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Background: Circulating tumor cells (CTCs) in peripheral blood may represent the possible presence of early tumor dissemination. However, relatively few studies were designed to investigate the change of CTC status by adjuvant chemotherapy in operable breast cancer patients. Patients and methods: Peripheral blood (7.5ml) was collected from 95 patients with stage II/III breast cancer before neoadjuvant chemotherapy (NAC). NAC consisted of anthracycline and paclitaxel chemotherapy and additional trastuzumab treatment for patients with HER2-positive tumors. Results: The average age of patients was 52.6 year old (median 52.0). One or more CTCs were detected in 18 (18.9%) of 95 patients. CTCs were detected in 6 (12.0%) of 50 patients with clinical stage II disease and 12 (26.7%) of 45 patients with clinical stage III disease. According to tumor subtypes, CTCs were detected in 5 (17.9%) of 28 patients with hormone receptor (HR)-positive and HER2-negative tumors (L subtype), 3 (12.5%) of 24 patients with HR-positive and HER2-positive tumors (L-H subtype), 4 (22.2%) of 18 patients with HR-negative and HER2-positive tumors (H subtype), and 6 (24.0%) of 25 patients with HR-negative and HER2-negative tumors (TN subtype). After NAC, 17 (94.4%) of 18 patients who were CTC-positive before chemotherapy changed into negative status. 30 (31.6%) of 95 patients had a pathologic complete response (pCR) after NAC. There was no correlation between CTC status before NAC and pathological response. At the median follow up of 27 months, distant metastasis was observed in 9 patients (9.5%). Patients with clinical stage III, TN subtype, or non-pCR had a significantly worse disease-free survival (DFS). However, CTC status before NAC was not a significant prognostic factor. Conclusion: NAC has a significant impact on CTC status irrespective of tumor subtypes. CTC status before NAC was not a significant prognostic factor in this study. The reason of which may be that most of patients showing positive for CTCs before NAC have changed into negative after NAC. [ABSTRACT FROM AUTHOR]

Background: Recently, it is a hot topic that the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) may differ between the primary tumors and the paired recurrent metastatic tumors. On the other hand, the concordance of the ER, PR, and HER2 status between the primary tumor and ipsilateral axillary lymph node metastases is reported to be high in previous study. However, in these reports, the majority of lymph nodes metastases examined are macrometastases obtained from axillary lymph node dissection. The aim of the present study is to compare the ER, PR, and HER2 status of the primary breast tumors with that of sentinel lymph node micrometastases and macrometastases. Methods: A total of 770 breast cancer patients underwent sentinel lymph node biopsy between 2006 and 2010 at our hospital. Among them, 87 patients who had only one node positive were eligible for our study. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Result: We analyzed 76 patients with 50(66%) patients with macrometastasesn and 26 (34%) micrometastases, except 11 cases those were indeterminate for IHC. ER status of primary tumor and the paired metastatic lymph node were almost full concordance except one case, in which ER was negative in primary tumor but ER was positive in lymph node. Discordance for PR was 15.8% (n = 12). Among these, six patients had PR-positive on primary and PR-negative in lymph node while six patients had PR-negative in primary and PR-positive in lymph node. Discordance for HER2 between primary tumor and metastatic lymph node was 5.3% (n = 4). Among these, three had negative in primaries and positive in lymph nodes while one had positive in primary and negative in lymph node. A discordance between primary and lymph node in HER2, ER, or PR status was observed in 14 of 67 (18.4%) cases. Conclusions: The concordance in HER2, ER, and PR was high between the primary tumor and sentinel lymph nodes. However some cases had discordance of receptor status and these result may cause of discordance for distant metastases or poor prognosis. [ABSTRACT FROM AUTHOR]

In some cases of human epidermal growth factor 2 (HER2)-negative breast cancer, including triple-negative breast cancer, HER2 expression is sporadically and strongly upregulated, a condition known as HER2 heterogeneity. We investigated the clinicopathological features of patients with HER2 heterogeneity in triple-negative breast cancers treated with neoadjuvant chemotherapy. Thirty-nine patients with triple-negative breast cancer who had undergone preoperative chemotherapy participated in this study. To assess for HER2 heterogeneity, we used dual in situ hybridization slides. We evaluated the association between HER2 heterogeneity and clinicopathological factors such as rates of pathologic complete response (pCR) and of recurrence-free survival. Of the 39 patients, 15 (38.5%) had cancers with HER2 heterogeneity. The pCR rates were 13.3% among patients with HER2 heterogeneity and 20.8% among those with HER2 nonheterogeneity, but the difference was not significant. The recurrence-free survival rate was significantly lower in patients with HER2 heterogeneity than in those without (P = 0.025). HER2 heterogeneity is a significant predictor of poor prognosis in patients with triple-negative breast cancer treated with neoadjuvant chemotherapy., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

