Takayuki Kadoya

Desumoylation Activity of Axam, a Novel Axin-Binding Protein, Is Involved in Downregulation of β-Catenin

ABSTRACT Axam has been identified as a novel Axin-binding protein that inhibits the Wnt signaling pathway. We studied the molecular mechanism by which Axam stimulates the downregulation of β-catenin. The C-terminal region of Axam has an amino acid sequence similar to that of the catalytic region of SENP1, a SUMO-specific protease (desumoylation enzyme). Indeed, Axam exhibited activity to remove SUMO from sumoylated proteins in vitro and in intact cells. The Axin-binding domain is located in the central region of Axam, which is different from the catalytic domain. Neither the Axin-binding domain nor the catalytic domain alone was sufficient for the downregulation of β-catenin. An Axam fragment which contains both domains was able to decrease the level of β-catenin. On substitution of Ser for Cys547 in the catalytic domain, Axam lost its desumoylation activity. Further, this Axam mutant decreased the activity to downregulate β-catenin. Although Axam strongly inhibited axis formation and expression of siamois, a Wnt-response gene, in Xenopus embryos, AxamC547S showed weak activities. These results demonstrate that Axam functions as a desumoylation enzyme to downregulate β-catenin and suggest that sumoylation is involved in the regulation of the Wnt signaling pathway.

Complex permittivities of breast tumor tissues obtained from cancer surgeries

The variability in measurements of complex permittivities of tumor tissues between multiple samples could be attributed to the volume fraction of cancer cells in the excised tumor tissue. By the use of a digital photomicrograph image and hematoxylin-eosin staining, it was found that the malignant tumor tissue was not fully occupied by the cancer cells, but the cells were distributed locally in the stroma cells depending on the growth of cancer. The results showed that the volume fraction of cancer cells in the tumor tissue had a correlation to the measured conductivity and dielectric constant in the frequency range from 1 GHz to 6 GHz. It introduces a method to understand and gauge variability in measurements between different tumors.

Role of FDG-PET/CT in evaluating surgical outcomes of operable breast cancer – Usefulness for malignant grade of triple-negative breast cancer

BACKGROUND The aim of this study was to evaluate the significance of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for speculating the malignant level and prognostic value of operable breast cancers. METHODS Of 578 consecutive patients with primary invasive breast cancer who underwent curative surgery between 2005 and 2010, 311 patients (53.8%) who received FDG-PET/CT before initial therapy were examined. RESULTS Receiver operating characteristics (ROC) curve analysis showed the cutoff value of the maximum standardized uptake value (SUVmax) to predict cancer recurrence was 3.8 in all patients and 8.6 in patients with the triple-negative subtype, respectively. In all patients, 3-year DFS rates were 98.8% for patients with a tumor of SUVmax ≤ 3.8 and 91.6% for patients with a tumor of SUVmax > 3.8 (p < 0.001). High value of SUVmax was significantly associated with large tumor size (p < 0.001), lymph node metastasis (p = 0.040), high nuclear grade (p < 0.001), lymphovascular invasion (p = 0.032), negative hormone receptor status (p < 0.001), and positive HER2 status (p = 0.014). Based on the results of multivariate Cox analysis in all patients, high SUVmax (p = 0.001) and negative hormone receptor status (p = 0.005) were significantly associated with poor prognosis. In patients with triple-negative subtype, 3-year DFS rates were 90.9% for patients with a tumor of SUVmax ≤ 8.6 and 42.9% for patients with a tumor of SUVmax > 8.6 (p = 0.002), and high SUVmax was the only significant independent prognostic factor (p = 0.047). CONCLUSION FDG-PET/CT is useful for predicting malignant behavior and prognosis in patients with operable breast cancer, especially the triple-negative subtype.

JAMP, a Jun N-terminal kinase 1 (JNK1)-associated membrane protein, regulates duration of JNK activity.

ABSTRACT We report the identification and characterization of JAMP (JNK1 [Jun N-terminal kinase 1]-associated membrane protein), a predicted seven-transmembrane protein that is localized primarily within the plasma membrane and associates with JNK1 through its C-terminal domain. JAMP association with JNK1 outcompetes JNK1 association with mitogen-activated protein kinase phosphatase 5, resulting in increased and prolonged JNK1 activity following stress. Elevated expression of JAMP following UV or tunicamycin treatment results in sustained JNK activity and a higher level of JNK-dependent apoptosis. Inhibition of JAMP expression by RNA interference reduces the degree and duration of JNK activation and concomitantly the level of stress-induced apoptosis. Through its regulation of JNK1 activity, JAMP emerges as a membrane-anchored regulator of the duration of JNK1 activity in response to diverse stress stimuli.

