Tsuyoshi Tachibana

Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas.

Purpose: Human invariant natural killer T (NKT) cells are novel, distinct lymphocyte populations with a restricted T-cell receptor repertoire (Vα24-Vβ11). They play a pivotal role in immunoregulation and in antitumor activities. This study focused on Vα24+ NKT cells in colorectal carcinomas and their clinicopathologic significance. Experimental Design: Vα24+ NKT-cell infiltration immunohistochemistry was studied in a total of 103 colorectal carcinoma cases. The degree of NKT-cell infiltration in tumors was evaluated as low (<7 NKT cells/5 HPF) or high (≥7 NKT cells/5 HPF). The correlation between the degree of infiltrated Vα24+ NKT cells and clinicopathologic variables was studied statistically. Results: A small number of Vα24+ NKT cells were found in the normal colorectal mucosa (2.6 ± 3.7 cells/5 HPF); however, their number increased remarkably in colorectal carcinomas (15.2 ± 16.3 cells/5 HPF; P = 0.0003) and a majority showed phenotype of activation. Higher NKT-cell infiltration was more frequent in women than in men (P = 0.034) and correlated with fewer lymph node metastases (P = 0.042). Patients with high NKT-cell infiltration showed higher overall (P = 0.018) as well as disease-free (P = 0.0006) survival rates. Intratumor NKT-cell infiltration was an independent prognostic factor for the overall (P = 0.033) and disease-free (P = 0.0064) survival rates. Conclusions: Increased infiltration of Vα24+ NKT cells was observed in colorectal carcinomas. Higher Vα24+ NKT-cell infiltration in colorectal carcinomas was an independent prognostic factor for favorable prognosis.

Absence of Smooth Muscle Actin-Positive Pericyte Coverage of Tumor Vessels Correlates with Hematogenous Metastasis and Prognosis of Colorectal Cancer Patients

Objectives: Immature microvessels, which are not covered by pericytes, are irregular and leaky. We hypothesized that tumor cells can penetrate immature microvessels more easily than mature microvessels. In this study, we investigated the maturation of angiogenesis by the immunohistochemical staining of colorectal cancer specimens and determined the correlation between the microvessel count or the maturity of microvessels and clinicopathological variables. Methods: Ninety-two surgical specimens from our department were used. Double immunostaining of endothelial cells with anti-CD34 antibody and pericytes with anti-α-smooth muscle actin antibody was performed. The microvessel density (MVD) and microvessel pericyte coverage index (MPI) as an index of microvessel maturation were evaluated. Results: The MVD showed a significant positive correlation with tumor size, depth of invasion and Dukes’ stage. The MPI showed a significant positive correlation with the histological differentiation of the tumor tissues and distant metastasis at the time of operation. The high MVD group (≧26.0, n = 50) tended to have a poorer prognosis than the low MVD group (<26.0, n = 42) (p = 0.097). Next, the 50 patients in the high MVD group were classified into two subgroups of high MPI (≧78.1%, n = 25) and low MPI (<78.1%, n = 25). MPI showed a significant negative correlation with hematogenous metastasis, and the low MPI group demonstrated a significantly poorer survival than the high MPI group (p = 0.040). Conclusions: These findings demonstrate that immature neovascularization was observed in poorly differentiated tumors and was correlated with metastasis, resulting in a poorer prognosis. Taken together, not only microvessel density but also vascular maturation were crucial factors for colorectal cancer patients.

Reappraisal of Surgical Treatment for Radiation Enteritis

Although radiation enteritis is a well-recognized sequel of therapeutic irradiation, the standard surgical method is not universally agreed upon. Not only the short-term effect but also the long-term effect after a surgical intervention has been fairly well reported. To reassess the surgical therapy for radiation enteritis, we retrospectively analyzed 48 patients (5 males and 43 females, mean age 58.6 years) who had been operated on in our department. These patients were divided into two types according to the time of surgery or the clinical manifestation, and operative methods were analyzed. Patient’s status such as bowel movement, body weight, and serum albumin value after surgery were analyzed, together with the patients survival. Our surgical methods were small intestinal resection for the intestinal obstruction, and pull-through reconstruction for proctitis. Two patients died of multiple organ failure caused by perforated peritonitis irrespective of emergent operation. Although the overall morbidity was 21.7%, there was no leakage when bowels were anastomosed. Overall survival after radiation-related complication in patients without previous neoplastic disease recurrence was 89%, 79%, and 69%, at 1, 3, and 5 years after surgery, respectively. Bowel motility, serum albumin level, and body weight recovered gradually soon after the operation and reached satisfactory levels within 6 months. Our analysis showed that small bowel injury should be treated by generous resection of the affected bowel followed by careful anastomosis of the disease-free ends, while rectal resection is best dealt with by restorative proctectomy. This may provide a good quality of life and minimize major postoperative complications such as leakage.

Brain metastasis from colorectal cancer

PurposeThe mechanism of brain metastasis is not well understood, but the affinity between cancer cells and neural tissues may be involved in the process. The aim of our study is to elucidate the involvement of neural cell adhesion molecule (NCAM) and therapeutic parameters in patients with brain metastasis from colorectal cancer.MethodsWe retrospectively identified 17 patients with brain metastasis from colorectal cancer. Data were collected with regard to patients’ characteristics, location, and stage of primary tumor, and extent and location of metastatic disease. NCAM histochemical staining was undertaken using a paraffin block, and compared with 56 Dukes C patients and 13 Dukes D patients.ResultsNeural cell adhesion molecule expression was significantly higher in the primary tumors of the brain metastasis patients than in the lesions of the Dukes C and Dukes D control groups (p=0.0004). Patients whose tumor was managed by radiosurgery survived longer than patients who had had whole brain radiation or those who had been left untreated.ConclusionThe fact that NCAM expression was high in the primary tumors of brain metastasis patients suggests that the affinity of cancer cells to a particular organ is important for circulation-mediated metastasis. Controlling local tumors using radiosurgery is certainly going to play an important role in extending survival and improving the patient’s quality of life (QOL).

