Differential mucin phenotypes and their significance in a variation of colorectal carcinoma

AIM: To investigate mucin expression profiles in colorectal carcinoma (CRC) histological subtypes with regard to clinicopathologic variables and prognosis. METHODS: Mucin (MUC)2 and MUC5AC expressions were assessed by immunohistochemistry for a total of 250 CRC cases that underwent surgical resection. CRCs included 63 well-to-moderately differentiated adenocar-cinomas (WMDAs), 91 poorly differentiated adenocarcinomas (PDAs), 81 mucinous adenocarcinoma (MUAs), and 15 signet-ring cell carcinomas (SRCCs). MUC2 and MUC5AC were scored as positive when ≥ 25% and ≥ 1% of cancer cells were stained positive, respectively. The human mutL homolog 1 and human mutS homolog 2 expressions were assessed by immunohistochemistry in PDAs to investigate mismatch-repair (MMR) status.Tumors that did not express either of these two were considered MMR-deficient. Results were analyzed for associations with clinicopathologic variables and the prognosis in individual histological CRC subtypes. RESULTS: MUC2-positive and MUC5AC-positive WMDA percentages were 49.2% and 30.2%, respectively. In contrast, MUC2-positive and MUC5AC-positive PDA percentages were 9.5% and 51.6%, respectively. MUC2 levels tended to decrease and MUC5AC levels tended to increase from WMDA to PDA. In 21 tumors comprising both adenoma and adenocarcinoma components in a single tumor (4 WMDAs, 7 PDAs, and 10 MUAs), MUC2 was significantly downregulated in PDA and MUC5AC was downregulated in PDA and MUA in the adenoma-carcinoma sequence. These results suggested that MUC2 levels might be associated with malignant potential and that MUC5AC expression was an early event in tumorigenesis. Despite worse prognoses than WMDA, high MUC2 expression levels were maintained in MUA (95.1%) and SRCC (71.5%), which suggested a pathogenesis for these subtypes distinct from that of WMDA. No significant associations were found between MUC2 expression and any clinicopathologic variables in any histological subtype. MUC5AC expression in PDA was closely associated with right-sided location (P = 0.017), absence of nodal metastasis (P = 0.010), low tumor node metastasis stage (P = 0.010), and MMR deficiency (P = 0.003). MUC2 expression in WMDA was a marginal prognostic factor for recurrence/metastasis-free survival (RFS) by univariate Cox analysis (P = 0.077) but not by multivariate Cox analysis (P = 0.161). MUC5AC expression in PDA was a significant prognostic factor for RFS by univariate Cox analysis (P = 0.007) but not by multivariate Cox analysis (P = 0.104). Kaplan-Meier curves and log-rank tests revealed that MUC2 expression was marginally associated with a better WMDA prognosis [P = 0.064 for RFS and P = 0.172 for overall survival (OS)] but not for PDA. In contrast, MUC5AC expression was significantly and marginally associated with a better PDA prognosis in terms of RFS and OS, respectively(P = 0.004 for RFS and P = 0.100 for OS), but not for WMDA and MUA. CONCLUSION: Mucin core protein expression profiles and clinical significance differ according to histological CRC subtypes. This may reflect different pathogeneses for these tumors.

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved and serum Hepatitis B virus(HBV)-DNA level became undetectable.Three years after the start of additional adefovir treatment,hepatocellular carcinoma (HCC)was detected and the patient underwent a successful hepa-tectomy.Our findings suggest tha-t the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis,but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis,allowing HCC surgery.

