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Background: Neoadjuvant chemotherapy (NAC) with taxane and FEC concurrently with trastuzumab is a potent regimen in women with HER2-positive breast cancer (BC), and several studies revealed high pCR rates in BC patients treated with this regimen. In the present study, we compared the status of biomarkers before and after NAC, and evaluated rates and patterns of discordant biomarker expression. We also evaluated differences of prognosis between patients with discordant biomarker expression and those with concordant expression. Patients and Methods: We investigated 118 Japanese women with invasive HER2 positive BC. Patients received 12 cycles of paclitaxel or 4 cycles of docetaxel followed by 4 cycles of FEC-75 with concomitant trastuzumab for 24 weeks and were followed for ≥ 1 year after surgery. Of these, 27 patients with residual tumors 5 mm or larger were analyzed. HER2, ER, PgR, and Ki67 were examined in primary and residual tumors. Furthermore, recurrence-free survival (RFS) and overall survival (OS) were analyzed between patients classified based on these biomarkers. Results: Patients with pCR after NAC (75/118; 63.5%) had significantly better RFS than non-pCR patients (median follow-up: 41 months). Residual tumors were obtained from 27 of 43 non -pCR patients and examined for immunohistochemical biomarker expression. In 14/27 non-pCR patients (51.9%), residual tumors were HER2 negative, despite being HER2 positive before NAC: HER2 score changed from 3+ to 0 or 1+ in 8/18 patients (44.4%) and from 2+ to 0 or 1+ in 6/9 (66.7%). ER expression changed in 2 patients (1 positive to negative and 1 negative to positive). Patterns of biomarker expression in residual tumors were HER2 (+)/ER (-), 6 patients (22.2%); HER2 (+)/ER (+), 7 (25.9%); HER2 (-)/ER (+), 11 (40.7%); and triple negative (TN), 3 (11.1%). Recurrence was observed in 8/27 (29.6%) non-pCR patients, and patterns of biomarker expression in residual tumors were HER2 (+)/ER (-), 3 patients; HER2 (+)/ER (+), 2; and HER2 (-)/ER (+), 3. In addition, 1 patient with a HER2 (+)/ER (+) tumor and 1 patient with a HER2 (-)/ER (+) tumor died. RFS and OS were not statistically different between patients classified based on ER and Ki67 expressions. However, in the 18 non-pCR patients with primary tumor HER2 score of 3+ (overexpression of HER2 protein), the 10 with HER2-positive residual tumors showed significantly lower RFS than the 8 with HER2-negative (p < 0.04). Conclusions: Although this regimen achieved a high pCR rate in HER2-positive BC patients, about 40% still had residual tumors. In the present study, we found that positive HER2 expression seen in pre-NAC tumors became negative in 52% of residual tumors after NAC. Theses HER2-negative residual tumors might not respond well to trastuzumab therapy, and residual tumors remaining HER2 positive might show low or no response to trastuzumab therapy. Moreover, the prognosis seems worse for non-pCR patients with HER2-positive residual tumors. However, Ki67 was not a significant prognostic factor. Examining biomarker expression of residual tumors after NAC seems very important for deciding further adjuvant therapy. [ABSTRACT FROM AUTHOR]

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]

Background: The Ki67 labeling index (LI) is regarded as a significant prognostic marker in ER-positive/HER2-negative breast cancer patients. The expression of PgR has recently been identified as another prognostic marker. In the present study, we investigated the prognostic utilities and most suitable cut-off values for Ki67 and PgR, and evaluated the relationship between Ki67 LI and PgR expression in ER-positive/HER2-negative breast cancer., Patients and Methods: In the present study, 177 consecutive Japanese women with ER-positive/HER2-negative invasive carcinoma of no special type who were treated between 2000 and 2001 were enrolled. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were analyzed according to Ki67 LI and PgR expression, and significant cut-off values for selecting patients with a poor prognosis were evaluated., Results: The cut-off values for Ki67 LI as a prognostic marker plotted against P values showed bimodal peaks at 10% and 30%. Among the cut-off points examined for the PgR status, 20% PgR positivity was the most significant for predicting survival differences (RFS: P = 0.0003; CSS: P < 0.0001). A multivariate analysis showed that PgR (≥20%) was an independent prognostic marker (RFS: P = 0.0092; CSS: P = 0.00014). Furthermore, in the intermediate risk group with Ki67 LI of 10-30%, the low PgR <20% group had a markedly poorer prognosis for RFS and CSS (RFS: P < 0.0001; CSS: P < 0.0001)., Conclusions: The expression of PgR is a potent prognostic indicator for evaluating the long-term prognosis of ER-positive/HER2-negative breast cancer, and the most suitable cut-off value was found to be 20%. Furthermore, the PgR status is a powerful method for selecting patients with a poor prognosis among ER-positive/HER2-negative patients at intermediate risk, as assessed using Ki67 LI.