The Efficacy and Safety of Preoperative Chemotherapy With Triweekly Abraxane and Cyclophosphamide Followed by 5-Fluorouracil, Epirubicin, and Cyclophosphamide Therapy for Resectable Breast Cancer: A Multicenter Clinical Trial

BACKGROUND It has been reported that tri-weekly Abraxane therapy has better outcomes in recurrent breast cancer than tri-weekly Cremophor-based taxol therapy, and that cyclophosphamide combined with taxane shows an enhanced antitumor effect. We conducted a phase II clinical trial of preoperative chemotherapy with a combination of TRI-ABC. PATIENTS AND METHODS From September 2011 to September 2013, 4 cycles of preoperative chemotherapy with TRI-ABC followed by 4 cycles of FEC were administered in patients with resectable breast cancer. In patients with HER2-positive breast cancer, tri-weekly Trastuzumab was administered with TRI-ABC. The primary end point was the pathological complete response (pCR) rate in the breasts and lymph nodes. RESULTS The treatment outcomes and safety were evaluated in 54 patients who received at least 1 dose of chemotherapy. All patients underwent radical surgery, and the overall pCR rate of 37% (20 of 54) was achieved. The pCR rates according to each subtype were 8% (2 of 24) in hormone receptor (HR)-positive HER2-negative breast cancer, 56% (5 of 9) in HR-positive HER2-positive breast cancer, 63% (5 of 8) in HR-negative HER2-positive breast cancer, and 62% (8 of 13) in triple-negative breast cancer. Multivariate analysis revealed that HR negativity and HER2 positivity were predictive factors of pCR. Clinical response was observed in 49 patients (91%). The safety profile was acceptable. CONCLUSION Preoperative chemotherapy with TRI-ABC followed by FEC showed high efficacy and excellent safety. Further clinical studies should be conducted to compare the efficacy of TRI-ABC followed by FEC with conventional taxane-anthracycline regimens.

Ability of contrast-enhanced ultrasonography to determine clinical responses of breast cancer to neoadjuvant chemotherapy

OBJECTIVE We aimed to determine whether contrast-enhanced ultrasonography can predict the effects of neoadjuvant chemotherapy on breast cancer. METHODS The clinical responses of 63 consecutive patients with breast cancer (T1-4, N0-1, M0) to neoadjuvant chemotherapy between October 2012 and May 2015 were assessed using contrast-enhanced magnetic resonance imaging, positron emission tomography/computed tomography and contrast-enhanced ultrasonography. Perfusion parameters for contrast-enhanced ultrasonography were created from time-intensity curves based on enhancement intensity and temporal changes to objectively evaluate contrast-enhanced ultrasonography findings. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography, magnetic resonance imaging and positron emission tomography/computed tomography to predict a pathological complete response were compared after confirming the pathological findings of surgical specimens. RESULTS Twenty-three (36.5%) of the 63 patients achieved pathological complete response. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography for predicting pathological complete response were 95.7% (82.5-99.2%), 77.5% (69.9-79.5%) and 84.1% (74.5-86.7%). The sensitivity of contrast-enhanced ultrasonography was significantly greater than that of magnetic resonance imaging (95.7 vs. 69.6%, P = 0.047). The specificity and accuracy were significantly greater and tended to be greater, respectively, for contrast-enhanced ultrasonography than positron emission tomography/computed tomography (specificity, 77.5 vs. 52.5%, P = 0.02; accuracy, 84.1 vs. 69.8%, P = 0.057). CONCLUSIONS Contrast-enhanced ultrasonography might serve as a new diagnostic modality when planning therapeutic strategies for patients with breast cancer after neoadjuvant chemotherapy.

Role of FDG-PET/CT in Prediction of Underestimation of Invasive Breast Cancer in Cases of Ductal Carcinoma In Situ Diagnosed at Needle Biopsy

BACKGROUND The aim of this study was to evaluate the significance of FDG-PET/CT for predicting the underestimation of invasive breast cancer in cases of DCIS at needle biopsy. PATIENTS AND METHODS Of 83 consecutive cases with diagnoses of DCIS at primary needle biopsy who underwent curative surgery between 2010 and 2013, the association between the SUVmax on FDG-PET/CT before excision and the underestimation of invasive breast cancer was examined. RESULTS There were 29 (34.9%) cases diagnosed to have invasive breast cancer at excision. Receiver operating characteristics curve analysis showed the cutoff value of the SUVmax to predict underestimation of invasive breast cancer was 1.6. The rates of underestimation were 61.5% for patients with a tumor of SUVmax > 1.6 and 11.4% for patients with a tumor of SUVmax ≤ 1.6 (P < .001). A high value of SUVmax was significantly associated with symptomatic presentation (P < .001), palpability (P < .001), mass formation (P = .013), high Breast Imaging Reporting and Data System category (P = .011), and core needle biopsy (P = .007). In multivariate analysis, high SUVmax was only a significant predictive factor of underestimation of invasive breast cancer (hazard ratio, 11.7; 95% confidence interval, 3.70-37.0; P < .001). CONCLUSION SUVmax on FDG-PET/CT is useful for predicting the underestimation of invasive breast cancer in cases of DCIS at needle biopsy.