Shear wave elastography in hepatitis C patients before and after antiviral therapy

AIM To investigate shear wave(SW) propagation velocity in patients with untreated hepatitis C and patients with sustained virological response(SVR). METHODS A total of 136 hepatitis C patients [85 patients who had not received antiviral therapy(na?ve group) and 51 patients who had received antiviral therapy and subsequently achieved SVR of at least 24 wk(SVR group)] and 58 healthy volunteers and outpatients without liver disease(control group) underwent evaluation of liver stiffness by SW elastography(SWE). Various parameters were evaluated in the chronic hepatitis C patients at the time of SWE.RESULTS SW propagation velocity(Vs) was 1.23 ± 0.14 m/s in the control group, 1.56 ± 0.32 m/s in the SVR group, and 1.69 ± 0.31 m/s in the na?ve group. Significant differences were seen between the control group and the SVR group(P = 0.0000) and between the SVR group and the na?ve group(P = 0.01417). All four fibrosis markers were higher in the na?ve group than in the SVR group. In the na?ve group, Vs was positively correlated with alanine aminotransferase(ALT)(r = 0.5372), α feto protein(AFP)(r = 0.4389), type Ⅳ collagen(r = 0.5883), procollagen Ⅲ peptide(P-Ⅲ-P)(r = 0.4140), hyaluronic acid(r = 0.4551), and Mac-2 binding protein glycosylation isomer(M2BPGi)(r = 0.6092) and negatively correlated with albumin(r =-0.4289), platelets(r =-0.5372), and prothrombinactivity(r =-0.5235). On multiple regression analysis, Vs was the most strongly correlated with ALT(standard partial regression std β = 0.4039, P = 0.00000). In the SVR group, Vs was positively correlated with AFP(r = 0.6977), type IV collagen(r = 0.5228), P-Ⅲ-P(r = 0.5812), hyaluronic acid(r = 0.5189), and M2BPGi(r = 0.6251) and negatively correlated with albumin(r =-0.4283), platelets(r =-0.4842), and prothrombin activity(r =-0.4771). On multiple regression analysis, Vs was strongly correlated with AFP(standard partial regression std β = 0.5953, P = 0.00000) and M2BPGi(standard partial regression std β = 0.2969, P = 0.03363).CONCLUSION In hepatitis C patients, liver stiffness is higher in treatment-na?ve patients than in those showing SVR. SWE may be a predictor of hepatocarcinogenesis in SVR patients.

Role of bile acid sequestrants in the treatment of type 2 diabetes

Cholestyramine is a first-generation bile acid sequestrant(BAS) and antihyperlipidemic agent that currentl y has limited use because of its relatively weak effect on lowering low density-lipoprotein(LDL)-chol es terol(C) and poor tolerability.The current first choice drugs for hyper-LDL-cholesterolemia are 3-hy droxy-3-me t hyl-glutaryl coenzyme A reductase inhibitors(statins) because of their strong LDL-C lowering effects and efficacy in prevention of card io vascular disease.Howe ver,after lowering the target levels of LDL-C in very high risk patients,combination therapy with statins and other antihyper lipidemic drugs may become more important for treatment of hyper-LDL-cholesterolemia.Second-generation BASs such as coles evelam and colestimide have a glucose-lowering effect and improved tolerance,which has led to re-evaluation of their utility in combination with statins or antidiabetic agents.

Pulmonary artery sarcoma successfully treated by right pneumonectomy after definitive diagnosis

Pulmonary artery sarcoma(PAS)is a rare and lethal neoplasm that is usually diagnosed during surgery or autopsy.Early diagnosis and radical surgical resection offer the only chance for survival.However,making a preoperative histopathological diagnosis is quite difficult.We encountered a 57-year-old woman presenting a PAS that mimicked a pulmonary thromboembolism.After confirming a definitive diagnosis using a catheter suction biopsy,we successfully performed a right pneumonectomy via a median sternotomy without cardiopulmonary bypass.Eighteen months after surgery,no recurrence was observed.