Somatic mutation in human epidermal growth factor receptor-related 2 gene (HER2) is one of the driver mutations in lung cancer. HER2 mutations are found in about 2% of lung adenocarcinomas (ADCs). Previous reports have been based mainly on diagnostic screening by Sanger sequencing or next-generation sequencing (NGS); however, these methods are time-consuming and complicated. We developed a rapid, simple, sensitive mutation detection assay for detecting HER2 12 base pair-duplicated insertion mutation based on the Eprobe-mediated PCR method (Eprobe-PCR) and validated the sensitivity of this assay system for clinical diagnostics. We examined 635 tumor samples and analyzed HER2 mutations using the Eprobe-PCR method, NGS, and Sanger sequencing. In a serial dilution study, the Eprobe-PCR was able to detect mutant plasmid DNA when its concentration was reduced to 0.1% by mixing with wild-type DNA. We also confirmed amplification of the mutated plasmid DNA with only 10 copies per reaction. In ADCs, Eprobe-PCR detected the HER2 mutation in 2.02% (9/446), while Sanger sequencing detected it in 1.57% (7/446). Eprobe-PCR was able to detect the mutation in two samples that were undetectable by Sanger sequencing. All non-ADC samples were wild-type. There were no discrepancies between frozen and formalin-fixed paraffin-embedded tissues in the nine samples. HER2 mutations detected by NGS data validated the high sensitivity of the method. Therefore, this new technique can lead to precise molecular-targeted therapies., Competing Interests: We have the following interests: YK is an inventor of Japanese Patent Application 2012-158229 (”Nucleic acid probe, design method of nucleic acid probe, and detection method for target sequence”, WO 2014/013954 A1). Tatsuo Ichihara (TI) and Yasumasa Mitani (YM) are employed by K.K. DNAFORM. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS.

The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07-4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The carboxyl terminus of the Hsc70-interacting protein (CHIP) is considered to induce the ubiquitination and degradation of several oncogenic proteins, and play a role in the inhibition of tumor progression and invasion under experimental conditions. However, the impact of CHIP expression on the prognosis of breast cancer patients has not yet been established. In this study, using an immunohistochemical method, 272 patients with invasive breast cancer were assessed for the expression of CHIP (graded scores 0-3) and the statuses of biomarkers, such as estrogen receptor (ER), progesterone receptor (PgR), and HER2. The relationships between the statuses of CHIP and biomarkers as well as clinical features were also evaluated, and that between the expression of CHIP and patient prognosis was analyzed. We revealed that the strong expression of CHIP correlated with positive ER (P < 0.001), positive PgR (P < 0.001), and negative HER2 (P = 0.02). In postmenopausal patients, relapse-free survival (RFS) was significantly better in the high CHIP group than in the low CHIP group (P = 0.042). In addition, RFS and cancer-specific survival (CSS) were significantly better in patients with ER-positive/CHIP score 3 tumors than in those with ER-negative/CHIP score 0 tumors (RFS: P = 0.038, CSS: P = 0.0098). The methylation status of CHIP gene promoter did not always account for the down-regulation of its expression. In conclusion, the overexpression of CHIP is a potent prognostic factor of a good prognosis in ER-positive breast cancer patients in the postmenopausal phase., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Based on recent findings of aromatase and estrogen receptor beta (ERβ) expression in non-small-cell lung cancer, we assessed the clinicopathological and prognostic significance of aromatase and ERβ expression and their relationship to epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma., Materials and Methods: We evaluated 150 resected primary lung adenocarcinoma specimens. Expression of aromatase, ERα, ERβ, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was evaluated by immunostaining, and EGFR and KRAS mutations were analyzed. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method., Results: Expression of aromatase, ERα, ERβ, PR, and HER2 was detected in 88.0%, 1.3%, 79.3%, 2.7%, and 39.3% of specimens, respectively. In patients with EGFR wild-type lung adenocarcinoma, high aromatase expression was an independent predictor of poor OS (hazard ratio [HR]=2.638; 95% confidence interval [CI], 1.173-5.936; P=.019) and RFS (HR=2.505; 95% CI, 1.154-5.434; P=.020). Positive ERβ expression was also an independent predictor of poor RFS (HR=4.013; 95% CI, 1.219-13.207; P=.022). Furthermore, high aromatase expression was a significant predictor of poor survival only in females (OS, P=.010; RFS, P=.007), whereas positive ERβ expression was an important predictor of poor survival only in males (OS, P=.073; RFS, P=.051). No prognostic significance was observed in patients with EGFR mutations., Conclusions: Our findings suggest that EGFR wild-type lung adenocarcinoma is an estrogen-dependent carcinoma, and aromatase expression and ERβ expression are potent prognostic markers for EGFR wild-type lung adenocarcinoma.

