Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). PATIENTS AND METHODS: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. RESULTS: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m2, range 15.8-39.9 vs 22.4 kg/m2, range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms. CONCLUSION: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Risk factors for joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Endocrine treatment-related adverse events have a strong impact on patients' quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side effect of aromatase inhibitors, evaluation of associated risk factors may yield significant findings. PATIENTS AND METHODS: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers for assessment of patient-reported outcomes (PROs) in this prospective cohort study (SAVS-JP, UMIN000002455). Patients completed the self-report questionnaire at baseline and after 3, 6, 9, and 12 months of treatment for evaluation of frequency of treatment-related joint symptoms (arthralgia, decrease in range of joint motion, and joint stiffness). RESULTS: We obtained PROs from 362 patients (92.6 %) at baseline and at one or more subsequent points. New or worsening from baseline of joint symptoms were reported by 260 patients (71.8 %). More than 90 % of the symptoms were mild or moderate and nearly 80 % had occurred by 6 months. Multivariate analysis showed that a short time span after menopause [odds ratio (OR) 0.95, 95 % confidence interval (CI) 0.90-0.99; P = 0.02] and adjuvant chemotherapy (OR 2.29, 95 % CI 1.06-4.95; P = 0.03) were significant independent risk factors for joint symptoms. No significant relationships between body mass index (BMI) and joint symptoms were identified. Eighteen patients discontinued treatment during the 1st year and eight of them reported joint symptoms. CONCLUSION: Taking into consideration that PROs may yield higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials, we found that a short time span after menopause and use of adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These findings might prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors in postmenopausal Japanese women.

Transport mechanisms for soy isoflavones and microbial metabolites dihydrogenistein and dihydrodaidzein across monolayers and membranes.

Isoflavone data concerning the metabolism and permeability on intestinal epithelial cells are scarce, particularly for microbial isoflavone metabolites. This study evaluates the absorption mechanisms for the isoflavones, genistein and daidzein, and their microbial metabolites, dihydrogenistein (DHG) and dihydrodaidzein (DHD). The permeability characteristics of isoflavones were compared by using the Caco-2 human colon adenocarcinoma cell line for a parallel artificial membrane permeability assay, and comparing their physicochemical properties. The data suggest that genistein, DHG and DHD were efficiently transported by passive diffusion according to the pH-partition hypothesis. Genistein was conjugated by phase II metabolizing enzymes and acted as a substrate of the breast cancer resistance protein (BCRP). Daidzein was not conjugated but did act as a substrate for BCRP, multidrug resistance-associated proteins, and P-glycoprotein. In contrast, DHG and DHD were markedly more permeable than their parent isoflavones; they were therefore difficult to transport by the efflux effect, and glucuronidation/sulfation was limited by the flux time.

Primary culture of breast cancer: a model system for epithelial-mesenchymal transition and cancer stem cells.

BACKGROUND: A novel model system to study the cellular, molecular, and genetic characteristics of breast cancer stem cells is needed. Personalized prognostic models are indispensable for assessing the effect of so-called tailor-made adjuvant therapy. MATERIALS AND METHODS: Surgically-extirpated tissues were dispersed with Dispase and cultured in commonly used medium. The expression of tumor markers was detected with immunohistochemistry, and gene expression profiles of tissues and cells were analyzed using the Agilent Human Microarray. RESULTS: We established a primary culture, which exhibited mesenchymal morphology. The gene expression profile of the primary culture revealed that the cells underwent epithelial-mesenchymal transition and had cancer stem cell properties. CONCLUSION: A primary culture of breast cancer cells can be easily established and could be used for studying breast cancer stem cells and assessing treatment of a patient.

MyD88 associated ROS generation is crucial for Lactobacillus induced IL-12 production in macrophage.

