after the initial surgery. Chemoradiation can be managed to obtain a complete remission of some locally advanced rectal cancers.

[Complete remission in a case of sigmoid colon cancer with multiple liver metastases-treatment with arterial chemotherapy and percutaneous microwave coagulation therapy].

A 59-year-old man was admitted to our hospital for advanced sigmoid colon carcinoma with synchronous multiple liver metastases. The patient received sigmoidectomy with regional lymph node dissection on June 8, 1998. We started intra-arterial combination chemotherapy on July 1, 1998. MMC (4 mg/body) was administered via rapid intra-arterial infusion on day 1. After MMC administration, 5-day intra-arterial continuous infusion of 5-FU at 500 mg/body/day was performed with oral administration of LV (30 mg/body/day). The treatment cycle was defined as every three weeks. The patient was treated with 4 courses of chemotherapy. From September 30, he received intra-arterial infusion of bolus MMC 4 mg/body, LV 6 mg/body and 5-FU 1,000 mg/body/4 hrs every two weeks with oral administration of Tegafur-uracil 400 mg/day. After 4 intra-arterial chemotherapy sessions, the metastatic liver tumors disappeared except for a focus in the right lobe. Therefore we decided to give the remnant liver metastasis percutaneous microwave coagulation therapy (PMCT). He obtained a complete remission in the liver metastases after two PMCT (70 W, 60 sec) sessions. Intra-arterial chemotherapy is effective for unresectable metastatic liver tumors from colon cancer. If a patient shows a partial response on the metastatic tumors through the chemotherapy, one must consider other modalities such as PMCT.

A case of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) with multiple polyps arising in the cecum and appendix.

We present the case of a 32-year-old female with cecal and appendiceal polyps that were removed by laparoscopy-assisted surgery. She also had recurrent nosebleeds due to telangiectases in the nasal mucosa and arteriovenous malformations in the lung, all of which contributed to the diagnosis of hereditary hemorrhagic telangiectasia.

A study of dendritic and endothelial cell interactions in colon cancer in a cell line and small mammal model.

AIM: Historically, cancer therapy directly targeting tumor cells have yielded suboptimal clinical results, and therefore anti-angiogenic therapy that targets tumor cells indirectly through impairing tumor vasculature is now considered to be one of the novel approaches potentially effective against various types of cancer. In this study, we evaluated whether lysates of endothelium could be effectively pulsed in dendritic cells (DCs), to enhance their anti-tumor effects. METHODS: For this purpose, we prepared DCs of BALB/c mouse, incubated them with lysates of autologous or xenogeneic endothelium, and tested their anti-tumor effects in two syngeneic models of colon cancer. RESULTS: DCs pulsed with the respective endothelium lysates significantly inhibited the growth of subcutaneous tumors as well as pulmonary metastases in mice, and their anti-tumor effect was superior to that of unpulsed DCs. Immunohistopathological analysis showed significant decrease in the mean vascular density of tumors, correlating well with the extent of tumor inhibition. In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes and activation of natural killer cells, with a lytic activity against activated endothelium but not tumor cells. In addition, antibodies reacting with activated endothelium, but not tumor cells, were detected in murine sera by ELISA, and their function was confirmed by complement-dependent cytotoxicity assay. CONCLUSIONS: Our present results suggest that lysates of endothelium can be effectively pulsed in DCs and enhance their anti-tumor effects through induction of anti-angiogenesis, and therefore should have important clinical implications for adjuvant cancer therapy.

Effect of high ligation on the long-term result of patients with operable colon cancer, particularly those with limited nodal involvement.

OBJECTIVE: To find out what effect the extent of nodal dissection has on patients with operable colonic cancer. DESIGN: Retrospective study. SETTING: Teaching hospital, Japan. PATIENTS: 564 consecutive patients who had potentially curative operations for colon cancer. Patients treated by limited nodal dissection, in which only pericolonic nodes were dissected, were excluded. MAIN OUTCOME MEASURES: Disease free survival classified by extent of nodal dissection. RESULTS: High ligation gave no significant advantage when patients were subgrouped according to degree of nodal involvement. However, number of patients with aggressive involvement (including intermediate or central nodes) was small. 511 patients (91%) had limited nodal involvement (no nodal involvement or nodal involvement confined to pericolonic nodes). High ligation of the vessels gave no advantage even with meticulous subgrouping according to age, site, and depth of invasion. CONCLUSION: Most patients with colonic cancer had limited nodal involvement. High ligation did not affect the long term results in these patients, so, less invasive low ligation should be considered. A larger study will be necessary to clarify the indications for low and high ligation for patients with aggressive nodal involvement.

Morphological characteristics of Schwann cells in the islets of Langerhans of the murine pancreas.

