Prognostic Value of MRI Assessment of Residual Peritumoral Edema in Breast Cancer Treated With Neoadjuvant Chemotherapy.

BACKGROUND: Peritumoral edema (PE) identified on T2-weighted breast MRI is a factor for poor prognosis in breast cancer. PURPOSE: To assess the prognostic value of residual PE (rPE) in patients with PE positive breast cancer prior to neoadjuvant chemotherapy (NACT) who subsequently underwent curative surgery. STUDY TYPE: Retrospective. POPULATION: In total, 128 patients with nonmetastatic invasive breast cancer who underwent breast MRI before and after NACT. FIELD STRENGTH/SEQUENCE: Axial precontrast 2D fast spin echo T2W fat-suppressed sequence. Axial dynamic 3D gradient echo T1W fat-suppressed sequence. ASSESSMENT: PE was diagnosed when a signal intensity as high as water was detected surrounding the tumor on a T2-weighted breast MRI. PE was qualitatively evaluated by three readers with more than 20 years of experience in interpreting breast field imaging findings. Residual cancer burden (RCB) were assessed post-NACT. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as the endpoints of this study. STATISTICAL TESTS: Chi-square test; Kaplan-Meier method, log-rank test, and Cox proportional hazard model. A P-value <0.05 was considered statistically significant. RESULTS: Pre-PE was observed in 64 out of 128 patients. Of these, rPE was observed in 21. In the log-rank test, breast cancer with rPE had significantly worse RFS and OS than that without rPE. Cox proportional hazard analysis identified rPE as a significant prognostic factor for recurrence (hazard ratio, 11.6; 95% confidence interval [CI], 3.05-43.8) and death (hazard ratio, 17.8; 95% CI, 3.30-96.3). Breast cancer with rPE had significant worse RFS and OS than that without rPE in RCB class II, and significant worse OS in pathological complete response, class I and class II in the log-rank test. DATA CONCLUSION: rPE on a T2-weighted breast MRI was a significant factor for breast cancer recurrence and death in patients with pre-PE-positive breast cancer treated with NACT. TECHNICAL EFFICACY: Stage 2.

A case of ductal carcinoma in situ (DCIS) with markedly elevated CA15-3 levels requiring 2 years of diagnosis.

BACKGROUND: CA15-3 is often elevated in breast cancer recurrence and rarely in ductal carcinoma in situ (DCIS). We report a case of DCIS with elevated CA15-3 levels, which was diagnosed after over 2 years of follow-up. CASE PRESENTATION: A 74-year-old woman presented with a left-sided breast mass and pain. Redness, swelling, and induration were observed in the left breast. Ultrasonography revealed a non-mass lesion in the left 3 o'clock position, skin thickening, and axillary lymphadenopathy. Serum CA15-3 levels were markedly high at 640 U/mL, suggesting inflammatory breast cancer. However, biopsies showed no malignancy. We diagnosed chronic mastitis with elevated CA15-3 levels and followed up with magnetic resonance imaging and a biopsy, as needed. Finally, DCIS was diagnosed 27 months after the first visit. She underwent a left mastectomy and a sentinel lymph node biopsy; DCIS had spread 6.5 cm and was immunohistochemically positive for CA15-3. No metastasis was found in the lymph nodes, but incidental Hodgkin lymphoma was observed. Postoperative normalization of CA15-3 levels indicated that she had DCIS with elevated CA15-3 levels. The patient underwent chemotherapy for Hodgkin lymphoma postoperatively, and there was no evidence of recurrence 1 year after surgery. CONCLUSION: High CA15-3 levels can also be observed in DCIS, indicating that CA15-3 should not be used solely in breast cancer staging.

[A Case of Breast Metastasis from Renal Cell Carcinoma].