It is well known that some strains of lactic acid bacteria (LAB) can induce IL-12 which plays an important role in modulating immune responses. However, the mechanisms by which LAB induce IL-12 production remain unclear. Here, we examine the role of toll-like receptors (TLR's) and reactive oxygen species (ROS) in IL-12 production by LAB stimulated peritoneal macrophages. Our results indicate that a TLR is not necessary for IL-12 induction by LAB, whilst the universal adaptor protein, MyD88, is essential. Specific strains of LAB induced ROS that correlated with both the frequency of phagocytosis and IL-12 production. Reduction in IL-12 production by NADPH oxidase inhibitors or ROS scavengers demonstrates the crucial role of ROS in IL-12 induction. Interestingly, deficiency of TLR2, 4, 9 or MyD88 did not affect the phagocytosis of LAB strain KW3110, a potent IL-12 inducer, and ROS production was significantly reduced only in MyD88 deficient macrophages. These results suggest the existence of TLR-MyD88 independent LAB recognition and MyD88 related ROS induction mechanisms. We show here the importance of ROS for IL-12 induction and provide new insights into IL-12 induction by LAB.

Transport mechanisms of flavanone aglycones across Caco-2 cell monolayers and artificial PAMPA membranes.

OBJECTIVES: We recently reported that flavanone aglycones (hesperetin, naringenin and eriodictyol) are efficiently absorbed via proton-coupled active transport, in addition to transcellular passive diffusion, in Caco-2 cells. Here, we aimed to evaluate in detail the absorption mechanisms of these flavanones, as well as homoeriodictyol and sakuranetin. METHODS: We evaluated the absorption mechanisms of the above compounds by means of in vitro studies in Caco-2 cells in parallel with an artificial membrane permeation assay (PAMPA) under pH-gradient and iso-pH conditions. KEY FINDINGS: Comparison of the permeability characteristics of flavanones in Caco-2 cells and in PAMPA under these conditions, as well as a consideration of the physicochemical properties, indicated that hesperetin, naringenin, eriodictyol and homoeriodictyol were efficiently transported by passive diffusion according to the pH-partition hypothesis, except in the case of sakuranetin. However, transport of all flavanones were remarkably temperature-dependent, and was significantly reduced when Caco-2 cells were treated with amino acid-modifying reagents. CONCLUSIONS: Our data confirm that both passive diffusion and an active transport mechanism contribute to flavanone absorption through human intestinal epithelium.

Orally administered Lactobacillus paracasei KW3110 induces in vivo IL-12 production.

Lactic acid bacteria (LAB) are popularly used as probiotics, and some strains of LAB have anti-allergic functions in vivo. Although in vitro studies show that LAB modulate the T helper type (Th) 1/Th2 balance and inhibit IgE secretion by inducing IL-12, it is not known how LAB regulates allergies in vivo. In this study, we evaluated in vivo IL-12 production after oral administration of Lactobacillus paracasei KW3110, a strain reported to improve allergies, to mice. Orally administered KW3110 interacted with CD11b positive cells and induced IL-12 mRNA expression at Peyer's patch. In addition, blood IL-12 levels increased transiently 10 h after administration of KW3110. Based on these results, we found that oral administration of KW3110 induces IL-12 in vivo. Our findings should contribute to understanding of the in vivo function of LAB.

High-performance liquid chromatographic purification of oligomeric procyanidins, trimers up to nonamers, derived from the bark of Jatoba (Hymenaea courbaril).

Procyanidin oligomers with different degrees of polymerization (up to nonamers) were efficiently purified from the bark of Jatoba (Hymenaea courbaril) by using a recently developed chromatographic separation method. Purification relied on a hydrogen bonding interaction between phenolic hydroxyl groups of the procyanidins and polyethylene glycol (PEG)-coated resin in a packed column. The individual procyanidins were identified by using electrospray ionization mass spectrometry (ESI-MS) and verified by a thiolytic degradation analysis. Our results demonstrate that Jatoba bark contained a large amount of procyanidins from monomer to nonamers or higher polymers composed of only B-type linked units (flavan-3-ol units linked through C-4 to C-8 (or C-6)) of epicatechin (EC) without gallate esters.