We investigated the fatty acid composition and regiospecific distribution of triacylglycerol in Juglans mandshurica Maxim. var. sachalinensis (Komatsu) Kitam and Juglans regia L. oils. Significant differences are observed in the fatty acid compositions and regiospecific distribution of triacylglycerol in both oils. In addition, we measured volatile compounds and tocopherol content in two walnut oils. In results of volatile compound analysis, vanillin is specifically detected from J. mandshurica var. sachalinensis oil, and was not detected in J. regia L. oil. Notably, γ-tocopherol content in the J. mandshurica var. sachalinensis oil was significantly higher than J. regia L. oil.

Background/aim: This phase II trial evaluated the efficacy and safety of neoadjuvant nab-paclitaxel plus cyclophosphamide (CPA) plus trastuzumab (AbraC-HER) in patients with early HER2-positive breast cancer., Patients and Methods: This was a single-arm, open-label, single-center prospective phase II study. The primary endpoint was pathological complete response rate (pCR rate). The secondary endpoints were clinical antitumor efficacy and the frequency and severity of adverse events., Results: Fifty-nine patients were enrolled in this study. pCR (ypT0/is ypN0) was achieved in 29 patients (49%). The overall response rate was 88.1% (52/59) in all patients. Dose reductions because of adverse events occurred in 3 patients (5.1%) and relative dose intensity was 98%. Compared to Abra-HER, AbraC-HER induced fewer adverse effects., Conclusion: Treatment with nab-paclitaxel plus CPA plus trastuzumab was tolerable and effective with a high pCR rate. This AbraC-HER neoadjuvant therapy may be a feasible new treatment option for patients with early HER2-positive breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The postharvest properties of two ultra-late maturing peach cultivars, "Tobihaku" (TH) and "Daijumitsuto" (DJ), were investigated. Fruit were harvested at commercial maturity and held at 25°C. TH exhibited the characteristics of normal melting flesh (MF) peach, including rapid fruit softening associated with appropriate level of endogenous ethylene production In contrast, DJ did not soften at all during 3 weeks experimental period even though considerable ethylene production was observed. Fruit of TH and DJ were treated with 5,000 ppm of propylene, an ethylene analog, continuously for 7 days. TH softened rapidly whereas DJ maintained high flesh firmness in spite of an increase in endogenous ethylene production, suggesting that DJ but not TH lacked the ability to be softened in response to endogenous and exogenous ethylene/propylene. DNA-seq analysis showed that tandem endo-polygalacturonase ( endoPG ) genes located at melting flesh (M) locus, Pp-endoPGM ( PGM ), and Pp-endoPGF ( PGF ), were deleted in DJ. The endoPG genes at M locus are known to control flesh texture of peach fruit, and it was suggested that the non-softening property of DJ is due to the lack of endoPG genes. On the other hand, TH possessed an unidentified M haplotype that is involved in determination of MF phenotype. Structural identification of the unknown M haplotype, designated as M 0 , through comparison with previously reported M haplotypes revealed distinct differences between PGM on M 0 haplotype ( PGM-M 0 ) and PGM on other haplotypes ( PGM-M 1 ). Peach M haplotypes were classified into four main haplotypes: M 0 with PGM-M 0 ; M 1 with both PGM-M 1 and PGF ; M 2 with PGM-M 1 ; and M 3 lacking both PGM and PGF . Re-evaluation of M locus in association with MF/non-melting flesh (NMF) phenotypes in more than 400 accessions by using whole genome shotgun sequencing data on database and/or by PCR genotyping demonstrated that M 0 haplotype was the common haplotype in MF accessions, and M 0 and M 1 haplotypes were dominant over M 2 and M 3 haplotypes and co-dominantly determined the MF trait. It was also assumed on the basis of structural comparison of M haplotypes among Prunus species that the ancestral haplotype of M 0 diverged from those of the other haplotypes before the speciation of Prunus persica ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Nakano, Kawai, Fukamatsu, Akita, Watanabe, Asano, Takata, Sato, Fukuda and Ushijima.)