The present study demonstrated the three-dimensional architecture of peri-insular nerve plexuses in the murine pancreas by the combined use of light microscopy of S-100 immunostained sections, transmission electron microscopy (TEM) of thin sections, and scanning electron microscopy (SEM) of KOH digested tissues. By light microscopy of thin sections immunostained with anti-S-100 antibody, Schwann cells were often found on the margin of the islets as if delimiting the islet and exocrine parenchyma. In thick sections, Schwann cells of the islet connected their thin and slender processes with each other to form a delicate network on the surface of the islet. By TEM, Schwann cells were observed as an attenuated sheet that invested the surface of the islet. Axon terminals were usually found on the outer surface of these membranous Schwann cells. SEM of KOH digested tissues revealed that nerves reaching the islet spread on the insular surface. Schwann cells in this portion extended their thin membranous processes, which directly covered the basal part of several endocrine cells as a whole. Numerous axons with varicosities were usually found on the surface of these membranous Schwann cells, but sometimes crept beneath them. These findings indicate that "the interstitial cells" described by light microscopists are peculiar-shaped Schwann cells present in the islets. The functional significance of the rich innervation of the islets is also briefly discussed in the present study.

Thoracic empyema associated with recurrent colon cancer: report of a case and review of the literature.

Many types of infections associated with colorectal cancer have been reported. Here, we describe a rare case of thoracic empyema that was observed during immunotherapy for recurrent colon cancer. Culture of the pleural fluid yielded Streptococcus bovis, which is known to be associated with gastrointestinal lesions, especially colorectal malignancies. The possible correlation between these two clinical entities-empyema and colon cancer-is discussed.

Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow.

Under the physiological shear condition, cultured colon cancer cells bound to laminin (LM), but not to fibronectin or vitronectin. Most of the tethered cells did not roll, but arrested immediately and spread within 10-30 min on LM under the continuous presence of shear flow. The tethering of Colo201 was partially inhibited by monoclonal antibodies (mAbs) to alpha6 integrin and a combination of mAbs to beta1 and beta4 integrins, but not by mAb to 67KD laminin receptor. Some Colo201 cells still tethered at 4 degrees C. This suggests that alpha6beta1 and alpha6beta4 integrins participate in Colo201 tethering on LM, although other non-integrin molecules play roles. In contrast, the spread of Colo201 was effectively inhibited by the mAbs to integrin alpha2, alpha6 and beta1 chains. The effect of anti-alpha2 plus anti-alpha6 mAbs was almost equal to anti-beta1, suggesting that Colo201 cells mainly use alpha2beta1 and alpha6beta1 integrins for spreading on LM. When the cells were perfused on subconfluent endothelial cells (HUVEC) cultured on LM, they did not tether on HUVEC but did on coated LM exposed at intercellular gap area. Immunohistochemistry revealed that LM abundantly existed in the cytosol of human portal and hepatic vein endothelial cells. These data suggest that LM can mediate from tethering to spreading of colon cancer cells under the blood flow and plays an essential role in haematogeneous metastasis.

Bcl-X(L) antisense sensitizes human colon cancer cell line to 5-fluorouracil.

Resistance to 5-fluorouracil (5-FU) has been frequently found in the treatment of digestive tract cancer patients. Our previous study suggested that high expression of endogenous Bcl-X(L), might be associated with resistance to 5-FU in colorectal cancer. The aim of this study is to analyze the role of Bcl-X(L) in 5-FU resistance and to explore a new therapeutic strategy using Bcl-X(L) antisense. First, western blot analysis shows that Bcl-X(L) rather than Bcl-2 is overexpressed in primary adenocarcinoma of colon. Second, when Colo320 cells, with undetectable endogenous Bcl-XL expression, were transfected with Bcl-XL gene, they acquired high resistance to 5-FU. Finally, antisense oligodeoxynucleotides (ODNs) that targeted the start codon of Bcl-X(L) mRNA (AS1) prove to be the most effective in DLD1 cells with high endogenous Bcl-X(L) expression. Bcl-X(L) protein expression was decreased in a dose-dependent manner when the cells were treated with AS1 ODNs, while non-sense and sense controls and 5-FU had no effect on Bcl-X(L) protein. 5-FU treatment induced a level of apoptosis 10-fold higher in DLD1 cells than in untreated control cells, while the same dose of 5-FU induced a 55-fold higher level of apoptosis in DLD1 cells treated with Bcl-XL antisense oligodeoxynucleotides (P = 0.0003). Moreover, AS1 ODNs coupled with 5-FU decreased viable colon cancer cells 40% more than did 5-FU alone (P < 0.05). These results suggest that Bcl-X(L) is an important factor for 5-FU resistance and the suppression of Bcl-X(L) expression by the specific antisense ODNs can increase the sensitivity of colon cancer cells to 5-FU.