Transepithelial transport of flavanone in intestinal Caco-2 cell monolayers.

Our recent study [S. Kobayashi, S. Tanabe, M. Sugiyama, Y. Konishi, Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers, Biochim. Biophys. Acta, 1778 (2008) 33-41] shows that the mechanism of absorption of hesperetin involves both proton-coupled active transport and transcellular passive diffusion. Here, as well as analyzing the cell permeability of hesperetin, we also study the transport of other flavanones, naringenin and eriodictyol, using Caco-2 cell monolayers. Similar to hesperetin mentioned, naringenin and eriodictyol showed proton-coupled polarized transport in apical-to-basolateral direction in non-saturable manner, constant permeation in the apical-to-basolateral direction (J(ap-->bl)) irrespective of the transepithelial electrical resistance (TER), and preferable distribution into the basolateral side after apical loading in the presence of a proton gradient. Furthermore, the proton-coupled J(ap-->bl) of hesperetin, naringenin and eriodictyol, were inhibited by substrates of the monocarboxylic acid transporter (MCT), such as benzoic acid, but not by ferulic acid. In contrast, both benzoic and ferulic acids have no stimulatory effect on J(ap-->bl) of each flavanone by trans-stimulation analysis. These results indicates that proton-driven active transport is commonly participated in the absorption of flavanone in general, and that its transport is presumed to be unique other than MCT-mediated transport for absorption of phenolic acids (PAs), sodium-dependent MCT (SMCT) nor anion exchanger-mediated transport.

Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers.

The cell permeability of hesperetin and hesperidin, anti-allergic compounds from citrus fruits, was measured using Caco-2 monolayers. In the presence of a proton gradient, hesperetin permeated cells in the apical-to-basolateral direction at the rate (Jap-->bl) of 10.43+/-0.78 nmol/min/mg protein, which was more than 400-fold higher than that of hesperidin (0.023+/-0.008 nmol/min/mg protein). The transepithelial flux of hesperidin, both in the presence or absence of a proton gradient, was nearly the same and was inversely correlated with the transepithelial electrical resistance (TER), indicating that the transport of hesperidin was mainly via paracellular diffusion. In contrast, the transepithelial flux of hesperetin was almost constant irrespective of the TER. Apically loaded NaN3 or carbonyl cyanide m-chlorophenylhydrazone (CCCP) decreased the Jap-->bl of hesperetin, in the presence of proton gradient, by one-half. In the absence of a proton gradient, both Jap-->bl and Jbl-->ap of hesperetin were almost the same (5.75+/-0.40 and 5.16+/-0.73 nmol/min/mg protein). Jbl-->ap of hesperetin in the presence of a proton gradient was lower than Jbl-->ap in the absence of a proton gradient. Furthermore, Jbl-->ap in the presence of a proton gradient remarkably increased upon addition of NaN3 specifically to the apical side. These results indicate that hesperetin is absorbed by transcellular transport, which occurs mainly via proton-coupled active transport, and passive diffusion. Thus, hesperetin is efficiently absorbed from the intestine, whereas hesperidin is poorly transported via the paracellular pathway and its transport is highly dependent on conversion to hesperetin via the hydrolytic action of microflora. We have given novel insight to the absorption characteristics of hesperetin, that is proton-coupled and energy-dependent polarized transport.

MyD88 but not TLR2, 4 or 9 is essential for IL-12 induction by lactic acid bacteria.

