Clinical Features, Prognosis, Diagnostic Approaches and Treatment of Multiple Primary Malignancies in the Digestive System.

BACKGROUND/AIM: Additional primary malignancy (APM) risk is increasing with improved prognosis of cancer survivors. In order to clarify risk factors and patients susceptible to develop APMs, we investigated the clinical features, prognosis, and approaches for diagnosis and treatment in these patients. PATIENTS AND METHODS: Among 874 patients newly diagnosed with gastrointestinal tract (GIT) or hepato-biliary-pancreatic (HBP) cancers between 2011 and 2014, 124 with a synchronous and/or metachronous APM were identified. Patient characteristics, time interval between the malignancies, clue to detect APMs, treatment approaches, and prognosis were investigated. RESULTS: Patients with APMs were older and predominantly male. Half of the metachronous APMs were detected within 3 years after the first primary malignancy (PM). The main clue to detect synchronous and metachronous APMs was preoperative screening for current PM, and follow-up of prior PM, respectively. There was no significant difference in the overall survival between colon cancer patients with or without APMs. CONCLUSION: Multiple PMs were present in 14.2% of patients. Male and old age were identified to be risk factors for APM. Pre-operative screening and post-operative regular follow-ups are important for detecting synchronous or metachronous APMs.

Beneficial Effects of Lemon Balm Leaf Extract on In Vitro Glycation of Proteins, Arterial Stiffness, and Skin Elasticity in Healthy Adults.

Glycation, a non-enzymatic glycosylation of proteins, induces tissue damage in association with various diseases and aging phenomena. Pentosidine, an advanced glycation end product, is involved in aging phenomena such as tissue stiffness. In this study, we aimed to find a potent anti-glycation food material and to verify its health benefits by clinical trial. From among 681 hot water plant extracts, lemon balm (Melissa officinalis; LB) leaf extract was selected and revealed to have more potent inhibitory activity for pentosidine formation than a representative anti-glycation agent, aminoguanidine. Rosmarinic acid (RA), a typical polyphenol in Lamiaceae plants, was identified as a major active component in LB extract (LBE). Furthermore, LBE or RA dose-dependently suppressed glycation-associated reactions such as increased fluorescence, yellowing of collagen fiber sheets, and degeneration of the fibrous structure of elastin fiber sheets. An open-label, parallel-group comparative trial was conducted in 28 healthy Japanese subjects aged 31-65 y who consumed LB tea (LB group) or barley tea (Control group) for 6 wk. The LB group showed significant reductions in brachial-ankle pulse wave velocity, reflecting arterial stiffness, and b* (yellow) color values in forearm skin compared with the Control group. A gender-stratified analysis revealed that cheek skin elasticity was significantly improved in the LB group compared with the Control group only in female subjects. It is concluded that the hot water extract of LB leaf has the potential to provide health benefits with regard to glycation-associated tissue damage in blood vessels and skin of healthy adults.

Eosinophilic funiculitis initially diagnosed as irreducible inguinal hernia: A case report.

BACKGROUND: Most groin masses are first suspected to be groin hernias. More than 80% of bulging groin lesions are reportedly diagnosed as hernias by ultrasonography. Establishment of the correct diagnosis of hernia among all differential diagnoses is not easy. We herein describe a very rare case of groin eosinophilic funiculitis that presented as an irreducible groin hernia. CASE PRESENTATION: A 59-year-old man presented to our hospital with suspicion of a right groin hernia. He had a 1-week history of a painful right groin tumor. The tumor was about 4 cm without skin redness or warmth, irreducible even in the supine position, and associated with mild tenderness. Enhanced computed tomography showed that the mass seemed to be connected to the intra-abdominal structures. With time, the patient's pain did not increase, the inflammatory response did not worsen, and no ischemic signs were observed by enhanced computed tomography. Therefore, we diagnosed the tumor as an irreducible but not incarcerated hernia and performed elective surgery. Intraoperative examination revealed no hernia sac, and a 4-×3-cm tumor was observed around the spermatic cord. A malignant tumor was not completely ruled out. High orchiectomy was performed after consultation with the urologists. Pathological examination of the tumor showed no malignant features, and the final diagnosis was eosinophilic funiculitis with massive inflammatory changes and eosinophil invasion. CONCLUSION: Eosinophilic funiculitis is very rare; only three cases have been reported to date. We should always consider unusual causes of groin masses during a surgical approach to hernia-like lesions.

Lactobacillus casei Shirota enhances the preventive efficacy of soymilk in chemically induced breast cancer.