In orchards, measuring crown characteristics is essential for monitoring the dynamics of tree growth and optimizing farm management. However, it lacks a rapid and reliable method of extracting the features of trees with an irregular crown shape such as trained peach trees. Here, we propose an efficient method of segmenting the individual trees and measuring the crown width and crown projection area (CPA) of peach trees with time-series information, based on gathered images. The images of peach trees were collected by unmanned aerial vehicles in an orchard in Okayama, Japan, and then the digital surface model was generated by using a Structure from Motion (SfM) and Multi-View Stereo (MVS) based software. After individual trees were identified through the use of an adaptive threshold and marker-controlled watershed segmentation in the digital surface model, the crown widths and CPA were calculated, and the accuracy was evaluated against manual delineation and field measurement, respectively. Taking manual delineation of 12 trees as reference, the root-mean-square errors of the proposed method were 0.08 m ( R 2  = 0.99) and 0.15 m ( R 2  = 0.93) for the two orthogonal crown widths, and 3.87 m 2 for CPA ( R 2  = 0.89), while those taking field measurement of 44 trees as reference were 0.47 m ( R 2  = 0.91), 0.51 m ( R 2  = 0.74), and 4.96 m 2 ( R 2  = 0.88). The change of growth rate of CPA showed that the peach trees grew faster from May to July than from July to September, with a wide variation in relative growth rates among trees. Not only can this method save labour by replacing field measurement, but also it can allow farmers to monitor the growth of orchard trees dynamically., Competing Interests: The authors declare that they have no conflict of interest.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker., Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided., Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008)., Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.

The diagnostic utility of 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for breast cancer is controversial. The histological type or tumor size of breast cancer has been reported to be associated with a greater likelihood of positive FDG uptake. Compared to invasive ductal carcinomas (IDCs), invasive lobular carcinomas (ILCs) have a lower level of FDG uptake and are detected at a significantly lower sensitivity. The role of preoperative FDG-PET for ILCs may, thus, be limited. Few data evaluating the significance of FDG-PET in ILCs are available. Here, we evaluated the clinical significance of FDG-PET for ILC patients. We retrospectively investigated the cases of 196 consecutive patients with primary breast cancer who were diagnosed as having ILC (n=15) or IDC (n=181) and underwent FDG-PET preoperatively. Fifteen (7.7%) of patients were histopathologically diagnosed as ILC. A univariate analysis revealed that tumor size, extent of tumor, estrogen receptor (ER) expression and progesterone receptor (PgR) expression were significantly different between the ILC and IDC groups. The maximum standardized uptake value (SUV max ) values of the primary tumors were not significantly different between the two groups but, regardless of the larger size of tumor or ductal spread, the SUV max was relatively lower in the ILC group compared to the IDC group. The tumors in two ILC cases showed no FDG uptake. Among the ILC cases, there were linear associations between SUV max and tumor size and between SUV max and the nuclear grade by Pearson correlation (r=0.447, p=0.048 and r=0.519, p=0.024, respectively). Our findings imply that the preoperative FDG uptake in ILC may be reflective of the tumor size and the nuclear grade of the tumor. FDG uptake may be useful and predictive of aggressive features or prognosis in ILC patients., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Several studies have reported that high F18-fluorodeoxyglucose (FDG) uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. While these studies evaluated the prognostic value for cases with high FDG uptake, they did not elucidate the meaning of FDG negativity in primary breast cancer. In this study, we evaluated the clinicopathological features of breast cancer cases without FDG uptake. We retrospectively investigated the cases of 219 consecutive patients with primary breast cancer who underwent FDG-positron emission tomography (PET) preoperatively. Among the 219 patients, 25 (11.4%) did not have FDG uptake in the tumor. The 219 cases with breast cancer were divided into two groups based on the presence of FDG uptake in the primary tumor. The present univariate analysis revealed that histology, small invasive tumor size, high estrogen receptor (ER) or progesterone receptor (PgR) expression, low nuclear grade and absence of lymph node metastasis were significantly associated with negative FDG uptake in the primary tumor. On the other hand, the size of ductal spread was not significantly different between the two groups. Multivariate analysis revealed that small-size tumor invasion and lower nuclear grade were statistically significant. Among the 25 cases without FDG uptake, there was no recurrent disease in spite of there being no case that underwent chemotherapy, while 4 cases among the 194 cases with FDG uptake had disease recurrence. Our findings imply that preoperative FDG negativity in primary breast cancer is effective in predicting better prognosis, but is less effective in predicting ductal spread. Cases without FDG uptake in the primary tumor may have a lower risk of recurrent disease and may be able to safely avoid adjuvant chemotherapy., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Mutations in GNAS, which encodes Gsα, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol-secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome.

Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.