Effect of proton pump inhibitors on glycemic control in patients with diabetes

Gastrin is a linear peptide hormone which is secreted mostly in the stomach pyloric antrum G cells. Although the main role of this hormone is the promotion of the secretion of gastric acid from the stomach parietal cells, gastrin can also behave as a growth factor and stimulate gastric cell proliferation. It is also reported that gastrin promotes β cell neogenesis in the pancreatic ductal complex, modest pancreatic β cell replication, and improvement of glucose tolerance in animal models, in which the remodeling of pancreatic tissues is promoted. These findings suggest the possibility that gastrin has the potential to promote an increase of β cell mass in pancreas, and therefore that gastrin may improve glucose tolerance. Proton pump inhibitors(PPIs) are wildly used clinically for the therapy of gastro-esophageal reflex disease, gastritis due to excess stomach acid, and gastric ulcers. PPIs indirectly elevate serum gastrin levels via a negative feedback effect. Recent evidence has revealed the beneficial effect of PPIs on glycemic control especially in patients with type 2 diabetes mellitus(T2DM), probably via the elevation of the levels of serum gastrin, although the detailed mechanism remains unclear. In addition, the beneficial effects of a combination therapy of gastrin or a PPI with a glucagon-like peptide-1 receptor agonist on glycemic control in animal models have been demonstrated. Although PPIs may be possible candidates for a new approach in the therapy of diabetes, a prospective, longterm, randomized, double-blind, placebo-controlled study is needed to establish the effect of PPIs on glycemic control in a large number of patients with T2 DM.

Post-colonoscopy colorectal cancer rate in the era of highdefinition colonoscopy

AIM To investigate the post-colonoscopy colorectal cancer(PCCRC) rate for high-definition(HD) colonoscopy compared with that for standard-definition colonoscopy reported previously.METHODS Using medical records at Sano Hospital(SH) and Dokkyo Medical University Koshigaya Hospital(DMUKH), we retrospectively obtained data on consecutive patients diagnosed as having CRC between January 2010 andDecember 2015. The definition of PCCRC was diagnosis of CRC between 7 and 36 mo after initial high-definition colonoscopy that had detected no cancer, and patients were divided into a PCCRC group and a non-PCCRC group. The primary outcome was the rate of PCCRC for HD colonoscopy. The secondary outcomes were factors associated with PCCRC and possible reason for occurrence of early and advanced PCCRC.RESULTS Among 892 CRC patients, 11 were diagnosed as having PCCRC and 881 had non-PCCRC. The PCCRC rate was 1.7%(8/471) at SH and 0.7%(3/421) at DMUKH. In comparison with the non-PCCRC group, the PCCRC group had a significantly higher preponderance of smaller tumors(39 mm vs 19 mm, P = 0.002), a shallower invasion depth(T1 rate, 25.4% vs 63.6%, P = 0.01), a non-polypoid macroscopic appearance(39.0% vs 85.7%, P = 0.02) and an earlier stage(59.7% vs 90.9%, P = 0.03). Possible reasons for PCCRC were "missed or new" in 9 patients(82%), "incomplete resection" in 1(9%), and "inadequate examination'" in 1(9%). Among 9 "missed or new" PCCRC, the leading cause was non-polypoid shape for early PCCRC and blinded location for advanced PCCRC.CONCLUSION The PCCRC rate for HD colonoscopy was 0.7%-1.7%, being lower than that for standard-definition colonoscopy(1.8%-9.0%) reported previously employing the same methodology.

Intragastric surgery using laparoscopy and oral endoscopy for gastric submucosal tumors

We review the techniques and outcomes of the intragastric resection for gastric submucosal tumors(GSTs) using laparoscope and oral endoscope. In the literature, the mean operation time, intraoperative blood loss, pathological size of the tumor and postoperative hospital stay were 134 min, minimal, 31 mm and 6.4 d, respectively. There were no particular perioperative complications during the follow-up period(mean: 121.3 mo). Intragastric surgery using laparoscopy and oral endoscopy can be considerably beneficial for patients with GSTs locating in the upper third of the stomach between 2-5 cm in diameter and < 8 cm2 in crosssectional area and located in the upper third of the stomach.