The patient was a woman in her 90s. Right radical nephrectomy for right renal cell carcinoma had been performed 2 years and 6 months ago. Since then, there had been no recurrence. However, computed tomography during postoperative follow- up period showed a 3 cm mass in the right breast, and the patient was referred to our department. Breast ultrasonography indicated a well-circumscribed, oval, and almost smooth-surfaced tumor, 27 mm in size, located in the D region of the right breast. Results of a core needle biopsy showed metastatic renal cell carcinoma and clear cell carcinoma. Preoperative examination confirmed intramammary metastases of renal cell carcinoma. Given that the patient did not experience systemic metastases, partial mastectomy of the right breast was performed. Metastatic renal cell carcinoma is associated with poor prognosis. Generally, standard treatment in this disease is chemotherapy. However, surgical resection is selected with the aim of improving the prognosis and achieving radical cure of patients with this complication if these patients are in an oligometastatic state and complete resection of metastatic lesions is feasible, as in the present case. To achieve radical cure, the patient underwent partial mastectomy under local anesthesia, which is a relatively minimally invasive surgery.

Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer.

BACKGROUND: Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. METHODS: In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K-AKT-mTOR signaling pathway was also examined. RESULTS: The relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. CONCLUSIONS: In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K-AKT-mTOR signaling pathway.

Reconstruction of Geometric and Optical Parameters of Non-Planar Objects with Thin Film.

Here, we propose a novel method to estimate the parameters of non-planar objects with thin film surfaces. Being able to estimate the optical parameters of objects with thin film surfaces has a wide range of applications from industrial inspections to biological and archaeology research. However, there are many challenging issues that need to be overcome to model such parameters. The appearance of thin film objects is highly dependent on the surface orientation and optical parameters such as the refractive index and film thickness. First, we therefore analyzed the optical parameters of non-planar objects with thin film surfaces. Next, we proposed and implemented an analysis procedure and demonstrated its effectiveness for studying planar objects with thin film surfaces. Finally, we developed a device to acquire the shapes and optical parameters of objects with thin film surfaces using a camera and demonstrated the effectiveness of our method experimentally. Then, we surveyed the errors caused by the light source. We discussed the difference between the theoretically obtained parameters and experimental data obtained using a hyper spectral camera.

Oncogenic signaling pathways associated with immune evasion and resistance to immune checkpoint inhibitors in cancer.

Immune checkpoint inhibitors (ICIs) are novel class of anti-cancer drugs that exhibit significant therapeutic effects even in patients with advanced-stage cancer. However, the efficacy of ICIs is limited due to resistance. Therefore, appropriate biomarkers to select patients who are likely to respond to these drugs as well as combination therapy to overcome the resistance are urgently necessary. Cancer is caused by various genetic alterations that lead to abnormalities in oncogenic signaling pathways. The aberrant oncogenic signaling pathways serve as not only prognostic and predictive biomarkers, but also targets for molecularly targeted therapy. Growing evidence shows that the aberrant oncogenic signaling pathways in cancer cells facilitate the resistance to ICIs by modulating the regulation of immune checkpoint and cancer immune surveillance. Indeed, it has been demonstrated that some molecular targeted therapies significantly improve the efficacy of ICIs in preclinical and clinical studies. In this review, we highlighted several oncogenic signaling pathways including receptor tyrosine kinases (RTKs), MAPK, PI3K-AKT-mTOR, JAK-STAT, Hippo, and Wnt pathways, and summarized the recent findings of the mechanisms underlying the regulation of cancer immunity and the ICI resistance induced by these aberrant oncogenic signaling pathways in cancer cells. Moreover, we discussed potential combination therapies with ICIs and molecularly targeted drugs to overcome the resistance and increase the efficacy of ICIs.

Wnt5a-induced cell migration is associated with the aggressiveness of estrogen receptor-positive breast cancer.