Somatic mutations of the catalytic subunit of the cyclic AMP-dependent protein kinase (PRKACA) gene have recently been identified in about 35% of cortisol-producing adenomas (CPAs), with the affected patients showing overt Cushing's syndrome. Since we recently reported higher prevalence of mutations of the KCNJ5 gene and associations with autonomous cortisol secretion in Japanese aldosterone-producing adenomas than in Western countries, there might be different features of CPAs between Japan and the West. We therefore investigated mutations of the PRKACA gene in Japanese patients with several adrenal tumors secreting cortisol, including overt Cushing's syndrome, subclinical Cushing's syndrome, and aldosterone-producing adenomas (APAs) co-secreting cortisol operated on at Gunma University Hospital. Of the 13 patients with CPA who showed overt Cushing's syndrome, 3 (23%) had recurrent somatic mutations of the PRKACA gene, p.L206R (c.617 T>G), and there were no mutations in subclinical Cushing's syndrome. Among 33 APAs, 24 had somatic mutations of the KCNJ5 gene, either G151R or L168R, 11 (33%) had autonomous cortisol secretion, but there were no mutations of the PRKACA gene. We established a PCR-restriction fragment length polymorphism assay and revealed that the mutated allele was expressed at a similar level to the wild-type allele. These findings demonstrated that 1) the prevalence of Japanese patients with CPA who showed overt Cushing's syndrome and whose somatic mutations in the PRKACA gene was similar to that in Western countries, 2) the mutation might be specific for CPAs causing overt Cushing's syndrome, and 3) the mutant PRKACA allele was expressed appropriately in CPAs.

S-1 is a novel oral anticancer agent consisting of tegafur, a prodrug of 5-fluorouracil, and 2 modulators. A phase I study of sequential S-1 and cyclophosphamide(CPA)therapy was conducted to determine the dose-limiting toxicities(DLTs)and recommended doses(RDs)in patients with metastatic or recurrent breast cancer(MBC). Patients with MBC received sequential S-1 and CPA. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at escalating doses of 40, 50, 65, and 80mg/m2/day and CPA at 100 mg/body/day on days 15-28. The schedule was repeated twice at a 4-week interval. The purposes of this study were to determine the RDs, safety, and efficacy of the regimen. A total of 12 patients were registered. No patients experienced DLTs, and the RDs of S-1 and CPA were 80mg/m2/day and 100 mg/body/day, respectively. The response rate was 50. 0%. In conclusion, sequential therapy with S-1 and CPA could be safely and effectively used for the treatment of MBC, and the RDs for this regimen were determined to be 80mg/m2/day for S-1 and 100 mg/m2/day for CPA.

Anthracyclines and taxanes are standard anticancer drugs used in breast cancer chemotherapy. In general, the efficacy of chemotherapy is lower in patients with estrogen receptor (ER)-positive tumors compared to patients with ER-negative tumors. Although less chemosensitive, ER-positive disease includes a subset of patients who significantly benefit from adjuvant chemotherapy. The collagen gel droplet-embedded culture-drug sensitivity test (CD-DST) is an in vitro chemosensitivity test that has several advantages over conventional tests. The aim of the present study was to examine the correlation between CD-DST and the expression of Ki67, an indicator of tumor proliferation, to evaluate the efficacy of anthracyclines and taxanes in patients with ER-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. CD-DST was performed in 68 patients with ER-positive and HER2-negative breast cancer between August 2001 and November 2006. The specimens obtained during surgery were used for the CD-DST and immunohistological examination of Ki67 expression. Chemosensitivity to the anticancer drugs adriamycin (ADM), epirubicin (EPI), docetaxel (DOC) and paclitaxel (PTX) was estimated using CD-DST. Results obtained from the CD-DST showed the chemosensitivity to each anticancer drug to be ADM, 23.7%; EPI, 75.0%; DOC, 69.2% and PTX, 43.6%. Ki67 expression was significantly higher in the group that was sensitive to DOC compared to the group that was resistant to DOC (P=0.048) and PTX (P=0.036). In addition, a significant correlation was observed between a Ki67 labeling index (LI) of >30% and chemosensitivity to PTX. In conclusion, results obtained from CD-DST and Ki67 expression levels are able to identify a subset of patients with ER-positive and HER2-negative breast cancer who exhibit sensitivity to chemotherapy, particularly to taxane therapy.

Background: Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer., Materials and Methods: Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI)., Results: Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p = 0.036), and LVI (p = 0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p < 0.0001). A statistically significant difference was observed between the Ki-67 LI and nuclear grade (p = 0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p = 0.003)., Conclusions: Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.