Soy foods are known to be effective for breast cancer prevention. The habitual consumption of soy isoflavones in combination with the probiotic Lactobacillus casei Shirota (LcS) was shown to decrease the risk of breast cancer occurrence in our previous population-based case-controlled study among Japanese women. The present study aimed to elucidate the cooperative prevention mechanism of soymilk and LcS using an animal carcinogenic model. Female Sprague-Dawley rats received a high-fat, AIN-76A diet containing soymilk, LcS, both soymilk and LcS, or none and were orally exposed to 2-amino-1-methyl-6-penylimidazo[4,5-b]pyridine at a dose of 85 mg/kg bodyweight eight times for 2 weeks. The development of palpable mammary tumors was monitored for 17 weeks. Tumor tissues were immunohistochemically examined for estrogen receptor (ER)-α, Ki-67 and CD34. Compared with the control group, the incidence and multiplicity of mammary tumors were reduced by soymilk alone and soymilk in combination with LcS, while tumor volume was decreased by LcS alone and LcS in combination with soymilk. An immunohistochemical analysis revealed that soymilk in combination with LcS more effectively reduced the numbers of ER-α-positive and Ki-67-positive cells in tumors than soymilk alone and that both soymilk and LcS inhibited tumor angiogenesis. These results demonstrated that soymilk prevents the development of mammary tumors and that LcS suppresses tumor growth, potentially enhancing the preventive efficacy of soymilk. The habitual consumption of LcS in combination with soymilk might be a beneficial dietary style for breast cancer prevention.

Active neovascularization and possible vascular-centric development of gastric and periscapular elastofibromas.

An elastofibroma is a benign and rare fibrous lesion that most commonly occurs in the periscapular region. A gastrointestinal elastofibroma is extremely rare. In the present study, six cases of elastofibromas including a case in the stomach were evaluated. The gastric case revealed widely distributed lesions in the submucosal layer with perivascular fibrotic lesions (PVFLs) and some PVFLs were distributed to the skip lesions of elastofibroma. These PVFLs were also observed in all five periscapular cases and invariably contained elastic fibers which showed various degree of maturation. CD34-positive stromal cells were observed not only in elastofibromas but also in PVFLs in each case. These findings suggested the possibility of the PVFLs were the primary lesions of elastofibroma and their vascular-centric development. The percentage of the CD105-positive vessels in elastofibroma group was significantly higher than in the control group. This result indicates active neovascularization in elastofibromas.

Novel regulatory effect of angiotensin II type 1 receptor-interacting molecule on vascular smooth muscle cells.

We have recently cloned a novel molecule that interacts with the angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP). In this study, we tested the hypothesis that ATRAP modulates angiotensin II-induced responses in vascular smooth muscle cells. The results of immunoprecipitation and bioluminescence resonance energy transfer assay demonstrated a direct interaction between ATRAP and AT1R at baseline and showed that angiotensin II enhanced the interaction of these proteins >2-fold. The results of immunofluorescence analysis also demonstrated that >65% of ATRAP constitutively colocalized with an endosome marker. Although only 36% of ATRAP colocalized with AT1R at baseline, angiotensin II enhanced the colocalization of these molecules and made 92% of ATRAP colocalize with AT1R on a quantitative fluorescence analysis. Overexpression of ATRAP by adenoviral transfer decreased the cell surface AT1R number from 4.33 to 2.13 fmol/10(6) cells at baseline and from 3.04 to 1.26 fmol/10(6) cells even after removal of angiotensin II. ATRAP also suppressed angiotensin II-mediated increases in c-fos gene transcription and transforming growth factor-beta production. Furthermore, this suppression was accompanied by inhibition of angiotensin II-induced activation of 5-bromodeoxyuridine incorporation. Finally, ATRAP knockdown by small-interference RNA activated angiotensin II-induced c-fos gene expression, which was effectively inhibited by valsartan, an AT1R-specific antagonist. These results indicate that ATRAP promotes internalization of AT1R and attenuates the angiotensin II-mediated c-fos-transforming growth factor-beta pathway and proliferative response in vascular smooth muscle cells, suggesting a novel strategy to inhibit vascular fibrosis and remodeling through a novel and specific blockade of AT1R signaling.

Expression of MAK-V/Hunk in renal distal tubules and its possible involvement in proliferative suppression.

MAK-V/Hunk is an SNF1-related serine/threonine kinase which was previously shown to be highly expressed in the mammary gland and central nervous system. In this study, we found MAK-V/Hunk is abundantly and specifically expressed in the thick ascending limbs and distal convoluted tubules (DCT) of the kidney from the embryonic stage to the adult stage. We demonstrated that dietary salt depletion significantly enhances renal MAK-V/Hunk mRNA levels compared with a normal-salt diet. To analyze the possible renal cellular function of this kinase, we employed mouse distal convoluted tubule (mDCT) cells. The results of reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that MAK-V/Hunk is expressed endogenously in mDCT cells. Overexpression of MAK-V/Hunk by adenoviral gene transfer significantly inhibited the ANG II-induced stimulation of c-fos gene transcription and suppressed the ANG II-mediated increases in transforming growth factor-beta production into the medium. This phenomenon was accompanied by inhibition of ANG II-induced activation of BrdU incorporation. On the other hand, the MAK-V/Hunk knockdown by siRNA activated the ANG II-induced c-fos gene expression. In the consecutive sections stained for MAK-V/Hunk and AT(1) receptor, MAK-V/Hunk-immunopositive distal tubules expressed the AT(1) receptor. This is the first report on the intrarenal localization of MAK-V/Hunk and its cellular function in renal tubular cells.