Elevated expression of Wnt5a is associated with malignancy, cell invasion, and metastasis. The role of Wnt5a expression in breast cancer remains elusive. We investigated the significance of Wnt5a expression in breast cancer. The relationship between Wnt5a expression and clinicopathologic factors was assessed in invasive breast cancer (n = 178) resected at Hiroshima University Hospital between January 2011 and February 2014. Wnt5a was expressed in 69 of 178 cases (39%) of invasive breast cancer and correlated strongly with estrogen receptor (ER) expression (P < 0.001). Wnt5a expression in ER-positive breast cancer correlated significantly with lymph node metastasis, nuclear grade, and lymphatic invasion. The recurrence-free survival was shorter in breast cancer patients with Wnt5a expression than in those without (P = 0.024). The migratory capacity of ER-positive breast cancer cells increased with constitutive expression of Wnt5a and decreased with Wnt5a knockdown. DNA microarray analysis identified activated leukocyte cell adhesion molecule (ALCAM) as the primary gene induced by Wnt5a. ALCAM was expressed in 69% of Wnt5a-positive but only 27% of Wnt5a-negative cancers (κ = 0.444; P < 0.001). The inhibition of ALCAM reversed the enhanced migratory effect of Wnt5a, confirming the importance of this protein in the migration of ER-positive breast cancer cells. Wnt5a expression is related to high malignancy and a poor prognosis in ER-positive breast cancer. We suspect that Wnt5a expression increases the malignancy of breast cancer by increasing the migratory capacity of cancer cells through the induction of ALCAM expression.

Impact of Ph.D. training: a comprehensive analysis based on a Japanese national doctoral survey.

Ph.D. training in academic labs offers the foundation for the production of knowledge workers, indispensable for the modern knowledge-based society. Nonetheless, our understanding on Ph.D. training has been insufficient due to limited access to the inside of academic labs. Furthermore, early careers of Ph.D. graduates are often difficult to follow, which makes the evaluation of training effects challenging. To address these limitations, this study aims to illustrate the settings of Ph.D. training in academic labs and examine their impact on several training outcomes, drawing on a national survey of a cohort of 5000 Ph.D. graduates from Japanese universities. The result suggests that a supervising team structure as well as the frequency of supervision, contingent to a few contextual factors, determine the Ph.D. graduates' career decisions, performance, and degrees of satisfaction with the training programs.

Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma.

OBJECTIVES: To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. METHODS: Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. RESULTS: Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P < 0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P < 0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.00001) and visual counting (cut-off value: 28.5%; P < 0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.0001) and visual counting (cut-off value: 19.7%, P < 0. 0001). CONCLUSIONS: The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.

PCR and culture identification of pathogenic Leptospira spp. from coastal soil in Leyte, Philippines, after a storm surge during Super Typhoon Haiyan (Yolanda).

Leptospirosis is a zoonosis caused by pathogenic Leptospira spp. Most of the outbreaks of leptospirosis occur after floods caused by heavy rain in countries where Leptospira spp. are endemic. It has been believed that the overflow of seawater rarely causes outbreaks of leptospirosis because the leptospires are killed by salt water. On 8 November 2013, a storm surge caused by Super Typhoon Haiyan (Yolanda) inundated the entire coastal areas of Tacloban and Palo in Leyte, Philippines. The present study was carried out in order to determine whether the environmental leptospires in soil were able to survive after the storm surge in the affected areas. We collected 23 wet soil samples along the coastal areas of Tacloban and Palo 2 months after the storm surge. The samples were suspended in HEPES buffer, and the supernatants were cultured in liquid or semisolid Korthof's medium supplemented with five antimicrobial agents to inhibit the growth of contaminants. Leptospires were isolated from primary cultures of 22 out of 23 samples. The DNA of pathogenic Leptospira species was detected in 11 samples (47.8%) by analysis of flaB by nested PCR. Eventually, two pathogenic Leptospira strains were isolated and showed the highest 16S rRNA gene sequence similarity to Leptospira kmetyi. When these isolates were experimentally mixed with soil, they were found to survive in seawater for 4 days. These results show the possibility that leptospires living in soil survived after the storm surge. Our findings may serve as a warning that when seawater inundates the land during a storm surge or a tsunami, an outbreak of leptospirosis could occur in the disaster-stricken area.

Airway stenting for tracheal obstruction due to lymph node metastasis of hepatocellular carcinoma.