Fig mosaic virus (FMV), a negative-strand RNA virus, is recognized as a causal agent of fig mosaic disease. We performed RT-PCR for 14 FMV isolates collected from symptomatic fig plants in Japan and Serbia using primers corresponding to the conserved 13 nt stretches found at the termini of FMV genomic segments. The resulting simultaneous amplification of all FMV genomic segments yielded four previously identified segments of FMV and two novel segments. These novel FMV genomic RNA segments were found in each of the 14 FMV isolates analysed. In Northern blot studies, both the sense and antisense strands of these novel RNA molecules accumulated in FMV-infected fig leaves but not in uninfected fig leaves, confirming that they replicate as FMV genomic segments. Sequence analysis showed that the novel RNA segments are similar, in their structural organization and molecular evolutionary patterns, to those of known FMV genomic RNA segments. Our findings thus indicate that these newly discovered RNA segments are previously unidentified FMV genomic segments, which we have designated RNA5 and RNA6.

Context: Mutations of the KCNJ5 gene have recently been identified in patients with aldosterone-producing adenomas (APA)., Objective: Our objective was to investigate the expression and mutations of the KCNJ5 gene in Japanese patients with APA., Design and Patients: We sequenced KCNJ5 cDNA and measured KCNJ5 mRNA levels in 23 patients with APA operated on at Gunma University Hospital., Main Outcome Measures: Mutations and mRNA levels of the KCNJ5 gene were examined and compared to those in cortisol-producing adenomas (Cushing's syndrome) and pheochromocytomas., Results: Of the 23 patients with APA, 15 (65.2%) had two somatic mutations of the KCNJ5 gene: 12 cases of p.G151R (eight with c.451G>A, and four with c.451G>C) and three cases of p.L168R (c.503T>G). Levels of KCNJ5 mRNA were significantly higher in the APA with mutations than those without. Immunohistochemistry also showed a stronger staining of KCNJ5 on the cell membrane in the tumor with a mutation. Furthermore, a PCR-restriction fragment length polymorphism assay with c.503T>G revealed the mutant mRNA to be expressed at a similar level to the wild type. The level of KCNJ5 mRNA in cortisol-producing adenomas was approximately 30% of that in APA, and almost no expression was observed in pheochromocytomas., Conclusion: We found that: 1) a significant number of patients with APA had somatic mutations of the KCNJ5 gene; 2) KCNJ5 mRNA levels were higher in the APA with KCNJ5 mutations; and 3) the expression of KCNJ5 mRNA was significantly higher in APA than cortisol-producing adenomas and pheochromocytomas.

Papillary lesions of the breast include a broad spectrum of lesions, from benign papillomas to papillary carcinomas. It is difficult to determine whether a lesion is benign or malignant based on the fragmented material of a core needle biopsy (CNB). This study evaluated patients with papillary lesions examined using CNB. We retrospectively reviewed 31 papillary lesions diagnosed using CNB between 2004 and 2007. The clinical findings of benign and malignant papillary lesions were compared. The average patient age was 48.9 years. Twelve patients presented with a discharge and 10 patients presented with a lump. Eight patients were asymptomatic. The initial diagnoses by CNB of the 31 lesions were 25 intraductal papillomas, 4 intracystic papillomas and 2 adenomas. After CNB, excisional biopsies were performed in 23 patients and biopsies with a Mammotome(®) in 2 patients. Seven patients underwent regular follow-up. Five (16%) of the 31 patients with papillary lesions were ultimately diagnosed with breast cancer. The average distance from the nipple to a tumor diagnosed as malignant was 2.46 cm, which was longer than for a tumor diagnosed as benign. Ultimately, 5 papillary lesions (16%) were diagnosed as breast cancer. To avoid overlooking a malignancy, surgical excision is advantageous for papillary lesions, particularly those located far from the nipple.

Background: Trastuzumab and various chemotherapy combinations have shown superior results in patients with primary and metastatic breast cancer. However, cardiotoxicity becomes a major adverse event when trastuzumab is used with anthracycline-containing regimens. The purpose of this study was to determine the clinical and pathological efficacy of neoadjuvant chemotherapy (NAC), using trastuzumab and chemotherapy, with or without anthracyclines, for patients with primary breast cancer and human epidermal growth factor receptor 2 (HER2-)-positive tumors., Patients and Methods: A retrospective analysis of 41 patients with stage II and III primary breast cancer and HER2-positive tumors treated with NAC was performed. NAC consisted of weekly paclitaxel plus trastuzumab with (PTA group, n=21) or without anthracycline (PT group, n=20). Patients in the PTA group received four courses of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks followed by concomitant 80 mg/m² paclitaxel and trastuzumab weekly for 12 weeks, and those in the PT group received four courses of 80 mg/m² paclitaxel weekly (days 1, 8, and 15) followed by a 1-week break and trastuzumab weekly (days 1, 8, 15, and 29)., Results: The median age of the patients was 50 years. Of 41 patients, 21 (51%) had a pathological complete response (pCR). Patients with clinical stage II cancer had a higher pCR rate compared with those with clinical stage III. Patients with estrogen receptor (ER)-negative tumors showed a trend toward a higher pCR rate. No significant difference was observed according age, clinical stage, ER status, clinical response, or pathological response between the PTA and the PT groups. The pCR rate of the PTA and the PT groups was 47.6% and 55.0%, respectively. No significant difference in disease-free survival was observed between the two groups at a median follow-up of 32 months., Conclusion: Trastuzumab-containing NAC is effective irrespective of anthracycline use for treating patients with primary breast cancer and HER2-positive tumors.

