A case of coexistent poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), usual-type adenocarcinoma, and squamous cell carcinoma in situ of the cervix.

Poorly differentiated adenosquamous carcinoma (glassy cell carcinoma) of the cervix is extremely rare, accounting for 1-2% of all cervical cancers. Herein, we report a case with coexistent poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), "usual-type" adenocarcinoma, and squamous cell carcinoma in situ of the cervix. A female patient in her 60 s was referred to our hospital and diagnosed with poorly differentiated adenosquamous carcinoma based on cervical cytology and biopsy. The tumor was classified as clinical stage IB1 cervical cancer following magnetic resonance imaging; radical hysterectomy was performed. Histopathological examination revealed poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), usual-type adenocarcinoma, and squamous cell carcinoma in situ, all coexisting. All carcinoma regions showed identical sizes to high-risk human papillomavirus (HPV) in fragment analysis. The patient is currently alive, without evidence of recurrence, 31 months post surgery. In this case, three different carcinomas coexisted. Fragment analysis of the patient's HPV status suggested that all carcinomas were related to an infection with the same high-risk HPV type. To determine the precise mechanism of tumor development, i.e., whether the tumors were of the mixed or collision type, further studies are needed, including clonal analysis for the loss of heterozygosity pattern.

A Collaborative Study on the Classification of Silicone Oil Droplets and Protein Particles Using Flow Imaging Method.

In this study, we conducted a collaborative study on the classification between silicone oil droplets and protein particles detected using the flow imaging (FI) method toward proposing a standardized classifier/model. We compared four approaches, including a classification filter composed of particle characteristic parameters, principal component analysis, decision tree, and convolutional neural network in the performance of the developed classifier/model. Finally, the points to be considered were summarized for measurement using the FI method, and for establishing the classifier/model using machine learning to differentiate silicone oil droplets and protein particles.

Photometric Screening of Tetrabromobisphenol A in Resin Using Iron(III) Nitrate/Hexacyanoferrate(III) Mixture as a Colorimetric Reagent.

This study aims to provide a simple way to identify the possibility of tetrabromobisphenol A (TBBPA) present in polymers without the need for complicated separation with expensive equipment. Since the presence of phenolic hydroxyl groups is known to be identifiable by the reduction of Fe3+ to Fe2+ in a ferric coloring reagent, the possibility of TBBPA being present in a polymer can be screened by a photometric measurement. A mixed solution of iron(III) nitrate and potassium hexacyanide(III) acid was used as a ferric coloring reagent. With this method, the concentration of TBBPA can be estimated from the photometric absorbance corresponding to the depth of the blue color produced by reduction of the ferric reagent in the presence of Fe(NO3)3. The limit of detection (LOD) was determined to be approximately 2 mg/kg using the Student's t-test (99% confidence), and a reproducibility of approximately 3% was determined by the relative standard deviation (RSD) from measurements of calibration samples (n = 7). Furthermore, TBBPA in actual polymer samples was screened without the need for any complex processing steps. Because this colorimetric method measures TBBPA by detecting phenolic groups, it may overestimate the TBBPA concentration in the presence of other similar phenolic substances. Nonetheless, this simple colorimetric method should help to quickly identify the presence of TBBPA in various polymers.

Roles of ERCP in the Early Diagnosis of Pancreatic Cancer.

It has been reported that endoscopic retrograde cholangiopancreatography (ERCP) is of value in evaluating precise pancreatograms of the pancreatic duct (PD). Recently, institutions have tended to perform magnetic resonance cholangiopancreatography (MRCP) for the diagnosis of PD due to post-ERCP pancreatitis (PEP). In small pancreatic cancer (PC), including PC in situ (PCIS) which is undetectable on cross sectional images, endoscopic ultrasonography (EUS) and MRCP serve important roles in detecting local irregular stenosis of the PD or small cystic lesions. Subsequently, ERCP and associated serial pancreatic juice aspiration cytologic examination (SPACE) obtained by endoscopic nasopancreatic drainage (ENPD) may be useful in the diagnosis of very early-stage PC. Further prospective multicenter studies are required to establish a standard method of SPACE for the early diagnosis of PC.

Associations Between Plasma Betatrophin Levels and Coronary and Peripheral Artery Disease.

