Secretion of equine chorionic gonadotropin and its association with supplementary corpus luteum formation and progesterone concentration in Hokkaido native pony recipient mares.

The objectives of this study were to determine the plasma profile of equine chorionic gonadotropin (eCG) and its association with the formation of supplementary corpus luteum (CL) and plasma progesterone concentrations in embryo transfer Hokkaido native pony recipient mares. Blood samples and transrectal ultrasound examination of the reproductive tract were carried out weekly from the day of ovulation until week 32 of gestation (n = 4). Plasma concentrations of eCG and progesterone were measured by enzyme immunoassays. The eCG concentration was first detectable at week 5 for 2 mares and at week 6 for another 2 mares. Immediately after detection, the mean plasma eCG concentrations were observed to rise sharply and reach a peak at week 8. The concentrations then declined dramatically to a baseline (<0.5 IU/mL) by week 21. Plasma progesterone p=p concentrations increased in 2 phases. First, a sharp increase from 0.18 ± 0.05 ng/mL at ovulation to 15.9 ± 4.6 ng/mL at week 1 was observed, then a decrease to 9.69 ± 2.27 ng/mL by week 2, and maintained at this level until week 5 of gestation. The onset of the second rise occurred at week 6 and was observed to peak to 58.3 ± 21.8 ng/mL at week 10, then gradually declined to <10 ng/mL by week 26. The supplementary CLs were first detectable by pregnancy week 6 and 7 for 2 mares each. All supplementary and primary CLs regressed by week 26 for 3 mares and by week 30 for the remaining mare. The mean number of supplementary CL was 4.5 ± 0.8 and their formation in the right ovary (66.7%, 12/18) was higher (P < 0.05) than that in the left ovary (33.3%, 6/18). Among the mares, 1 mare that developed only 2 supplementary CL had 35% lower level of peak eCG and 65% lower concentration of peak progesterone compared with other 3 mares that had 5 or 6 supplementary CL. In conclusion, development of supplementary CL and blood concentrations of progesterone from around day 40 of gestation were associated with eCG concentration. The total number of supplementary CL formation in the present study in embryo transfer Hokkaido native pony recipient mares seemed higher than previously reported supplementary CL number in pregnant mares, with a greater rate in the right ovary than in left.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Percutaneous radiofrequency ablation for hepatocellular carcinoma located in the caudate lobe of the liver.

AIM: This study aimed to evaluate the effectiveness and safety of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) located in the caudate lobe of the liver. PATIENTS AND METHODS: Between 2012 April and 2014 February, 142 patients with HCC meeting the Milan criteria were enrolled in this study. Of these patients, nine patients had HCC located in the caudate lobe (caudate group). Six of the nine cases were located in the Spiegel lobe, two cases were located in the paracaval portion and one case was located in the caudate process. We evaluated the local recurrence rate and RFA-related complications in the caudate group and non-caudate group. RESULTS: The local recurrence rate in the caudate group was 12.5% at 1 year and 12.5% at 2 years, while the local recurrence rate in the non-caudate group was 14.9% at 1 year and 29.0% at 2 years; there were no significant differences between the groups. No complications were observed in the caudate group, and minor complications were observed in six patients (4.5%) in the non-caudate group. No major complications or mortalities were observed in either group, and the complication rates were not significantly different between the groups (P = 1). CONCLUSIONS: RFA for HCC in the caudate lobe and the non-caudate lobe has equivalent effectiveness and safety. RFA is a promising treatment option for HCC arising in the caudate lobe.

Feasibility and efficacy of intraperitoneal docetaxel administration as salvage chemotherapy for malignant gynaecological ascites.

Ovarian and endometrial cancers diagnosed at advanced stages are often associated with malignant ascites. This study aimed to determine the safety, feasibility and efficacy of intraperitoneal (IP) docetaxel (TXT) for the treatment of ascites. A phase I study, including nine patients, was undertaken to determine the maximum tolerable dose. Efficacy was retrospectively assessed in 18 patients treated with 40-70 mg/m(2) IP TXT between 2005 and 2012. In a phase I study, the dose was safely escalated to a maximum of 70 mg/m(2), at which level no patients had grade -3 haematological adverse events. In a retrospective study of 18 patients, seven had an Eastern Cooperative Oncology Group performance status of 3; 16 had prior paclitaxel administration and two, with doses of 40 and 70 mg/m(2), experienced a serological response and a decrease in paracentesis. Thus, palliative treatment of recurrent OC should be further studied with 40 mg/m(2) among more patients, and 70 mg/m(2) could be evaluated for first-line IP chemotherapy.