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A combined method with dispersive liquid-liquid microextraction (DLLME) and electrothermal atomic absorption spectrometry (ETAAS) has been developed for determining gold(III). Dicyclohexylamine, a new extractant for gold(III), showed excellent performance in DLLME. Acetone was indispensable to the quantitative extraction of gold(III), contributing to decrease in hydration, decrease in the difference in the dielectric constants between the supernatant phase and the sedimented phase, and dissolution of a part of chloroform as an extraction solvent to the supernatant phase as well as improvement of dipersibility. In DLLME using a mixture of 1.0mL of acetone and 100microL of chloroform containing 50mmolL(-1) of dicyclohexylamine, gold(III) could be extracted selectively and effectively from 8mL of a sample solution in the presence of iron(III), cobalt(II), nickel(II), copper(II), palladium(II), and platinum(IV) at pH 1. The extracted gold(III) was determinable by ETAAS; the detection limit was 0.002microgL(-1) (three times the standard deviation of the blank values, n=8) as a gold(III) concentration in 8mL of sample solution. The proposed method was applicable to the determination of gold in platinum metal and its alloy as well as effluent without any interference by the matrices.

A phase II clinical trial was conducted to examine the clinical and pathologic efficacy and safety of neoadjuvant paclitaxel with or without trastuzumab in women with advanced or metastatic breast cancer. A total of 49 patients with advanced or metastatic breast cancer (clinical stage IIB -IV) were included. Patients with HER2-negative tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break for 4 cycles. Patients with HER2-positive tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break and a trastuzumab 4 mg/kg loading dose, intravenously, followed by 2 mg/kg weekly for 4 cycles. The age of the patients was 51.6 +/- 1.6 years (mean +/- SE) and the size of their tumors was 5.8 +/- 0.4 cm (mean +/- SE). Thirty-two patients had HER2-negative tumors and 17 had HER2-positive tumors. Of 49 patients, 13 (26.5%) had a clinical complete response and 24 (49.0%) had a clinical partial response. Five (10.2%) patients had a pathological complete response (pCR) and three (6.1%) patients had a near pCR in the breast. A total of eight (16.3%) patients had a pCR or near pCR in the breast. The pCR or near pCR rate was 3.1% in the HER2-negative group and 41.2% in the HER2-positive group. With a median follow-up of 28 months (range, 1-45), the 3-year overall survival was 88%. Clinical responders showed a significantly better overall survival than non-responders (p < 0.01). Pathological responders showed a better overall survival than non-responders. There was no significant difference in overall survival between patients with HER2-positive and -negative tumors. In conclusion, combined neoadjuvant weekly paclitaxel and trastuzumab achieved high clinical and pathological response rates for HER2 -overexpressing breast cancers, despite the omission of an anthracycline.

Objective: Talaporfin sodium (Laserphyrin, Meiji Seika, Tokyo, Japan) is a second-generation photosensitizer developed in Japan. It is characterized by both mild and short-term skin photosensitivity. The objective of this study was to evaluate the efficacy and the pharmacokinetic characteristics in tumor tissues in patients with head and neck cancer., Methods: (1) Four hours after administration intravenous injection of talaporfin sodium (40 mg/m(2)), 100mg tissue specimens were taken from the central part of the tumor. The samples were analyzed by reverse phase liquid chromatography and concentrations were measured. (2) Four hours after intravenous injection of talaporfin sodium (40 mg/m(2)), we gave 60-150 J/cm(2) of 664 nm laser irradiation with a diode laser (PD laser, Panasonic, Japan). Biopsies were performed at 4 weeks and at 3 months after treatment and periodically thereafter to confirm the treatment efficacy of photodynamic therapy (PDT)., Results: Of the 14 patients who grope informed consent, more than 1 microg/g of talaporfin sodium was found in the tumor tissues in 13. Moreover, in 9 patients, tumor-to-normal-tissue ratios ranged from 2.32:1 to 5.69:1, which indicates that more than double the amount of talaporfin sodium was maintained within the tumor than in normal tissues. We have enrolled 22 patients with head and neck cancer with no clinically recognizable metastases after obtaining written informed consent to participate in this study. PDT using talaporfin sodium exhibited the equivalent efficacy to that of conventional PDT using hematoporphyrin derivative (HpD)., Conclusions: The results using a combination of talaporfin sodium and PD laser achieved a primary treatment outcome equivalent to that of conventional PDT. This method has also proven to be advantageous because of the reduced incidence of side effects such as photosensitivity and local edema.