Infertility in men with inflammatory bowel disease

Inflammatory bowel disease(IBD) predominantly affects young adults. Fertility-related issues are therefore im-portant in the m-anagem-ent of patients with IBD. However, relatively m-odest attention has been paid to reproductive issues faced by m-en with IBD. To investigate the effects of IBD and its treatm-ent on m-ale fertility, we reviewed the current literature using a system-atic search for published studies. A PubM ed search were perform-ed using the m-ain search term-s "IBD AND m-ale infertility", "Crohn's disease AND m-ale infertility", "ulcerative colitis AND m-ale infertility". References in review articles were used if relevant. We noted that active inflammation, poor nutrition, alcohol use, sm-oking, m-edications, and surgery m-ay cause infertility in m-en with IBD. In surgery such as proctocolectom-y with ileal pouch-anal anastom-osis, rectal incision seem-s to be associated with sexual dysfunction. Of the m-edications used for IBD, sulfasalazine reversibly reduces m-ale fertility. No other m-edications appear to affect m-ale fertility significantly, although sm-all studies suggested som-e adverse effects. There are lim-ited data on the effects of drugs for IBD on m-ale fertility and pregnancy outcom-es; however, patients should be inform-ed of the possible effects of paternal drug exposure. This review provides inform-ation on fertility-related issues in m-en with IBD and discusses treatm-ent options.

Study of pruritus in chronic hepatitis C patients

AIM:To investigate the occurrence and severity of pruritus in chronic hepatitis C patients treated with or without interferon(IFN)therapy.METHODS:A total of 89 patients with chronic hepatitis C and 55 control(non-hepatitis)patients were asked to rate their experience of diurnal and nocturnal pruritus in the preceding week using a visual analogue scale(VAS)and a five-point scale,respectively.Blood samples were taken and serum thymus and activationregulated chemokine(TARC)levels were measured by enzyme-linked immunosorbent assay.RESULTS:A significantly greater proportion of chronic hepatitis C patients experienced nocturnal pruritus compared with control(58.4%vs 5.5%,P<0.0001).Chronic hepatitis C patients also had more severe pruritus compared with control patients,indicated by the higher mean VAS scores in both the IFN-treated and non-IFN-treated groups.In particular,patients who received combined peginterferon alfa-2b and ribavirin had significantly higher mean VAS scores than those receiving peginterferon alfa-2a or no IFN treatment.SerumTARC levels did not correlate with pruritus scores,and no significant differences in TARC levels were observed between the IFN-treated and non-IFN-treated groups.CONCLUSION:Patients with chronic hepatitis C experience pruritus more than those without.Serum TARC levels do not correlate with pruritus severity in chronic hepatitis C patients.

Histopathological confirmation of similar intramucosal distribution of fluorescein in both intravenous administration and local mucosal application for probebased confocal laser endomicroscopy of the normal stomach

Probe-based confocal laser endomicroscopy(p CLE) is capable of acquiring in vivo magnified cross-section images of the gastric mucosa. Intravenous injection of fluorescein sodium is used for confocal imaging. However, it is still under debate if local administration of the dye to the mucosa is also effective for confocal imaging as it is not yet clear if topical application also reveals the intramucosal distribution of fluorescein. The objective of this study was to evaluate the intramucosal distribution of fluorescein sodium after topical application and to compare the distribution to the conventional intravenous injection used for confocal imaging. p CLE of the stomach uninfected with Helicobacter pylori was performed in a healthy male employing intravenous administration and local mucosal application of fluorescein. The mucosa of the lower gastric body was biopsied 1 min and 5 min after intravenous administration or local mucosal application of fluorescein, and the distribution of fluorescein in the biopsy samples was examined histologically. Green fluorescence was already observed in the cytoplasm of fundic glandular cells in the biopsied deep mucosa 1 min after local mucosal application of fluorescein. It was also observed in the foveolar lumen and inter-foveolar lamina propria, although it was noted at only a few sites. In the tissue biopsied 5 min after the local mucosal application of fluorescein, green fluorescence was more frequently noted in the cytoplasm of fundic glandular cells than in that 1 min after the local mucosal application of fluorescein, although obvious green fluorescence was not identified in the foveolar lumen or inter-foveolar lamina propria. The distribution of intravenously administered fluorescein in the cytoplasm of fundic glandular cells was also clearly observed similarly to that after local mucosal application of fluorescein. Green fluorescence in more cells was observed in many cells 5 min after intravenous administration compared with that after 1 min. The presence of fluorescein in the mucosa was observed within a short time after local mucosal application of fluorescein, suggesting that pC LE images similarly to those after intravenous fluorescein administration can be acquired by local mucosal application of fluorescein.