Raised serum levels of interleukins 6 and 8 and antiphospholipid antibodies in an adult patient with Henoch-Schönlein purpura.

BACKGROUND: The long-term prognosis of Henoch-Schönlein purpura (HSP) is determined by the severity of renal involvement, known as HSP nephritis, which varies considerably from patient to patient. There is now increasing evidence that dysregulated cytokine production plays a crucial role in human autoimmune and inflammatory processes. AIM: To explore the possible contributions of serum antistreptolysin O, C-reactive protein, IgA, interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-α, anticardiolipin antibody (aCL) and antiphosphatidylserine-prothrombin complex antibody (anti-PSPT) in the pathogenesis of HSP, and to evaluate correlations between those biological parameters and the clinical features. METHODS: Records were reviewed of 58 patients with HSP who presented initially with palpable purpura between 2003 and 2009. Serum IL-6 levels were determined by chemiluminescent enzyme immunoassay, IL-8 levels by ELISA and TNF-α levels by quantitative sandwich enzyme immunoassay. Serum aCL and anti-PSPT levels were measured according to our previously published procedures. RESULTS: There was a significant correlation between the serum IL-6 and IgA anti-PSPT levels, and also between the serum IL-8 and IgA anti-PSPT levels. Serum IL-8 and IgA aCL levels were both significantly higher in patients with renal involvement than in those without. Serum IL-6 and IgM anti-PSPT levels were also significantly higher in patients with gastrointestinal symptoms than in those without. CONCLUSIONS: We suggest that serum IL-6 and IL-8 associated with antiphospholipid antibodies play a pivotal role in the induction of HSP. Based on our results, IL-8 and IgA aCL levels could be useful as markers to monitor the development of HSP nephritis, and IL-6 and IgM anti-PSPT levels could be used as markers to monitor the development of gastrointestinal involvement.

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations.

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

Stromal expression of cathepsin K in squamous cell carcinoma.

BACKGROUND: Cathepsin K (CTSK), a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, may be produced by neoplastic cells as well as stromal macrophages and fibroblasts. Its expression is suggested as associated with increased invasive and metastatic potential. OBJECTIVES: The aim of this study is to examine stromal expression of cathepsin K in skin tumors. METHODS: A series of 13 normal skin and 109 skin tumours, including 51 benign and 58 malignant epidermal tumours were tested for CTSK and Ki-67 expression by immunohistochemical analysis. RESULTS: Stromal CTSK expression and the tumoral Ki-67 labelling index were significantly higher in invasive squamous cell carcinoma (SCC) than in other epidermal tumours. CONCLUSION: Cathepsin K-positive stromal fibroblasts may play a crucial role in SCC progression by promoting extracellular matrix degradation, thereby facilitating SCC growth and invasion into surrounding tissue and vasculature. CTSK inhibitors may be a potential novel therapeutic option to decrease SCC progression.

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease.

BACKGROUND: We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget's disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin-dependent kinases, is a key regulator of G(1)-S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT-mTOR-p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. OBJECTIVE: To investigate the immunohistochemical staining of the AKT-mTOR-p70S6K pathway in EMPD and to evaluate the relationships among the components. METHODS: Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)-AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-p70S6K/S6K1, p-ribosomal protein S6 (p-S6) and CDK2. Ten normal skin samples served as a control. RESULTS: Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1, p-S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1 and p-S6 and CDK2. CONCLUSIONS: The activation of the AKT-mTOR-p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT-mTOR-p70S6K pathway might be a potential therapeutic target in EMPD.

Activation of the mammalian target of rapamycin signalling pathway in epidermal tumours and its correlation with cyclin-dependent kinase 2.