Detectability of Breast Tumor by a Hand-held Impulse-Radar Detector: Performance Evaluation and Pilot Clinical Study

In this report, a hand-held impulse-radar breast cancer detector is presented and the detectability of malignant breast tumors is demonstrated in the clinical test at Hiroshima University Hospital, Hiroshima, Japan. The core functional parts of the detector consist of 65-nm technology complementary metal-oxide-semiconductor (CMOS) integrated circuits covering the ultrawideband width from 3.1 to 10.6 GHz, which enable the generation and transmission of Gaussian monocycle pulse (GMP) with the pulse width of 160 ps and single port eight throw (SP8T) switching matrices for controlling the combination of 4 × 4 cross-shaped dome antenna array. The detector is designed to be placed on the breast with the patient in the supine position. The detectability of malignant tumors is confirmed in excised breast tissues after total mastectomy surgery. The three-dimensional positions of the tumors in the imaging results are consistent with the results of histopathology analysis. The clinical tests are conducted by a clinical doctor for five patients at the hospital. The malignant tumors include invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS). The final confocal imaging results are consistent with those of Magnetic Resonance Imaging (MRI), demonstrating the feasibility of the hand-held impulse-radar detector for malignant breast tumors.

Technical Feasibility and Cosmetic Advantage of Hybrid Endoscopy-Assisted Breast-Conserving Surgery for Breast Cancer Patients

BACKGROUND We developed a new procedure called hybrid endoscopy-assisted breast-conserving surgery (EBCS), which consists of a combination of plastic surgery and endoscopic surgery techniques. The purpose of this study was retrospectively to analyze the clinical outcome of hybrid EBCS and compare the cosmetic outcomes between hybrid EBCS and conventional breast-conserving surgery (CBCS). PATIENTS AND METHODS We reviewed medical records of patients who had undergone hybrid EBCS (n=73) or CBCS (n=90) between May 2005 and April 2011 and had been followed up in our department until March 2012. The clinical outcomes and cosmetic outcomes of these two groups were compared. The safety of hybrid EBCS was also analyzed by confirming its complications and pathological surgical margin. RESULTS In the hybrid EBCS group, operation time was longer by 30-50 minutes. Blood loss was not significantly different between the two groups. The surgical margin of hybrid EBCS was as follows: 1 patient (1.4%) had a positive margin, 4 patients (5.5%) had a margin of <2 mm, in 9 patients (12.3%) the margin was ≥2 mm and <5 mm, and in 59 patients (80.8%) it was ≥5 mm. Seven cases (9.6%) of postoperative complications occurred in 6 hybrid EBCS patients. To date, no local recurrence has been observed in hybrid EBCS patients (postoperative observation period, 18.1±5.6 months). Compared with the CBCS group, the hybrid EBCS group had better cosmetic results, especially with a less noticeable operative scar (P<.01). CONCLUSIONS Hybrid EBCS can provide sufficient free margin, and its surgical curability is acceptable. Additionally, this method is superior to CBCS in terms of cosmetic outcome.

Evaluation of Malignancy Grade of Breast Cancer Using Perflubutane-Enhanced Ultrasonography

Whether the contrast effects of perflubutane on contrast-enhanced ultrasonography can predict the malignancy grade of breast cancer is unknown. We analyzed associations between perfusion parameters created from time-intensity curves based on enhancement intensity and temporal changes in contrast-enhanced ultrasonography and clinicopathologic factors in 100 consecutive patients with invasive breast cancer. Values of perfusion parameters were significantly greater in estrogen receptor-negative than -positive tumors (peak intensity, p = 0.0002; ascending slope, p = 0.006; area under the curve, p = 0.0006). Variations in the peak intensity of Ki-67 were significantly correlated in all tumors (r = 0.54, p < 0.0001) and in luminal (r = 0.43, p = 0.0002), human epidermal growth factor receptor type 2-positive (r = 0.47, p = 0.047) and triple-negative (r = 0.55, p = 0.043) tumors. Perfusion parameters on contrast-enhanced ultrasonography can provide excellent predictive value for high-grade malignancy and might help to determine appropriate therapeutic strategies.