Differential Expression of Glu-Tubulin in Basal-Like Phenotype Carcinoma of the Mammary Gland

High levels of tubulin expression have been described in a variety of human malignant tumors, and glu-tubulin, in which the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidase. Over-expression has been reported in the malignant tumors of the mammary gland and correlated with poor prognosis immunohistochemically. Furthermore, Nielsen et al. proposed that the use of a panel of four markers (ER, HER 2, CK 5/6, and EGFR) could accurately identify basal-like phenotype carcinoma (BPC) with widely available standard pathologic tools. In our study, major prognostic factors such as patient age, tumor size, histological grade, axillary lymph node metastasis, vessel invasion, and local recurrence in BPC were not significantly different from non BP carcinoma (NBPC). However, the BPC group showed a higher ratio of distant metastasis than that of the NBPC group. In triple-negative carcinoma (TNC) cases, staining for glu-tubulin was observed in 46 cases (63.8%), which consisted of 42 of the 58 BPC patients (72.4%) and 4 of the 14 NBPC patients (28.6%). A significant association was found between the expression of glu-tubulin and BPC, but not NBPC. It seems that our findings also agree with the observation that BPC exhibits aggressive biological behavior and increases the content of glu-tubulin, which plays a greater role in migration and invasion.

The Predictors of Psychological Status among Primary Breast Cancer Patients in Japan

This study examined the psychological status of Japanese ambulatory patients with primary breast cancer, with a focus on evaluating the impact of the patients’ self-repressive trait and the role of previously identified associated factors, including social support, attributes, and disease-related variables. The subjects included 112 women [mean (SD) age: 58.3 (12.7)] in Japan with postoperative primary breast cancer. The results showed that around 40% of the subjects were in a psychologically vulnerable situation. In addition, the self-repressive trait and support from family were significant predictors of both anxiety [self-repressive trait (β = 0.30, p = 0.000) and family support (β = -0.37, p = 0.001)] and depression [self-repressive trait (β = 0.26, p = 0.002) and family support (β = -0.42, p = 0.000)], whereas attributes and disease-related variables were not. Health care providers need to recognize that self-repressive patients may seem to be well-adjusted when, in fact, they are suffering. Careful assessment of self-repression and psychological status is needed. Family support can contribute to a better psychological status of patients. Nurses need to encourage and provide support for not only the patients but also the family members so that family members can also effectively care for the patients’ needs.

Quantitative Assessment of Chronic Skin Reactions Including Erythema and Pigmentation after Breast Conserving Therapy

Purpose: To evaluate long-term skin reactions following breast-conserving therapy by using the melanin-erythema index meter. Patients and Methods: 164 patients were followed for at least three years after breast-conserving therapy. For both the erythema and the melanin indices, the ratio of the irradiated-side index to the non-irradiated-side index was calculated. The time course of index ratios alternation was examined. Influences from additional therapies and patients’ age were also evaluated. Result: Both erythema and melanin index ratios of the breast skin were recovered to pre-radiation level three years after radiotherapy. However, both index ratios of the area administrated with 10-Gy boost irradiation were still high even after five years after radiotherapy. Endocrine therapy, chemotherapy and age had no significant influence on skin color reactions three years after radiotherapy. Conclusion: Quantitative assessment using the melanin-erythema index meter demonstrated that chronic skin reactions following breast conserving therapy had recovered to pre-radiation level for three years after irradiation except for the 10-Gy boost irradiated area.

