The frequency of early colorectal cancer derived from sessile serrated adenoma/polyps among 1858 serrated polyps from a single institution.

BACKGROUND AND AIM: Sessile serrated adenoma/polyps (SSAPs) are suspected to have a high malignant potential, although few reports have evaluated the incidence of carcinomas derived from SSAPs using the new classification for serrated polyps (SPs). The aim of study was to compare the frequency of cancer coexisting with the various SP subtypes including mixed polyps (MIXs) and conventional adenomas (CADs). METHODS: A total of 18,667 CADs were identified between April 2005 and December 2011, and 1858 SPs (re-classified as SSAP, hyperplastic polyp (HP), traditional serrated adenoma (TSA), or MIX) were removed via snare polypectomy, endoscopic mucosal resection, or endoscopic sub-mucosal dissection. RESULTS: Among 1160 HP lesions, 1 (0.1%) coexisting sub-mucosal invasive carcinoma (T1) was detected. Among 430 SSAP lesions, 3 (0.7%) high-grade dysplasia (HGD/Tis) and 1 (0.2%) T1 were detected. All of the lesions were detected in the proximal colon, with a mean tumor diameter of 18 mm (SD 9 mm). Among 212 TSA lesions, 3 (1%) HGD/Tis were detected but no T1 cancer. Among 56 MIX lesions, 9 (16%) HGD/Tis and 1 (2%) T1 cancers were detected, and among 18,677 CAD lesions, 964 (5%) HGD/Tis and 166 (1%) T1 cancers were identified. CONCLUSIONS: Among the resected lesions that were detected during endoscopic examination, a smaller proportion (1%) of SSAPs harbored HGD or coexisting cancer, compared to CAD or MIX lesions. Therefore, more attention should be paid to accurately identifying lesions endoscopically for intentional resection and the surveillance of each SP subtype.

Endoscopic mucosal resection and endoscopic submucosal dissection for en bloc resection of superficial pharyngeal carcinomas.

BACKGROUND AND STUDY AIM: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are being used increasingly to treat superficial oropharyngeal and hypopharyngeal carcinomas. The aim of this study was to clarify whether ESD provided better results than EMR for en bloc and complete resection of superficial pharyngeal carcinomas. PATIENTS AND METHODS: A total of 76 superficial pharyngeal carcinomas in 59 consecutively treated patients were included. Patients underwent either conventional EMR (using a transparent cap or strip biopsy) (n = 45 lesions) or ESD (n = 31 lesions) between October 2006 and January 2011. The rates of en bloc resection, complete resection (defined as en bloc resection with tumor-free margins), major complications, and local recurrence were evaluated retrospectively as the therapeutic outcomes. RESULTS: ESD yielded significantly higher rates of both en bloc and complete resection compared with EMR (en bloc 77.4 % [24/31] vs. 37.8 % [17/45], P = 0.0002; complete 54.8 % [17/31] vs. 28.9 % [13/45], P = 0.0379). ESD was more frequently complicated by severe laryngeal edema (4/21 [19.0 %] vs. 1/31 [3.2 %], P = 0.1446) and was also more time-consuming (124.9 ± 65.1 minutes vs. 57.2 ± 69.6 minutes; P = 0.0014). Local recurrence was observed more often after EMR than after ESD (3/45 [6.7 %] vs. 0/31 [0 %]), although this difference did not reach statistical significance (P = 0.2658). CONCLUSIONS: ESD appears to be a superior method of endoscopic resection of superficial pharyngeal carcinomas for achieving both en bloc and complete resection, although these benefits were also associated with a higher incidence of complications and a significantly longer procedure time. Large prospective studies are needed to compare ESD with conventional EMR for superficial pharyngeal carcinomas.