The aim of this study was to evaluate both the risk factors of local recurrence and the prognostic significance of local recurrence in relation to surgical treatment and/or radiation therapy of breast cancer. A total of 1574 primary breast cancer patients, undergoing surgical treatment and/or radiation therapy between 1980 and 2001, were included in this study. Radical mastectomy was performed in 1144 patients, subcutaneous mastectomy in 141 and breast-conserving therapy in 289. The clinical stage was significantly earlier in the subcutaneous mastectomy and breast-conserving therapy groups than in the radical mastectomy group. A positive surgical margin was observed in 9 (6.4%) out of 141 patients in the subcutaneous mastectomy group and 51 (176%) out of 289 in the breast-conserving therapy group. Local recurrence occurred more frequently in the subcutaneous mastectomy and breast-conserving therapy groups than in the radical mastectomy group. Independent prognostic factors in local recurrence were lymph node metastasis in the radical mastectomy group, and surgical margin in the subcutaneous mastectomy group and the breast-conserving therapy group. Independent prognostic factors in overall survival were local recurrence, lymph node metastasis and estrogen receptor status in the radical mastectomy group, and lymph node metastasis and estrogen receptor status in the breast-conserving therapy group. In conclusion, the surgical margin status is an important factor in the risk of local recurrence in patients who have undergone a subcutaneous mastectomy or breast-conserving therapy. The significance of local recurrence for overall survival may be different among these three treatments.

The purpose of this study was to analyze whether inter-site variation types on estrogen receptor (ER) and HER2 expression may be a predictive factor for evaluating the effectiveness of endocrine therapy in patients with ER-positive and HER2-positive breast cancer. A total of 366 consecutive women with invasive breast cancer who had undergone curative surgical treatment between 1996 and 2001 were included in this study. ER status was evaluated using the Allred score and HER-2 status was evaluated according to the HercepTest. In ER-positive and HER2-positive tumors, the expression of ER and HER2 was described as the co-expressed type or the differently expressed type using double staining with ER and HER2. Of the 366 patients, 249 (68.1%) were positive for ER and 74 (20.2%) were positive for HER2. ER-positive and HER2-negative tumors were found in 221 patients (60.4%), ER-negative and HER2-negative in 71 (19.4%), ER-negative and HER-2-positive in 46 (12.6%), and ER-positive and HER2-positive in 28 (7.7%). HER2 status was inversely correlated (p<0.01) with ER status. In ER-positive tumors, an inverse correlation between ER and HER2 was also observed. The co-expressed type was found in 10 patients, and the differently expressed type was found in 18. There was no difference in tumor size and nodal involvement between the two types. There was no significant difference in disease-free survival between patients with the co-expressed type tumor and the differently expressed type tumor. In patients with the differently expressed type tumor, those who received antiestrogen therapy showed a significantly better disease-free survival rate than those who did not receive antiestrogen therapy. As for patients with the co-expressed type of tumor, no significant difference in disease-free survival was observed between patients with and without antiestrogen treatment. The present study suggests that the co-expressed type of tumour might be a resistant factor to antiestrogen therapy in ER-positive and HER2-positive breast cancer.

Local control was compared between patients who had undergone breast-conserving therapy with and without nipple resection. We explored whether there was any difference in local control between the two treatment methods for patients with early breast cancer. A total of 333 women with breast cancer, who had undergone breast-conserving therapy between 1991 and 2002, were included in this study. Surgery consisted of a wide local excision of the primary tumor with a 2-cm free margin as the minimum distance. When the tumor was located under the nipple or close to the nipple, breast-conserving surgery with nipple resection was selected. A total of 320 patients received breast-conserving surgery without nipple resection and radiation therapy (BCT) and 13 patients breast-conserving surgery with nipple resection and radiation therapy (BCT-NR). There were no significant differences in age, tumor size, nodal status, clinical stage, ER status, histological type or surgical margin status between the two groups. The surgical margin was positive in 55 (17.2%) out of 320 patients in the BCT group and in one (7.7%) out of 13 patients in the BCT-NR group. There was no significant difference in the breast-free survival between the two groups. In conclusion, breast-conserving surgery with nipple resection and radiation therapy may be the treatment of choice for early breast cancer patients with the tumor located under the nipple or very close to the areola.