Peroxynitrite-mediated stress is associated with proliferation of human metastatic colorectal carcinoma in the liver.

3-Nitrotyrosine (3-NT), a product of peroxynitrite reaction, is abundantly observed in hepatocytes adjacent to human metastatic colorectal carcinoma. To elucidate its biological significance, we undertook to identify nitric oxide (NO)-producing cells and apoptosis under oxidative stress. We observed strong inducible NO-synthase (iNOS) immunoreactivity in the hepatocytes adjacent to metastatic tumor, revealing an identical pattern to 3-NT immunostaining. Furthermore, intense 3-NT immunostaining of hepatocytes was associated with apoptosis whereas carcinoma cells near those hepatocytes presented high proliferating-cell nuclear antigen. Our results suggest that contact of metastatic tumor induces apoptosis in adjacent hepatocytes through peroxynitrite, thus permitting the proliferation of cancer cells.

Vascular endothelial growth factor reduces mural cell coverage of endothelial cells and induces sprouting rather than luminal division in an HT1080 tumour angiogenesis model.

Vascular endothelial growth factor (VEGF) plays a central role in tumour angiogenesis. In a mouse intramuscular tumour model using VEGF‐transfected HT1080 human fibrosarcoma, we investigated the morphological features and patterns of remodelling in size‐matched tumours. Compared with the control tumours (C group), the VEGF‐transfected tumours (V group) showed vigorous neovascularization with larger vessels. Fenestrations and disruptions of endothelia were specific to the V group. Three types of vascular remodelling, i.e. sprouting, luminal division and intussusceptive microvascular growth, were present in both groups. Morphometric analyses revealed that mural cell coverage of the endothelial cells was significantly smaller in the V group compared with that in the C group (V group, 28.2 ± 18.6%; C group, 41.6 ± 21.1%; P < 0.0001). To determine the prevalence of remodelling patterns, the occurrences of abluminal and luminal processes on endothelial cell surfaces were quantified. Abluminal processes are defined as cytoplasmic protrusions of the abluminal membrane of endothelial cells, which can vary from tiny spurs to solid sprouts of the cell. On the other hand, luminal processes are defined as intraluminal protrusions of the endothelial cell membrane, including various membranous changes from filiform processes to rather thick cytoplasmic bulges. An abluminal process is thought to represent an initial morphological change in sprouting type angiogenesis, and a luminal process to be a sign of implementation of luminal division. The frequency of abluminal processes was significantly higher in the V group than in the C group (V group, 0.243 ± 0.138/µm; C group, 0.114 ± 0.101/µm; P < 0.0001). In contrast, the number of luminal processes on the endothelial cells per micrometre was statistically comparable between the groups (V group, 0.285 ± 0.252/µm; C group, 0.309 ± 0.236/µm, P = 0.381). These results indicate that sprouting is the main mode of VEGF‐induced tumour angiogenesis.

The administration of naked plasmid DNA into the liver induces antitumor innate immunity in a murine liver metastasis model.

Gene therapy is a promising strategy against advanced cancer; however, the safety of viral vectors and the effectiveness of non‐viral vectors have not yet been established. Recently, a hydrodynamics‐based procedure was reported to be an effective and safe method to deliver and transduce DNA into the liver. Herein, we propose a strategy for liver metastasis by a hydrodynamics‐based procedure to deliver naked non‐coding plasmid DNA (pDNA) into the liver as an immunocompetent organ.

What We Can Learn from Cases of Synchronous Acute Mesenteric Obstruction and Nonocclusive Mesenteric Ischemia: How to Reduce the Acute Mesenteric Ischemia-Related Mortality Rate.

Although the survival rate of patients with ischemic heart disease has recently increased, it remains unknown why the mortality rate of acute mesenteric ischemia (AMI) remains high. Here, we report a possible method of improving the survival rate of patients with AMI obtained through 2 cases of simultaneous acute mesenteric obstruction (AMO) and nonocclusive mesenteric ischemia (NOMI). Case 1 was a 74-year-old woman with atrial fibrillation, hypertension, and dyslipidemia as underlying diseases who developed NOMI immediately after undergoing SMA thrombolysis. Case 2 was a 69-year-old man with atrial fibrillation, hypertension, chronic heart failure, chronic renal failure, and old myocardial infarction who was diagnosed with SMA occlusion complicated by NOMI on the basis of abdominal angiography findings during the first visit. Cure was achieved by thrombolytic therapy, resection of the necrotic intestine, and continuous intra-arterial and/or intravenous injection of prostaglandin E1 (PGE1) in case 1 and by resection of the necrotic intestine and continuous intra-arterial and/or intravenous injection of PGE1 in case 2. AMO and NOMI have many background similarities (e.g., atherosclerosis, hypertension, and ischemic heart disease), making their coexistence very likely. However, no case of AMO plus NOMI has been reported until now. It is highly probable that concomitant NOMI is overlooked in cases of AMO. When managing AMO, NOMI should be considered as a complication, which may lower the patients potential risk of developing NOMI and contribute to improved prognosis of both AMO and AMI.