Although lactic acid bacteria (LAB) affect the immune system, for example, having an anti-allergic effect, little is known about the actual mechanisms of immune modulation. Toll-like receptors (TLRs) recognize conserved microbial molecular patterns, and are presumed to be involved in the recognition of LAB. However, there are few detailed reports examining the relationships between TLR and LAB. We measured here production of IL-12, a cytokine considered to play an important role in anti-allergic effects, induced by Lactobacillus paracasei strain KW3110 and other typical LAB by cells from TLR2-, TLR4-, TLR9- and myeloid differentiation factor 88 (MyD88)-deficient mice. Unexpectedly, similar cytokine production from wild-type and TLR2-, 4- and 9-deficient mice was observed. In contrast, cells from MyD88-deficient mice failed to respond to stimulation with LAB. It is therefore concluded that although LAB, including strain KW3110, are not likely to be recognized by TLR2, 4 or 9, MyD88 is essential for the response to these bacteria.

Angiosarcoma of the breast - specific findings of MRI.

We present a case of low-grade angiosarcoma of the breast. A 26-year old woman presented with a lump in the left breast. An elastic hard and ill-defined tumor, 80 x 50 mm in size, was palpated in the upper region of her left breast. Mammography showed a dense lesion with poorly defined border. Ultrasonography showed a hyper-and hypo-echoic lesion with an unclear border, but no definite tumor. Fine needle aspiration cytology showed no evidence of malignancy. Therefore, she was followed with a diagnosis of mastopathy. Six months later, the lump got enlarged. A contrast-enhanced MRI of the breast was performed. It showed a 100 x 60 mm enhancing vascular mass. Most parts of the tumor enhanced remarkably at the early phase, and prolonged enhancement was recognized at the late phase. Core needle biopsy was performed, and a possible angiosarcoma was diagnosed. It is not easy to diagnose the mammary angiosarcoma. MRI may contribute to the accurate diagnosis and play an important role regarding this entity.

Phenolic acids are absorbed from the rat stomach with different absorption rates.

The intestinal absorption characteristics of phenolic acids (PAs) have been elucidated in terms of their affinity for the monocarboxylic acid transporter (MCT). Recently, the involvement of the stomach has been implicated in the absorption of polyphenols. The present work demonstrates that the gastric absorption efficiency of each PA is apparently different between various PAs. Various PAs with different affinities for MCT were administered (2.25 mumol) to rat stomach, and then the plasma concentration of the PA was measured. The plasma concentration of ferulic acid (FA) peaked 5 min after administration in the stomach. At 5 min after administration, the plasma concentration of each PA increased in the order: gallic acid = chlorogenic acid < caffeic acid < p-coumaric acid = FA. This order matches their respective affinity for MCT in Caco-2 cells, which we have demonstrated in previous studies. These results indicated that MCT might be involved in the gastric absorption of PAs, similar to the intestinal absorption.

Non-involvement of the human monocarboxylic acid transporter 1 (MCT1) in the transport of phenolic acid.

Phenolic acids such as p-coumaric acid and microbial metabolites of poorly absorbed polyphenols are absorbed by the monocarboxylic acid transporter (MCT)-mediated transport system which is identical to the fluorescein/H(+) cotransport system. We focus here on the physiological impact of MCT-mediated absorption and distribution. We examined whether MCT1, the best-characterized isoform found in almost all tissues, is involved in this MCT-mediated transport system. The induction of MCT1 expression in Caco-2 cells by a treatment with sodium butyrate (NaBut) did not increase the fluorescein permeability. Moreover, the transfection of Caco-2 cells with an expression vector encoding MCT1 caused no increase in either the permeability or uptake of fluorescein. Furthermore, in the MCT1-expressing oocytes, no increase of p-coumaric acid uptake was apparent, whereas the uptake of salicylic acid, a substrate of MCT1, nearly doubled. Our data therefore establish that MCT1 was not involved in the MCT-mediated transport of phenolic acids.

Absorption and bioavailability of artepillin C in rats after oral administration.