AIM: Betatrophin, a recently identified circulating adipokine, affects lipid and glucose metabolism. However, association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated. METHODS: We investigated plasma betatrophin levels in 457 patients undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening. RESULTS: Of the 457 study patients, CAD was present in 241 patients (53%) (1-vessel [1-VD], n=99; 2-vessel [2-VD], n=71; 3-vessel disease [3-VD], n=71). Compared to 216 patients without CAD, 241 with CAD had higher betatrophin levels (median 1120 vs. 909 pg/mL, p＜0.001). A stepwise increase in betatrophin levels was found depending on the number of ＞50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD, and 1393 pg/ml in 3-VD (p＜0.001). Betatrophin levels correlated with the number of ＞25% stenotic segments (r=0.24, p＜0.001). PAD (ABI＜0.9) was found in 41 patients (9%). Plasma betatrophin levels were also significantly higher in 41 patients with PAD than in 416 without PAD (1354 vs. 981 pg/mL, p＜0.001). In the multivariate analysis, betatrophin levels were not a factor for CAD, but they were a significant factor for 3-VD and PAD independent of atherosclerotic risk factors. The odds ratios for 3-VD and PAD were 1.06 (95%CI=1.01-1.11) and 1.07 (95%CI=1.01-1.13) for a 100-pg/mL increase in betatrophin levels, respectively (p＜0.05). CONCLUSION: Plasma betatrophin levels were associated with the presence and severity of CAD and PAD, suggesting betatrophin has a role in atherosclerosis.

Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate.

Here we examine the mechanisms by which nanoparticles enable the oral absorption of water-insoluble, P-glycoprotein efflux pump (P-gp) substrates, without recourse to P-gp inhibitors. Both 200nm paclitaxel N-(2-phenoxyacetyl)-6-O-glycolchitosan (GCPh) nanoparticles (GCPh-PTX) and a simulated Taxol formulation, facilitate drug dissolution in biorelevant media, unlike paclitaxel nanocrystals. Verapamil (40mgkg-1) increased the oral absorption from low dose Taxol (6 or 10mgkg-1) by 100%, whereas the oral absorption from high dose Taxol (20mgkg-1) or low dose GCPh-PTX (6 or 10mgkg-1) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20mgkg-1). Imaging of ex-vivo rat ileum samples showed that fluorescently labelled GCPh nanoparticles are mucoadhesive and are taken up by ileum epithelial cells. GCPh nanoparticles were also found to open Caco-2 cell tight junctions. In conclusion, mucoadhesive, drug solubilising GCPh nanoparticles enable the oral absorption of paclitaxel via the saturation of the P-gp pump (by high local drug concentrations) and by particle uptake and tight junction opening mechanisms.

[Induction chemotherapy with S-1/oxaliplatin prevented colostomy in a patient with advanced rectal cancer].

A 72-year-old woman was admitted to our hospital with bloody stools and constipation. She was diagnosed with advanced lower rectal cancer with multiple liver and pulmonary metastases. Because the rectal cancer was located 2 cm from the anal verge, we suggested she undergo an abdominoperineal resection(Miles operation), but she refused to undergo a colostomy. Then, 6 courses of chemotherapy with S-1/oxaliplatin(SOX)were administered, and the local tumor, liver metastases, and pulmonary metastases were all significantly decreased in size(reduction rate 60%). After chemotherapy, she chose to undergo low anterior resection(LAR), D2. Postoperative recovery was uneventful, and she currently has stable disease with adjuvant SOX chemotherapy. Induction SOX chemotherapy was considered to be useful for maintaining the quality of life(QOL) in a patient with advanced rectal cancer.

Candida-associated gastric ulcer relapsing in a different position with a different appearance.

An 87-year-old, Japanese woman was shown to have a submucosal tumor-like lesion with a deep, central ulceration covered with thick, whitish exudate in the stomach. Biopsy showed Candida tropicalis but not Helicobacter pylori (H. pylori). She had no predisposing factors or history of peptic ulcers nor had taken non-steroidal anti-inflammatory drugs (NSAIDs), diagnosed with Candida-associated gastric ulcer. Though cured of the lesion, she developed another ulcer in a different position, in which Candida was demonstrated but H. pylori was undetectable. This is the first case of recurrent Candida-associated gastric ulcer in the world. Detected in both the original and recurrent lesions in an H. pylori-negative patient with no antecedent ulcers who had not taken NSAIDs, Candida is considered, contrary to the prevailing opinion, to play an etiologic role in ulcer formation.