BACKGROUND: The enzyme mammalian target of rapamycin (mTOR) integrates many different cellular signals to control cell growth and proliferation, protein synthesis and breakdown, and other processes. Dysregulation of mTOR is implicated in a range of human diseases, including cancers and cardiovascular disorders. To date, there has been no report on the expression of protein kinase B (AKT)/mTOR cell signalling in epidermal tumours. OBJECTIVES: This study was designed to investigate the activation of the mTOR signalling pathway in epidermal tumours and to correlate this with cyclin-dependent kinase 2 (CDK2) expression. METHODS: Immunohistological staining was performed with phosphorylated (p-) AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-ribosomal protein S6 (p-S6), p-p70 ribosomal protein S6 kinase 1 (p-p70S6K1) and CDK2 in 15 cases each of seborrhoeic keratosis, actinic keratosis, keratoacanthoma and Bowen's disease (BD), and 25 cases of squamous cell carcinoma (SCC). Fifteen normal skin (NS) samples served as control. RESULTS: Among 85 tumours, 40 (47%) were positive for p-AKT, 31 (36%) for p-mTOR, 44 (52%) for p-4EBP1, 38 (45%) for p-S6, and 39 (46%) for p-p70S6K1. CDK2 immunostaining was positive in all cases of SCC and BD, and in 67% of benign tumours. All of these markers were stained much more frequently in malignant tumours than in benign tumours or NS. p-AKT, p-mTOR, p-4EBP1, p-p70S6K1 and p-S6 each showed high correlation with CDK2. CONCLUSIONS: Constitutive activation of the AKT/mTOR pathway was frequent in epidermal tumours, especially in malignant tumours. Activation was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in epidermal tumours.

Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma.

BACKGROUND: Cytokeratin 19 (CK19) has been considered to be a putative marker for epidermal stem cells in the hair follicle bulge. Cumulative reports have shown that epidermal stem cells play an important role in skin carcinogenesis. However, to date there has been no report on the clinical alteration of the stem cells in squamous cell carcinoma (SCC). OBJECTIVES: To investigate alteration of the stem cells and proliferating cells and to assess their relationship and potential contribution to SCC. METHODS: Thirty paraffin-embedded neoplastic skin lesions, consisting of 10 cases each of actinic keratosis (AK), Bowen disease (BD) and SCC, were examined immunohistologically for CK19 and Ki-67. RESULTS: Positive reactivity for CK19 was seen in 30% of AK, 50% of BD and 80% of SCC lesions. There was significantly higher expression levels of CK19 in SCC than in AK and BD (P < 0.05). In addition, BD lesions harboured a significantly higher number of CK19-positive cells than did AK lesions (P < 0.05). There were significant differences in Ki-67 labelling indices between AK and BD and between AK and SCC (P < 0.001), but not between BD and SCC (P > 0.05). Furthermore, a serial section comparison study showed that there was a minor population of cells co-expressing CK19 and Ki-67 in a subset of the tumour cells of SCC samples. The percentage of CK19+ cells significantly correlated with that of Ki67+ cells in all examined neoplastic skin lesions. CONCLUSIONS: These results suggest that CK19 expression may be associated with the retention of stem cell characteristics or a state that is uncommitted to terminal squamous differentiation.

[Aortic valve replacement through right anterolateral thoracotomy for aortic stenosis after mediastinal radiation therapy].

A 76-year-old woman had severe aortic stenosis on transthoracic echocardiography [aortic valve area (AVA): 0.7 cm2, max pressure gradient (PG): 108 mmHg]. Since she was on radiation therapy for breast cancer, we considered that median sternotomy was a risk factor for mediastinitis, and right thoracotomy was chosen for aortic valve replacement. The operation was performed through a right anterolateral thoracotomy. Cardiopulmonary bypass was established with right femoral artery cannulation, right atrial cannulation, and right superior pulmonary vein cannulation for venting. The patient's postoperative course was uneventful. This method appears to be an alternative approach for aortic valve replacement in patients that are not suitable candidates for median sternotomy.

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget's disease.

BACKGROUND: The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget's disease (EMPD). AIM: To investigate the potential contribution of p53, p63 and p73 in the pathogenesis of EMPD. METHODS: In total, 35 paraffin wax-embedded tissue samples from patients with EMPD were examined using immunohistochemical staining for p53, p63 and p73. RESULTS: All of the 35 EMPD specimens, including all 6 invasive EMPD and 2 metastatic lymph-node specimens, showed nuclear overexpression of both p53 and p73. The expression levels (percentage of positive cells) of p53 and p73 (90.66 +/- 12.53% and 80.20 +/- 13.07%) in EMPD were significantly higher than those of normal skin. There was a significant correlation between the expression levels of p53 and p73 in EMPD. In 29 of 35 EMPD specimens, there was no nuclear expression of p63, and weak or moderate staining was found in only 6 specimens. The expression level of p63 in EMPD was significantly less than that in normal skin. CONCLUSIONS: Our study shows that the concordant overexpression of p53 and p73 and the decreased expression of p63 may play a pivotal role in the pathogenesis of EMPD. The decreased expression of p63 may play a more important role in the pathogenesis of EMPD than the overexpression of p53 and p73.