Artepillin C (AC), an active ingredient of Brazilian propolis, permeates intact across Caco-2 cells by transcellular passive diffusion. The permeation of AC across Caco-2 cells is as efficient as that of phenolic acids and the microbial metabolites of poorly absorbed polyphenols, which are actively absorbed by the monocarboxylic acid transporter (MCT) (Biochim. Biophys. Acta 2005, 1713, 138-144). Here, the absorption of orally administered AC in rats has been studied to evaluate its pharmacokinetics and bioavailability in vivo in comparison with those of p-coumaric acid (CA), a substrate of MCT. Rats were given 100 micromol/kg of body weight of AC or CA, and blood was subsequently collected from the portal vein and abdominal artery. AC, CA, and their metabolites were quantified by coulometric detection using HPLC-ECD. The serum concentration of intact AC and CA in the portal vein peaked at 5-10 min after administration, with a C(max) of 19.7 micromol/L for AC and 74.8 micromol/L for CA. The area under the curve (AUC) for intact AC and CA in the portal vein was calculated from the serum concentration as 182.6 and 3057.3 micromol.min.L(-1), respectively. The absorption efficiency of CA was about 17-fold higher than that of AC. Furthermore, the bioavailability of CA was about 278-fold higher than that of AC, and the ratio of AUC in the abdominal artery to AUC in the portal vein was 0.04 and 0.70, for AC and CA, respectively. Thus, AC is likely to be more susceptible to hepatic elimination than is CA. The bioactive compound of AC in vivo should be investigated further.

Transepithelial transport of artepillin C in intestinal Caco-2 cell monolayers.

The absorption characteristics of artepillin C (AC), an active ingredient of Brazilian propolis, were examined by measuring permeation across Caco-2 cell monolayers. The permeation rate in the basolateral-to-apical direction, J(bl-->ap), in the presence of proton gradient was 0.14 nmol/min/mg protein, whereas J(bl-->ap) in the absence of proton gradient was 1.14 nmol/min/mg protein. The latter value is nearly the same as the permeation rate in the apical-to-basolateral direction, J(ap-->bl), both in the presence and absence of proton gradient. In the presence of proton gradient, J(ap-->bl) was almost constant, irrespective of NaN(3) or benzoic acid. However, J(bl-->ap) dramatically increased upon the addition of NaN(3) or benzoic acid specifically to the apical side. In both the presence and absence of proton gradient, J(ap-->bl) also appeared to be constant irrespective of the paracellular permeability of Caco-2 cells. After AC was loaded apically in the presence of proton gradient, the intracellular AC increased with time. This accumulation was inhibited by apically loaded NaN(3). These indicate that AC transport occurs mainly via transcellular passive diffusion, although a considerable amount of AC was taken up intracellularly by monocarboxylic acid transporter (MCT) on the apical side and not transported out across the basolateral membrane, suggesting that different subtypes of MCT are involved.

Pharmacokinetic study of caffeic and rosmarinic acids in rats after oral administration.

p-Coumaric and ferulic acid are actively taken up by monocarboxylic acid transporter (MCT), whereas gallic acid, caffeic acid (CA), and rosmarinic acid (RA) are absorbed by paracellular diffusion in human intestinal Caco-2 cells, although CA has low affinity for MCT. We previously demonstrated that p-coumaric acid has a much higher absorption efficiency than gallic acid in rats, owing to the MCT-mediated absorption of p-coumaric acid in vivo (J. Agric. Food Chem. 2004, 52, 2527-2532). Here, absorption of orally administered CA and RA in rats has been studied to investigate their intestinal absorption characteristics and pharmacokinetics in vivo and to compare the results with those of p-coumaric and gallic acids obtained under identical conditions. Rats were given 100 micromol/kg body weight of CA and RA, and blood was collected from the portal vein and abdominal artery after administration. CA, RA, and their metabolites were quantified by a coulometric detection method using HPLC-ECD. The serum concentration of intact CA and RA in the portal vein peaked at 10 min after administration, with a C(max) of 11.24 micromol/L for CA and 1.36 micromol/L for RA. The area under the curve (AUC) for intact CA and RA in the portal vein was calculated from the serum concentration-time profile to be 585.0 and 60.4 micromol min L-1, respectively. The absorption efficiency of CA was about 9.7-fold higher than that of RA. Overall, the absorption efficiency of these compounds in vivo increases in the order: gallic acid = RA < CA < p-coumaric acid, which is in good agreement with results obtained in Caco-2 cells in vitro.