Inhibition of tumor growth by antibody to ADAMTS1 in mouse xenografts of breast cancer.

BACKGROUND: A disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS1), a member of the ADAMTS family of proteases, is involved in the shedding of epidermal growth factor (EGF)-like ligands such as amphiregulin, which activate the EGF receptor. Since ADAMTS1 has been implicated in aggressive breast carcinogenesis, we examined potential antitumor effects of antibody to ADAMTS1 in a mouse model of breast cancer. MATERIALS AND METHODS: BALB/c female mice were inoculated with syngenic 4T1 breast cancer cells and treated with anti-ADAMTS1 antibody or control IgG. Tumor volume and weight were evaluated. RESULTS: Mouse 4T1 cells expressed ADAMTS1 and its substrates amphiregulin and heparin-binding EGF. Treatment with antibody to ADAMTS1 inhibited tumor growth without any adverse effects. CONCLUSION: ADAMTS1 could be a promising molecular target for immunotherapy of breast cancer.

Predicting solvent stability in aprotic electrolyte Li-air batteries: nucleophilic substitution by the superoxide anion radical (O2(•-)).

There is increasing evidence that cyclic and linear carbonates, commonly used solvents in Li ion battery electrolytes, are unstable in the presence of superoxide and thus are not suitable for use in rechargeable Li-air batteries employing aprotic electrolytes. A detailed understanding of related decomposition mechanisms provides an important basis for the selection and design of stable electrolyte materials. In this article, we use density functional theory calculations with a Poisson-Boltzmann continuum solvent model to investigate the reactivity of several classes of aprotic solvents in nucleophilic substitution reactions with superoxide. We find that nucleophilic attack by O(2)(•-) at the O-alkyl carbon is a common mechanism of decomposition of organic carbonates, sulfonates, aliphatic carboxylic esters, lactones, phosphinates, phosphonates, phosphates, and sulfones. In contrast, nucleophilic reactions of O(2)(•-) with phenol esters of carboxylic acids and O-alkyl fluorinated aliphatic lactones proceed via attack at the carbonyl carbon. Chemical functionalities stable against nucleophilic substitution by superoxide include N-alkyl substituted amides, lactams, nitriles, and ethers. The results establish that solvent reactivity is strongly related to the basicity of the organic anion displaced in the reaction with superoxide. Theoretical calculations are complemented by cyclic voltammetry to study the electrochemical reversibility of the O(2)/O(2)(•-) couple containing tetrabutylammonium salt and GCMS measurements to monitor solvent stability in the presence of KO(2)(•) and a Li salt. These experimental methods provide efficient means for qualitatively screening solvent stability in Li-air batteries. A clear correlation between the computational and experimental results is established. The combination of theoretical and experimental techniques provides a powerful means for identifying and designing stable solvents for rechargeable Li-air batteries.

Fingertip amputation salvage on arterial anastomosis alone: an investigation of its limitations.

BACKGROUND: We have previously reported the importance of adequate and precise arterial anastomosis and the hypothesis that, up to subzone III, fingertip amputation salvage can be achieved on arterial anastomosis alone. These findings were reported during the meeting of the Japanese Society of Reconstructive Microsurgery. This is our follow-up report with insight and opinion on the limitations of complete fingertip amputation salvage on arterial anastomosis alone. METHODS: We examined 67 fingers (59 patients) with fingertip amputations presenting to our hospital between January 2005 and December 2008. Amputation levels and whether these injuries received only arterial or both arterial and venous anastomoses were noted. Fisher exact test was used to examine statistical differences between the groups. RESULTS: Amputation levels were 11 in subzone I, 20 in subzone II, 17 in subzone III, and 19 in subzone IV. Successful replantation was achieved in 87% (58 of 67) of fingers. There was no statistically significant difference between fingers receiving arterial alone versus both anastomoses in amputations of subzones I, II, and III. CONCLUSIONS: We found that with proper postoperative congestion care, no statistically significant difference in replantation success of fingers receiving arterial anastomosis alone versus both arterial and venous were noted up to subzone III. However, in subzone IV, regardless of the postoperative congestion, compete necrosis rates are high; thus, it is speculated that a venous anastomosis is necessary for successful replantation. It is preferable to perform as many anastomoses as possible, but we believe that it is also desirable for the procedure to be fast and less invasive. In cases that have no adequate vein, fingertip replantation can be achieved on arterial anastomosis alone up to subzone III.