We describe the case of an 80-year-old man with hepatocellular carcinoma (HCC) who developed tracheal obstruction due to peritracheal lymph node metastasis. A metastatic tumor that protruded into the airway was ablated using a neodymium yttrium-aluminium-garnet laser and then a self-expandable metallic stent (SEMS) was deployed in the trachea. Stenting resolved symptoms of severe dyspnea upon mild exertion and in the supine position. Three months later, the patient is alive and has resumed normal activities as an outpatient, despite having metastatic HCC. Peritracheal lymph node metastasis arising from HCC is very rare and a polypoid tumor growing from a metastatic lymph node into the trachea is also extremely unusual. Tracheal obstruction in this patient was successfully treated by airway stenting.

[A case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant 5-FU+CDDP therapy for esophageal cancer].

We present a case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant chemotherapy with 5-FU+CDDP for esophageal cancer. A 52-year-old woman visited another hospital with the complaint of discomfort during swallowing. Upper gastrointestinal endoscopy revealed an ulcerated lesion in the lower thoracic esophagus, which was pathologically diagnosed as squamous cell carcinoma. She was admitted to our institution, and the diagnosis of esophageal cancer Mt-Lt, type 2, cT2N1M0, stage II was made. We obtained informed consent for her treatment with both CRT and surgery, and she selected surgery. Therefore, she was administered neoadjuvant chemotherapy with 5-FU+CDDP therapy. On day 4, abnormalities of the central nerve, such as unconsciousness, difficulty in speaking, and muscle cramps were, observed. After the examinations she was diagnosed with encephalopathy. It should be noted that hyponatremia induced by renal sodium wasting syndrome(RSWS)was considerd to be the cause, and we report our case with the literature cited.

[A resected case of complete response after treatment with S-1 for recurrent squamous cell carcinoma component of the breast].

A resected case of complete response after treatment with S-1 for recurrent squamous cell carcinoma component of the breast is presented.A 65-year-old woman was admitted to another hospital because of a left breast tumor. A tumor approximately 6 cm in diameter was palpable in the subareolar-lower (DBE) region of the left breast; the diagnosis was breast cancer. We performed mastectomy and axillary lymph node dissection. The pathological diagnosis revealed squamous cell carcinoma of the left breast(pT3N1M0, Stage III A). FEC chemotherapy, a standard chemotherapy regimen for general breast cancer, was performed as first-line adjuvant therapy, but was withdrawn after 1 course due to sepsis shock. Weekly PTX chemotherapy as second-line treatment was also withdrawn after six courses due to interstitial pneumonia. Few skin rashes were observed along the incision scar of the left breast, but biopsy revealed skin invasion by local recurrence of squamous cell carcinoma of the breast. Treatment with S-1 was performed for 8 months, and she underwent resection of left skin, fat tissue, and underlying muscle, including the recurrent region. No residual primary carcinoma foci was found in the resected specimen; therefore, the pathological diagnosis revealed complete response for the squamous cell carcinoma component.

A case of HER-2-positive recurrent breast cancer showing a clinically complete response to trastuzumab-containing chemotherapy after primary treatment of triple-negative breast cancer.

We report a case of HER-2-positive recurrent breast cancer showing a clinically complete response to trastuzumab-containing chemotherapy 6 years after primary treatment of triple-negative breast cancer. The primary tumor was negative for HER-2 as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (1+, and ratio, 1.1), but examination of the recurrent lymph node metastasis showed positivity for HER-2 by FISH (ratio, 5.2). No lesions were detected in either her left breast or in other organs, and the patient was diagnosed as having HER-2-positive recurrent disease. Combination chemotherapy using weekly paclitaxel and trastuzumab was initiated, and a clinically complete response was achieved. This report suggests the benefit of routine evaluation of HER-2 status in recurrent breast cancer with the introduction of HER-2-targeting agents.

Salinity induces carbohydrate accumulation and sugar-regulated starch biosynthetic genes in tomato (Solanum lycopersicum L. cv. 'Micro-Tom') fruits in an ABA- and osmotic stress-independent manner.