Transepithelial transport of rosmarinic acid in intestinal Caco-2 cell monolayers.

The absorption characteristics of rosmarinic acid (RA) were examined by measuring permeation across Caco-2 cell monolayers using an HPLC-electrochemical detector (ECD) fitted with a coulometric detection system. RA exhibited nonsaturable transport even at 30 mM, and the permeation at 5 mM in the apical-to-basolateral direction, J(ap-->bl), was 0.13 nmol/min/mg of protein. This permeation rate is nearly the same as that of 5 mM chlorogenic acid (CLA) and gallic acid, which are paracellularly transported compounds. Almost all of the apically loaded RA was retained on the apical side, and J(ap-->bl) was inversely correlated with paracellular permeability. These results indicate that RA transport was mainly via paracelluar diffusion, and the intestinal absorption efficiency of RA was low. Furthermore, RA appeared to be unsusceptible to hydrolysis by mucosa esterase in Caco-2 cells. These results, together with our previous work (J. Agric. Food Chem., 52, 2518-2526 (2004), J. Agric. Food Chem., 52, 6418-6424 (2004)) suggest that the majority of RA is further metabolized and degraded into m-coumaric and hydroxylated phenylpropionic acids by gut microflora, which are then efficiently absorbed and distributed by the monocarboxylic acid transporter (MCT) within the body. The potential of orally administered RA in vivo will be further investigated.

Transepithelial transport of microbial metabolites of quercetin in intestinal Caco-2 cell monolayers.

m-Hydroxyphenylacetic acid (mHPA), 3,4-dihydroxyphenylacetic acid (DHPA), and 4-hydroxy-3-methoxyphenylacetic acid (HMPA) are major microbial metabolites of quercetin. After administration of quercetin to human subjects, these metabolites are readily detected in blood and urine. mHPA, DHPA, and HMPA are thought to exert protective biological activity within the body due to their antioxidant properties. However, very little work has been published concerning their absorption. I have examined the absorption characteristics of the quercetin metabolites in Caco-2 cells by a coulometric detection method using HPLC-ECD. All of them exhibited nonsaturable transport in Caco-2 cells up to 30 mM, whereas HMPA and mHPA also showed proton-coupled polarized absorption. The proton-coupled directional transport of HMPA and mHPA was inhibited by the substrate of the monocarboxylic acid transporter (MCT). A considerable amount of apically loaded HMPA and mHPA was taken up and transported through to the basolateral side, while almost all of the apically loaded DHPA was retained on the apical side. Furthermore, the transepithelial flux of DHPA was inversely correlated with the paracellular permeability of Caco-2 cells, although those of HMPA and mHPA were almost constant. These results indicate that transport of DHPA was mainly via paracellular diffusion, although HMPA and mHPA were absorbed to some extent by the MCT.

Isolated right ventricular metastasis of uterine cervical carcinoma.

Isolated direct metastasis of uterine cervical carcinoma to the right ventricular endocardium is very rare. A 68-year-old woman was initially diagnosed as having stage IIIb squamous cell carcinoma of the uterine cervix, and was treated with radiation therapy. After 2 years, she developed heart failure and presented with a mass in the right ventricle. The results of further examinations were consistent with a tumor or a thrombus in the right ventricle. She underwent excision of the mass under cardiopulmonary bypass, and histopathologic examination of the resected tissue revealed metastatic squamous cell carcinoma of the uterine cervix. She was discharged 3 weeks after the operation, and underwent chemotherapy. However, she was readmitted with drug-induced interstitial pneumonia and died 5 months after the surgery. Patients with an intracardiac mass and a history of uterine cervical cancer should be suspected of having a myocardial metastasis until it is proven otherwise.