Long-term outcomes of endoscopic submucosal dissection for undifferentiated-type early gastric cancer.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) of undifferentiated-type early gastric cancer (UD-EGC) is technically feasible; however, the long-term clinical outcomes of the procedure have not yet been fully investigated. The aim of our study was to elucidate long-term outcomes of ESD for UD-EGC. PATIENTS AND METHODS: Between September 2003 and October 2009, a total of 153 patients were diagnosed endoscopically as having UD-EGC fulfilling the expanded criteria for ESD. After informed consent was obtained, 101 patients were selected to undergo ESD and 52 to undergo surgical operation. We assessed the clinical outcomes of ESD in 101 consecutive patients with 103 UD-EGC lesions who were undergoing ESD for the first time. The overall mortality and disease-free survival rates after ESD were evaluated as the long-term outcomes. RESULTS: The rates of en bloc and curative resection were 99.0% (102/103) and 82.5% (85/103), respectively. We encountered one patient with nodal metastasis detected by computed tomography before diagnostic ESD, although curative resection of the primary lesion was achieved based on routine histological examination. Among the 78 patients without a past history of malignancy within the previous 5 years in whom curative resection of the primary lesion was achieved, no cases of local recurrence or distant metastasis were observed during follow-up; however, 1 synchronous and 2 metachronous lesions were detected in 2 patients (2.6%) after primary ESD. Thus, estimated over a median follow-up period of 40.0 months (range 19-92 months) and 36.0 months (range 9-92 months), the 3-and 5-year overall mortality rates were 1.9% and 3.9%, respectively, and the 3-and 5-year overall disease-free survival rates were both 96.7%. CONCLUSIONS: Although our single-center retrospective study may be considered to be only preliminary, our data indicate that ESD for UD-EGC may yield good long-term outcomes.

The effectiveness of a new multibending scope for endoscopic mucosal resection.

BACKGROUND AND STUDY AIMS: Each year at our institution we have been performing over 100 endoscopic mucosal resections (EMRs) for gastric tumor. However, there are some tumor locations where it is difficult to carry out this procedure, such as the lesser curvature or posterior wall of the gastric body, the cardia, and the lesser curvature of the antrum. To facilitate EMR of tumors in these locations, a multibending scope (the "M-scope", Olympus GIF-2T240M; Olympus Optical, Tokyo, Japan) has been developed, which has two independently curving segments. The aim of this study was to evaluate the effectiveness of this new multibending scope for EMR of gastric tumors. PATIENTS AND METHODS: Using the M-scope, we carried out EMR in 59 patients at the Jikei University Hospital. The lesions were located in the cardia in seven patients, in the gastric body in 30 patients, and in the antrum in 22 patients. The effectiveness of the M-scope was evaluated by experienced endoscopists; a score of 1 was given for very good effectiveness, and a score of 0 was given when there was no notable difference in effectiveness from the conventional scope. Evaluation was done according to the location of the lesions, the method used for EMR, and the tumor diameter. When the score for each item was equivalent to the average overall score for all the procedures or higher, the M-scope was defined as being effective. RESULTS: The overall score for all the procedures was 0.7 +/- 0.4 (average +/- SD) (very good in 43 procedures; no notable difference in 16 procedures). When assessed according to the location of the lesion, the mean effectiveness scores of the M-scope for lesions at the following locations were higher than the average overall score: the lesser curvature of the antrum (0.8 +/- 0.5); the posterior wall of the gastric body (1.0 +/- 0.0); the greater curvature of the gastric body (1.0 +/- 0.0); and the lesser curvature of the gastric body (0.9 +/- 0.4). The results suggested that the M-scope was effective for EMR of gastric tumors at these traditionally difficult locations. With regard to the scores assessed according to the method of EMR, the mean scores were 0.8 +/- 0.4 for the two-channel scope method and 0.9 +/- 0.4 for EMR using an insulated-tip diathermic knife (IT-EMR), again suggesting that the M-scope was effective for EMR by these methods. When evaluated according to tumor size, the score was 0.8 +/- 0.4 when the tumor was 11 mm or greater in diameter, indicating that the M-scope was effective for EMR of large tumors. CONCLUSION: The results of the study suggest that the M-scope is effective for EMR of tumors in the lesser curvature of the antrum, and in the posterior wall, lesser curvature, or greater curvature of the gastric body. With regard to the method of EMR, the M-scope is effective for both the two-channel scope method and IT-EMR. In relation to tumor size, the M-scope is effective for the resection of large tumors.

Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

PURPOSE: The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. METHODS: The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex. RESULTS: Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation. CONCLUSIONS: Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.

Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS).