Unilateral developments of osteoarthritis and Charcot's joint in a patient with neurofibromatosis.

BACKGROUND: Precise mechanism of developing neuropathic arthropathy known as Charcot's joint is not fully understood. CASE REPORT: A 55-year-old Japanese woman with neurofibromatosis-1 complained of right gonalgia in December 2001. Physical examination revealed a huge tumor in the right lower leg without signs of inflammation. Laboratory findings were unremarkable. Radiographic examination disclosed the presence of osteoarthropathy in the right knee joint. In contrast, radiologic findings of the right foot and ankle were compatible with neuropathic arthropathy. Further investigations could not reveal abnormal findings in the nervous system. To improve patient's quality of life, partial resection of the tumor was performed. The resected tissues were compatible with neurofibromatosis without malignant transformation. The patient newly noticed pains in the right ankle and tarsal joints one year after the operation. Restricted mobility and insufficient blood supply in the right knee arising from the huge tumor might accelerate development of osteoarthropathy through malnutrition of the chondrocytes. Because the patient did not experience the arthralgia before the operation, the tumor might damage the peripheral nerves unabling to receive afferent signals from such joints resulting in neuropathic arthropathy. CONCLUSIONS: The damaged peripheral nerves might be contributory to developing or accelerating neuropathic arthropathy.

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity.

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum.

Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains.

The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist).

Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXRalpha-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6 a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7 a) and 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7 c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7 a) was found to be the first RXRalpha/beta-selective (or RXRalpha/beta-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7 a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.

Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRalpha-preferential agonist possessing a sulfonamide moiety.

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (8 a) was found to prefer RXRalpha over RXRbeta and RXRgamma, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

Proton pump inhibitors relieve and prevent symptoms related to gastric acidity after esophagectomy.

BACKGROUND: Denervated stomach used as an esophageal substitute after esophagectomy often retains or spontaneously recovers acid production. The aims of the present study were to assess the relationship between esophageal acid exposure or gastric acidity and reflux-related symptoms after esophagectomy, and to assess the ability of proton pump inhibitors (PPIs) to relieve gastroesophageal reflux-related symptoms. METHODS: Forty-four patients underwent esophageal and gastric 24-h pH monitoring early after esophagectomy with gastric reconstruction. Initially, patients with both gastric acidity and reflux symptoms were treated with PPIs (Treatment group), then all patients with gastric acidity, whether symptomatic or not, were treated (Prevention group). Reflux-related symptoms were correlated with esophageal acid exposure and postoperative gastric acidity. Gastric acidity was then correlated with serum anti-Helicobacter pylori immunoglobulin G (IgG) titers and preoperative endoscopic findings RESULTS: Sixteen patients (36.4%) reporting reflux and showing gastric acid production were treated with PPIs, which provided relief to 13 (81.3%). Although symptoms did not correlate with the esophageal acid exposure, postoperative gastric acidity was significantly greater among patients who were symptomatic than among those who were not. Overall, acid production was lower in older patients (>64 years of age), although older patients who were H. pylori-negative and without chronic atrophic gastritis also showed high levels of gastric acidity. CONCLUSIONS: Proton pump inhibitors should be administered prophylactically early after esophagectomy to relieve and prevent reflux-related symptoms. Candidates for preventive therapy include those less than 64 years of age or older patients who are H. pylori-negative and without chronic atrophic gastritis.

The treatment dilemma caused by lumps in surfers' chins.

This is an account of 2 male surfing enthusiasts who recently sought care at our hospital after developing tumorous masses on their chins. Although the lesions appeared grossly benign, establishing a definitive treatment plan was perplexing because of the insidious nature of the protuberances. The lesion in the first patient was managed surgically. The approach was modified for the second patient because of information learned from the first. While the technical aspects of care management were simple, once the histologic structure of the tumor was defined, establishing an accurate clinical diagnosis before surgery was troublesome. The histologic findings for the lesion removed from the first patient consisted of primarily parenchymal fibrosis without concomitant structural abnormalities in overlying epidermis, suggesting that repetitive blunt trauma to the chin area while paddling the surfboard was probably the factor responsible for the pathogenesis of tumor formation. These findings and our experience in managing the 2 patients have formed the basis of this report.