Salinity stress enhances sugar accumulation in tomato (Solanum lycopersicum) fruits. To elucidate the mechanisms underlying this phenomenon, the transport of carbohydrates into tomato fruits and the regulation of starch synthesis during fruit development in tomato plants cv. 'Micro-Tom' exposed to high levels of salinity stress were examined. Growth with 160 mM NaCl doubled starch accumulation in tomato fruits compared to control plants during the early stages of development, and soluble sugars increased as the fruit matured. Tracer analysis with (13)C confirmed that elevated carbohydrate accumulation in fruits exposed to salinity stress was confined to the early development stages and did not occur after ripening. Salinity stress also up-regulated sucrose transporter expression in source leaves and increased activity of ADP-glucose pyrophosphorylase (AGPase) in fruits during the early development stages. The results indicate that salinity stress enhanced carbohydrate accumulation as starch during the early development stages and it is responsible for the increase in soluble sugars in ripe fruit. Quantitative RT-PCR analyses of salinity-stressed plants showed that the AGPase-encoding genes, AgpL1 and AgpS1 were up-regulated in developing fruits, and AgpL1 was obviously up-regulated by sugar at the transcriptional level but not by abscisic acid and osmotic stress. These results indicate AgpL1 and AgpS1 are involved in the promotion of starch biosynthesis under the salinity stress in ABA- and osmotic stress-independent manners. These two genes are differentially regulated at the transcriptional level, and AgpL1 is suggested to play a regulatory role in this event.

Report on improved information literacy in students at the Nagano Red Cross Nursing School.

Our new environment can afford one PC (personal computer) for every two students in the course of PC classes as well as for research. It has been clarified that the students acquired greater information literacy through this new environment and PC classes.

Th1 response during ribavirin and interferon-alpha combination therapy in chronic hepatitis C.

Ribavirin and interferon-alpha induce Th1 polarization of human CD4+ T cells. The study was conducted to investigate the whether cellular immune response during ribavirin/interferon-alpha therapy is associated with viral eradication by examining mRNA expression of molecules relevant to Th1 and Th2 polarization in CD4+ cells of 13 patients with chronic hepatitis C (seven patients with sustained viral response and six with transient response). Peripheral CD4+ T lymphocytes at 0, 4 and 24 weeks of treatment were tested. There were no significant differences in the mRNA levels at each point of time of the treatment between patients with sustained viral response and those with transient response. The percent increase in mRNA level of the IL-12R beta2 chain from the baseline to the end of the treatment was significantly higher in patients with sustained viral response (15.3+/-6.1%) than in those with transient response (-1.6+/-4.7%, p<0.05). There was no significant difference in percent changes in level of IL-12R beta1 chain mRNA between the two groups. In conclusion, the results of this study indicate that the increase of Th1 response is related to the inflammatory activity in the liver and possibly to ribavirin and interferon-alpha therapy. It is also suggested that the measurement of Th1 response has the potential to distinguish patients with relapse from those with sustained virus response.

Clinical implication of atrial and brain natriuretic Peptide in coronary artery bypass grafting.

Atrial natriuretic peptide and brain natriuretic peptide are known to be indices for heart failure. Atrial natriuretic peptide and brain natriuretic peptide changes in off-pump and on-pump coronary artery bypass grafting is hypothesized to be correlated to clinical implications of coronary artery bypass grafting. 20 consecutive off-pump and 20 consecutive on-pump coronary artery bypass grafting patients were studied. Perioperative atrial natriuretic peptide and brain natriuretic peptide values were measured and statistically analyzed in terms of 14 factors related to myocardial damage and recovery. Postoperative atrial natriuretic peptide plateaued on the third postoperative day and it decreased gradually down to the preoperative level by one month in the off-pump group. Postoperative brain natriuretic peptide plateaued, showed very slow decrease and it never reached down to the preoperative level. The peak brain natriuretic peptide level was correlated with aortic cross-clamp time, postoperative pleural effusion, and postoperative atrial fibrillation (p < 0.01). The atrial natriuretic peptide change reflected surgical prevention of ventricular remodeling. Brain natriuretic peptide > 450 microg.mL(-1) had strong predictive power for atrial fibrillation and pleural effusion and is a useful marker for management of coronary surgery patients.