We have newly synthesized osteotropic diclofenac with bisphosphonic moiety (DIC-BP) based on the concept of Osteotropic Drug Delivery System (ODDS) and investigated its potency of site-specific and controlled delivery of diclofenac to the bone in rats. After intravenous injection into rats, DIC-BP was predominantly distributed in the skeleton. DIC-BP once incorporated in the bone was gradually eliminated (t(1/2)=9.7 days), releasing diclofenac into the bone compartment. As a result, the bone concentration of regenerated diclofenac was apparently constant over 28 days. Furthermore, we evaluated the anti-inflammatory effects of DIC-BP compared with diclofenac (sodium salt) in adjuvant-induced arthritic rats. The mean effective doses (ED(50)) were 0.55 mg/kg and 1.3 mg/kg for daily oral administration of diclofenac and weekly intravenous injection of DIC-BP, respectively. Considering the frequency of medication of 17 times for diclofenac and 4 times for DIC-BP in the experimental period, ED(50) was corrected to 9.4 and 5.2 mg/kg (per experimental period) for diclofenac and DIC-BP, respectively. Moreover, DIC-BP exhibited no side effects of gastrointestinal damage, typical of non-steroidal anti-inflammatory drugs. Thus, ODDS of diclofenac shows promise as an approach for highly potent and non-toxic therapy of diclofenac, with less frequent medication.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I.v. effects of osteotropic estradiol on bone mineral density and uterine weight in ovariectomized rats.

An osteotropic drug delivery system (ODDS) based on the bisphosphonic prodrug was designed for 17beta-estradiol (E2) in order to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The bisphosphonic prodrug of E2, disodium [17beta-(3 '-hydroxy- 1',3',5'-estratrienyloxy) carbonylpropyl carboxamidomethylene] bisphosphonate (E2-BP) was synthesized and its effects on bone mineral density and uterine weight were investigated in ovariectomized (OVX) rats. E2-BP was injected intravenously once a week (4 injections/experiment), and E2 was administrated orally 5 times a week (20 administrations/experiment). Once a week treatment with 0.1 mg/kg E2-BP significantly restored bone mineral reduction by 61.8% without significantly increasing uterine weight. Similarly, once in 4 weeks treatment with 1.0 mg/kg E2-BP (1 injection/experiment) showed almost the same therapeutic effects. On the other hand, 5 times a week oral treatment with 1.0 mg/kg E2 significantly improved bone mineral density by 90.5%, but increased uterine weight up to 98.2% of that of the sham group. In vitro bone resorption analysis revealed that E2-BP exhibits antiresorptive activity not as a bisphosphonate but as a prodrug of E2. These results demonstrated that E2-BP has the potential to improve patient compliance in estrogen therapy by its minimal adverse effects and less frequent medication.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. V. Biological disposition and targeting characteristics of osteotropic estradiol.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17 beta-estradiol (E2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E2, disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized rats. After intravenous injection, E2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5 d. The bone concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E2 in the bone and plasma after injection of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E2. As compared with the conventional estrogenic products, E2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.

Physicochemical characterization of bisphosphonic carboxyfluorescein for osteotropic drug delivery.

Disodium (fluorescein-6-carbonyloxy)acetoaminomethylene bisphosphonate (CF-BP), a prodrug of 6-carboxy-fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug-delivery system based on this bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF-BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein. In the binding study, CF-BP bound very rapidly to hydroxyapatite without degradation and carboxyfluorescein was subsequently gradually released by hydrolysis of bound CF-BP. Hydrolysis of CF-BP in buffer solutions followed pseudo-first-order kinetics, and quantitative regeneration of carboxyfluorescein was observed. In addition, regeneration of carboxyfluorescein from CF-BP was accelerated in the presence of fresh rat plasma. These results suggest that CF-BP has the physicochemical properties required for site-specific and controlled delivery of carboxyfluorescein to bones.

[Endoscopic treatment of gastrointestinal cancers--indication and limitation].

Recently, endoscopic treatments have been applied for the curative treatment of early gastrointestinal cancers and for the palliative treatment of end-stage gastrointestinal cancers. As a curative treatment for early gastric cancers, the endoscopic Nd-YAG laser therapy was initially applied and a satisfactory results were obtained. However, the endoscopic mucosal resection (EMR) is evaluated as the reliable endoscopic treatment for early gastric cancers because curability can be histologically detected by resected specimen. EMR technique is also applied for early esophageal cancers and early flat or depressed colon cancers. EMR-L (EMR with the use of Ligating device) developed by us is mainly practiced in our department. By the use of EMR-L technique. Resectability has been improved compared with 2 channel EMR technique. As the palliation of end-stage gastrointestinal cancers endoscopy recanalization of malignant esophageal stenosis is very effective to improve the patient's QOL. The memorial metallic stent for esophageal stenosis is very useful to keep cavity for a long term after endoscopic recanalization. PEG (percutaneous endoscopic gastrostomy) is also very effective to reduce the symptoms of the patients with peritonitis carcinoma or ileus. In this paper, the present status of curative and palliative endoscopic treatment for gastrointestinal cancers was reported. In recent future, endoscopy will be more widely applied as a less invasive therapeutic procedure for gastrointestinal cancers.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: Pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I: synthesis and in vivo characterization of osteotropic carboxyfluorescein.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisphosphonic promoiety to the mineral component, hydroxyapatite, a bisphosphonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carboxyfluorescein (CF) as a model compound and the disposition after intravenous injection was studied in rats. The bisphosphonic prodrug of CF, disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. The microscopic observation showed that CF-BP was buried into the bone with a calcification of the bone. According to the remodeling of the bone, bisphosphonic prodrug buried was supposed to be released in the vicinity of the osteoclast or resorption surface of the bone. Thus, it is suggested that ODDS has a potential to achieve osteoclast-specific or resorption surface-specific targeting of the drugs.