Y chromosome microdeletion screening using a new molecular diagnostic method in 1030 Japanese males with infertility

The azoospermia factor(AZF)region is important for spermatogenesis,and deletions within these regions are a common cause of oligozoospermia and azoospermia.Although several studies have reported this cause,the present research,to the best of our knowledge,is the first large-scale study assessing this factor in Japan.In this study,1030 male patients with infertility who were examined for Y chromosome microdeletion using the polymerase chain reaction-reverse sequence-specific oligonucleotide(PCR-rSSO)method,a newly developed method for Y chromosome microdeletion screening,were included.The study enrolled 250 patients with severe oligospermia and 717 patients with azoospermia.Among the 1030 patients,4,4,10,and 52 had AZFa,AZFb,AZFb+c,and AZFc deletions,respectively.The sperm recovery rate(SRR)of microdissection testicular sperm extraction in patients with AZFc deletions was significantly higher than that in those without AZF deletions(60.0%vs 28.7%,P=0.04).In patients with gr/gr deletion,SRR was 18.7%,which was lower than that in those without gr/gr deletion,but was not statistically significant.In conclusion,our study showed that the frequency of Y chromosome microdeletion in male patients in Japan was similar to that reported in patients from other countries,and SRR was higher in patients with AZFc deletion.

Current status of sperm banking for young cancer patients in Japanese nationwide survey

This study aimed to ascertain the current status of Japanese sperm banking for young cancer patients. During 2015, we mailed the directors of 695 institutes where sperm cryopreservation might be performed with questionnaires requesting information on the number of patients, age, precryopreservation chemotherapy, semen analyses results and diagnoses, cryopreservation success rate, and causes of unsuccessful cryopreservation. Of these 695 institutes, 92 had cryopreserved sperm before chemotherapy within the study period. In all, 820 cancer patients （237 testicular, 383 hematological, 46 bone and soft tissue, 20 brain, and 134 other malignancy） consulted the responding institutes for sperm cryopreservation. Except for testicular tumor, the number of patients whose sperm was preserved before cancer treatment was low compared to that of young cancer patients. Approximately 20% of patients with malignancies other than testicular tumor underwent chemotherapy before cryopreservation. The success rate of cryopreservation in hematological malignancy was 82.5%, significantly lower than that of both the testicular cancer （93.6%） and other malignancy groups （95.6%） （P 〈 0.05）. The primary reasons for preservation failure were azoospermia and poor semen quality. Patients with hematological malignancies had a higher rate of unsuccessful cryopreservation compared to those in other groups, possibly due to the large number of patients requesting sperm cryopreservation after chemotherapy induction. In Japan, information regarding sperm banking prior to cancer treatment appears to be lacking. Information regarding sperm preservation before chemotherapy should be provided to all Japanese oncologists.

An association study of the single-nucleotide polymorphism c190C〉T （Arg64Cys） in the human testis-specific histone variant, H3t, of Japanese patients with Sertoli cell-only syndrome

Dear Editor,Approximately 20% of men with nonobstructive azoospermia （NOA） are diagnosed with infertility caused by genetic defects.1 These include chromosomal abnormalities, Y-chromosome microdeletions, and several specific gene mutations/deletions, such as in DAZ, RBMY, USP9Y, SYCP3, HSF2, PLK4, and TEX11.1,2 Several histones have been detected in mammalian testes, and testis-specific variants are specifically and highly expressed during spermatogenesis^3.