Invasive breast cancer (IBC) with cartilaginous or osseous metaplasia is rare. Here we report two cases of this unusual variation. Case 1: The patient was a 33-year-old woman with a right breast tumor, 2.2 cm in size. Mammograms (MMG) presented no specific findings, but ultrasound (US) showed a cystic-like lesion. Excisional biopsy confirmed IBC with cartilaginous and osseous metaplasia. Biopsy was followed with a modified radical mastectomy. One lymph node was positive, and both estrogen receptor (ER) and progesterone receptor (PgR) were negative. Case 2: The patient was a 43-year-old woman with a left breast tumor, 4.2 cm in size. MMGs presented no findings but US showed an irregular shaped, low-echoic area, suggesting malignancy. Core needle biopsy confirmed IBC with cartilaginous metaplasia. A total adenectomy and lymph node dissection with breast reconstruction using a lattisimus dorsi muscle flap were performed. Two of 18 lymph nodes were positive for metastasis and both ER and PgR were negative. IBC with cartilaginous or osseus metaplasia seem to be divided into two types pathologically, with or without intervening spindle cells, which is related to the prognosis. Matrix producing carcinoma (MPC) has no intervening spindle cells and a better prognosis than other types, however, MPC has been reported to have the same prognosis as ordinary breast cancer after for adjusting its stage. Our two cases were MPC's and no recurrence has been detected 5 and 3 years from the initial therapy, respectively.

A 60-year-old woman who had undergone a total glandectomy for non-invasive ductal carcinoma of the left breast at the age of 56 in another hospital had a local recurrence in the left preserved breast. The patient was referred to our hospital and underwent a mastectomy. After surgery, treatment of UFT and CPA was started. Seven months after surgery, metastasis occurred at the left supraclavicular lymph node, and CPA, THP-adriamycine and 5-FU therapy was started. Fourteen months after surgery, skin redness of the left upper arm, the left chest wall and contralateral breast, and a contralateral axillary lymph node swelling were recognized. Neither docetaxel nor mitoxantrone-combined therapy was effective. Trastuzumab therapy was started because of HER2 overexpression by immunohistochemistry, and partial response was received after 7 weeks. Four months later, multiple nodules in the chest wall were recognized, and weekly treatment of trastuzumab and paclitaxel was started. Skin redness and multiple nodules in the chest wall completely disappeared after 3 months. No recurrence has been found for 14 months.

Immunohistochemical double staining with estrogen receptor (ER) and epidermal growth factor receptor 2 (HER2) was conducted in tissue sample of 125 women with invasive breast cancer. The age at the time of surgery ranged from 28 to 82 years. The tumor size was 2 cm or less in 42 patients and larger than 2 cm in 83. Axillary lymph node status was positive in 53 patients and negative in 72. Estrogen receptor (ER) which was measured using enzyme immunoassay (EIA) was positive in 67 patients, negative in 50 and unknown in 8. Of the 125 patients evaluated, 83 (66.4%) were immunohistochemically positive for ER. ER by immunohistochemistry (IHC) (ER-IHC) was significantly (p<0.01) correlated with ER by EIA (ER-EIA). ER-EIA values in ER-IHC scores were 1.4 fmol/mg protein in score 0, 0.0 in score 1, 19.0 in score 3, 21.2 in score 4, 12.2 in score 5, 17.6 in score 6, 30.0 in score 7 and 114.8 in score 8. ER-EIA values in ER-IHC-score 8 were significantly higher than in scores 0, 2, 3, 4, 5, 6 and 7. Of the 125 patients, 35 (28%) were immunohistologically positive for HER2. HER2 expression was inversely correlated with ER expression. When evaluated even in ER-positive patients, HER2 overexpression was associated with lower ER levels. In this study, we conducted immunohistochemical double staining with ER and HER2, and demonstrated that low ER levels might be one factor in the relative resistance of HER2-positive and ER-positive tumors to hormonal therapy.

A 45-year-old woman underwent a modified radical mastectomy for right breast cancer in July 1996. As lymph node metastases were quite advanced, chemotherapy was started with anthracyclines. Four years after surgery, cough and dyspnea appeared. Chest radiograph and CT showed reticular shadows bilaterally and slight pleural effusion, suggesting lymphangitic lung metastasis of breast cancer. Biweekly intravenous docetaxel (TXT,45 mg/m2) was initiated. Four courses of TXT ameliorated her complaints and radiographic findings. A total of 30 continuous courses of TXT suppressed disease exacerbation for 18 months until new lesions manifested in January 2002. The main side effects were grade 2 leukopenia and alopecia. This case report describes a patient with long-term suppression of lymphangitic lung metastasis of breast cancer using biweekly TXT without severe side effects or worsening quality of life.