Healing of chronic gastric ulcer depends on gastric mucosal prostaglandin synthesis.

In the present study, the role of endogenous prostanoid synthesis in gastric mucosa in the healing of chronic gastric ulcers was investigated. Nineteen patients were divided into two groups in accordance with healing state after one month of treatment with cimetidine only: "healed group" and "unhealed group". Biopsy specimens taken from the mucosa around the ulceration (damaged gastric mucosa) and at a distance from the ulceration (normal gastric mucosa) at endoscopy prior to treatment were homogenized, and the mucosal prostanoid synthesis was determined using [14C]arachidonic acid. The mean value of prostaglandin E2 synthesis in the normal gastric mucosa of the healed group was 60% higher than in that of the unhealed group, but the difference was not significant. However, prostaglandin E2 synthesis in the damaged gastric mucosa of the healed group was 117% higher than in that of the unhealed group. The same tendency was observed for prostaglandin D2 and 6-keto prostaglandin F1 alpha synthesis as for prostaglandin E2. In our study it was demonstrated that there is a good correlation of prostaglandin synthesis in the damaged mucosa with healing of chronic gastric ulceration. Furthermore, our study indicated that prostaglandin synthesis, especially in damaged mucosa, might be important in the healing of gastric ulceration.

The anti-platelet actions of FR122047, a novel cyclooxygenase inhibitor.

The anti-platelet actions of 1-[(4,5-bis(4-methoxyphenyl)-2- thiazoyl)carbonyl]-4-methylpiperazine hydrochloride (FR122047) were investigated in vitro and in vivo. FR122047 was 100 times more potent than aspirin against arachidonic acid- and collagen-induced human and guinea-pig platelet aggregation in vitro. Its actions on platelets were a result of cyclooxygenase inhibition. The single oral dose of FR122047 inhibited arachidonic acid- and collagen-induced aggregation with an ED50 of 280 micrograms/kg and 530 micrograms/kg, respectively, in guinea-pigs. The anti-platelet action was augmented 5-10 times by repeated administration for 4 days. At 1 mg/kg the inhibitory actions were prolonged for 48 h and the drug concentration was < 0.1 ng/ml in platelet-poor plasma at 24 h and 0.282 ng/ml in platelet-rich plasma at 48 h. The safety margin in rats (minimum ulcerogenic dose/ED50 for anti-platelet aggregation) of FR122047 was more than 70, while that of aspirin was only 1.2. These results indicate that FR122047 is concentrated in platelets and may be a useful anti-platelet agent.

Expression of cytokeratin subtypes in colorectal mucosa, adenoma, and carcinoma.

The distribution pattern of cytokeratin (CK) subtypes, an intermediate filament of cytoskeleton, was examined in adenomas and carcinomas of the colon and rectum. For the detection of the cytokeratin subtypes, monoclonal antibodies to the 54 Kd keratin polypeptide (CK No. 7 according to Moll's classification), 52.5 Kd (CK No. 8), 45 Kd (CK No. 18), and 40 Kd (CK No. 19) were used for immunohistochemical observation. Although No. 7 was positive in normal mucosa and adenoma with mild to moderate atypia, it could not be recognized in carcinoma. On the other hand the expression of No. 18 was confirmed in carcinoma, adenoma, and normal mucosa, and there were some differences in its distribution pattern in those with or without glandular formation and in areas showing infiltration of tumor cells. No. 18 expression was on the luminal side of normal colonic mucosa, adenoma, and well-differentiated adenocarcinoma; in the infiltrating area its reactivity was localized diffusely in the cytoplasm of tumor cells showing moderately or poorly differentiated adenocarcinoma cells. As to No. 8 and No. 19, they were recognized in normal mucosa, adenoma, and carcinoma. These results suggested the intimate relationship between expression of CK subtypes, cellular differentiation, and structural differentiation of colorectal carcinoma.