Purpose: A deletion polymorphism of the Bim gene has been reported to be a prognostic factor for patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the Bim deletion polymorphism on survival among patients with completely resected NSCLC., Patients and Methods: The Bim polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy., Results: The Bim deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the Bim deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the Bim deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; P = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the Bim deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months v 26.9 months, respectively; P < .001). Multivariable analysis revealed that the Bim deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; P < .001). This trend remained apparent in subgroup analyses stratified by EGFR status, histology, and therapeutic modality., Conclusion: The Bim deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population., Competing Interests: Authors' disclosures of potential conflicts of interest and contributions are found at the end of this article.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jun AtsumiNo relationship to discloseKimihiro ShimizuNo relationship to discloseYoichi OhtakiNo relationship to discloseKyoichi KairaNo relationship to discloseSeiichi KakegawaNo relationship to discloseToshiteru NagashimaNo relationship to discloseYasuaki EnokidaNo relationship to discloseSeshiru NakazawaNo relationship to discloseKai ObayashiNo relationship to discloseYoshiaki TakaseNo relationship to discloseOsamu KawashimaNo relationship to discloseMitsuhiro KamiyoshiharaNo relationship to discloseMasayuki SuganoNo relationship to discloseTakashi IbeNo relationship to discloseHitoshi IgaiNo relationship to discloseIzumi TakeyoshiNo relationship to disclose

Background: Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27(Kip1). We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy., Methods: A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27(Kip1) were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement., Results: pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1%. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0% vs. grades 1-2, 36.8%), ER (negative, 78.6% vs. positive, 40.0%), PgR (negative, 75.3% vs. positive, 38.9%), Ki67 (high, 72.0% vs. low, 47.2%), and p27(Kip1) (low, 71.0% vs. high, 50.0%). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002)., Conclusions: High-HG, low-ER, low-PgR, high-Ki67, and low-p27(Kip1) were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals.

Background: L-type amino acid transporter 1 (LAT1) and ASC amino acid transporter 2 (ASCT2) have been associated with tumor growth and progression. However, the clinical significance of LAT1 and ASCT2 coexpression in the prognosis of patients with lung adenocarcinoma remains unclear., Methods: In total, 222 patients with surgically resected lung adenocarcinoma were investigated retrospectively. Tumor sections were stained immunohistochemically for LAT1, ASCT2, CD98, phosphorylated mammalian target-of-rapamycin (p-mTOR), and Ki-67, and microvessel density (MVD) was determined by staining for CD34. Epidermal growth factor receptor (EGFR) mutation status was also examined., Results: LAT1 and ASCT2 were positively expressed in 22% and 40% of cases, respectively. Coexpression of LAT1 and ASCT2 was observed in 12% of cases and was associated significantly with disease stage, lymphatic permeation, vascular invasion, CD98, Ki-67, and p-mTOR. Only LAT1 and ASCT2 coexpression indicated a poor prognosis for lung adenocarcinoma. Furthermore, this characteristic was recognized in early-stage patients, especially those who had wild-type, rather than mutated, EGFR. Multivariate analysis confirmed that the coexpression of LAT1 and ASCT2 was an independent factor for predicting poor outcome., Conclusions: LAT1 and ASCT2 coexpression is an independent prognostic factor for patients with lung adenocarcinoma, especially during the early stages, expressing wild-type EGFR.

CD147 functions as an induction of matrix metalloproteinases and tumor angiogenesis, and is highly expressed in various malignant neoplasms. Recently, CD147 is shown to form a complex with amino acid transporters such as L-type amino acid transporter (LAT1), system ASC amino acid transporter-2 (ASCT2) and 4F2hc as a heavy chain of LAT1. It remains unknown about the existence of these complexes in patients with pancreatic cancer. The aim of this study is to investigate the relationship between CD147 and these amino acid transporters. Ninety-seven patients with pancreatic cancer were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, Ki-67, microvessel density (MVD) determined by CD34, p-AKT, and p-mTOR. CD147 was highly expressed in 23% (22/97) of patients. A high expression of CD147 is significantly associated with N factor, LAT1, ASCT2, Ki-67, VEGF and p-mTOR. A high CD147 expression was identified as a significant prognostic predictor by univariate survival analysis. The coexpression of CD147 and LAT1, and that of CD147 and 4F2hc yielded a significantly worse prognosis than the single expression of LAT1, and that of 4F2hc, respectively. CD147 revealed a significant relationship with the expression level of LAT1 and ASCT2, correlated with tumor proliferation, angiogenesis and mTOR signaling.

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.

The results of several pulmonary resections using a uniportal approach have been published. However, there are no reports of uniportal thoracoscopic anatomic segmentectomy in Japan. We have a fundamental belief in "reduced-port surgery" and therefore routinely perform uniportal thoracoscopic surgery for patients with pneumothorax. This report describes a successful case of uniportal thoracoscopic anatomic segmentectomy through a 3.5-cm incision in a 76-year-old woman with primary lung cancer. The patient was pathologically diagnosed with multiple primary adenocarcinomas stage IA (T1aN0M0). Postoperatively, no analgesics were needed. The operative procedure is described in detail and includes technical tips such as the pulley method, extra-vessel exposure, the shaft-on-shaft technique, one-hand encircling, and one-hand exposure. The selection criteria for uniportal thoracoscopic segmentectomy limit its use.