The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy.

Activation of angiotensin II (Ang II) type 1 receptor (AT1R) signaling is reported to play an important role in cardiac hypertrophy. We previously cloned a novel molecule interacting with the AT1R, which we named ATRAP (for Ang II type 1 receptor-associated protein). Here, we report that overexpression of ATRAP significantly decreases the number of AT1R on the surface of cardiomyocytes, and also decreases the degree of p38 mitogen-activated protein kinase phosphorylation, the activity of the c-fos promoter and protein synthesis upon Ang II treatment. These results indicate that ATRAP significantly promotes downregulation of the AT1R and further attenuates certain Ang II-mediated hypertrophic responses in cardiomyocytes.

[Recurrence of esophageal cancer treated by combination TS-1/CDDP therapy].

A 68-year-old man underwent subtotal esophagectomy with two fields lymphadenectomy and postoperative chemotherapy so called low dose FP therapy for advanced esophageal cancer (Stage IIIa, pT 3, pN 1, M 0) in October 1999. As he was diagnosed with a recurrence of esophageal cancer as metastatic lymph node tumors which were placed in the right anterocervical and supraclavicular region in March 2001, he underwent enucleation of metastatic lymph node tumors and postoperative chemoradiation therapy, so-called low-dose FP-R therapy. Recently, since other metastatic lymph node tumors in the neck appeared again in August 2001, he underwent radical neck lymph node dissection and postoperative chemoradiation treatment, so-called FAP-R therapy. In October 2003, a chest CT showed multiple lung tumors. He was diagnosed with multiple metastatic lung tumors originating from esophageal cancer. Then, two courses of a combined chemotherapy consisting of TS-1 and CDDP were administered at an interval of one month. We judged the effect of this chemotherapy to be a partial response (PR), because the largest metastatic lung tumor 18 mm in diameter showed a reduction rate of 81.9%, and other tumors had almost disappeared in the chest CT after the combined therapy. No severe adverse effects of more than grade 3 were observed during this combined therapy. This combined chemotherapy consisting of TS-1 and CDDP may prove effective for treating recurrent cases of esophageal cancer.

Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression.

The cAMP-signaling pathway plays a crucial role in the regulation of the renin gene, but the mechanism involved remains poorly understood. We have focused our studies of renin gene regulation on the unique cAMP responsive element (huREN/CNRE, -135 to -107) in the human renin promoter. We have cloned a protein that binds to this unique CNRE and demonstrated that this protein is liver X receptor-alpha (LXRalpha), a transcriptional factor of the nuclear receptor family. Transient expression of LXRalpha in human renin-producing Calu-6 cells increased cAMP inducibility of human renin promoter. Similarly, LXRalpha-stably transfected Calu-6 cells exhibited increased cAMP inducibility of renin promoter as well as the endogenous renin gene. Site-directed mutation of huREN/CNRE, which disrupted LXRalpha binding, decreased cAMP-induced transcriptional activity of human renin promoter. Furthermore, we demonstrated that the binding of LXRalpha derived from human juxtaglomerular cells, the main production site of renin in the kidney, to the huREN/CNRE in vivo. These results suggest that LXRalpha plays an important role in the cAMP-mediated regulation of human renin gene transcription by binding to CNRE.

Acute renal failure due to cholesterol crystal embolism treated with LDL apheresis followed by corticosteroid and candesartan.

Cholesterol crystal embolism (CCE) is caused by the shedding of cholesterol crystals into the bloodstream, and it has been recently recognized as a serious complication after vascular procedures. Our case of CCE, which was diagnosed by skin and renal biopsies, occurred in a patient with hypertension and diabetes mellitus, 3 months after coronary angiography, with the development of renal failure and blue toes. After low-density lipoprotein apheresis (LDL-A), the skin lesions, including livedo reticularis and pain from the acrocyanotic toes, dramatically improved, with partial recovery of renal function. Following the administration of low-dose corticosteroid and candesartan--an angiotensin II type 1 receptor antagonist (ARB)--the eosinophilia disappeared and renal function improved gradually with a decrease in urinary protein excretion. Therefore, a combination therapy of LDL-A, low-dose corticosteroid, and an ARB is a possible treatment for CCE, although the possibility of spontaneous recovery of renal function cannot be eliminated for this patient.