Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

The relation between mindfulness and the fatigue of women with breast cancer: path analysis.

BACKGROUND: Although fatigue is a common and distressing symptom in cancer survivors, the mechanism of fatigue is not fully understood. Therefore, this study aims to investigate the relation between the fatigue and mindfulness of breast cancer survivors using anxiety, depression, pain, loneliness, and sleep disturbance as mediators. METHODS: Path analysis was performed to examine direct and indirect associations between mindfulness and fatigue. Participants were breast cancer survivors who visited a breast surgery department at a university hospital in Japan for hormonal therapy or regular check-ups after treatment. The questionnaire measured cancer-related-fatigue, mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance. Demographic and clinical characteristics were collected from medical records. RESULTS: Two-hundred and seventy-nine breast cancer survivors were registered, of which 259 answered the questionnaire. Ten respondents with incomplete questionnaire data were excluded, resulting in 249 participants for the analyses. Our final model fit the data well (goodness of fit index = .993; adjusted goodness of fit index = .966; comparative fit index = .999; root mean square error of approximation = .016). Mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance were related to fatigue, and mindfulness had the most influence on fatigue (ß = - .52). Mindfulness affected fatigue not only directly but also indirectly through anxiety, depression, pain, loneliness, and sleep disturbance. CONCLUSIONS: The study model helps to explain the process by which mindfulness affects fatigue. Our results suggest that mindfulness has both direct and indirect effects on the fatigue of breast cancer survivors and that mindfulness can be used to more effectively reduce their fatigue. It also suggests that health care professionals should be aware of factors such as anxiety, depression, pain, loneliness, and sleep disturbance in their care for fatigue of breast cancer survivors. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN number. 000027720) on June 12, 2017.

Evaluation of the Clinical Utility of the ICG Fluorescence Method Compared with the Radioisotope Method for Sentinel Lymph Node Biopsy in Breast Cancer.

PURPOSE: This study compared the clinical utility of indocyanine green (ICG) fluorescence and radioisotope (RI) for sentinel lymph node (SLN) detection in breast cancer. METHODS: Women with node-negative breast cancer underwent SLN biopsy using ICG fluorescence and RI. The primary end point was the sensitivity of ICG fluorescence compared with RI in the patients with tumor-positive SLNs. Secondary end points included detection rates for SLN, the additive effect of ICG fluorescence to RI, signature of positive SLNs according to tier, and adverse events related to ICG administration. RESULTS: A total of 847 women with clinical node-negative breast cancer underwent SLN biopsy, and 821 patients were included in the per-protocol analysis. SLN mapping was performed using ICG fluorescence and RI. The overall detection of SLNs using ICG fluorescence was identical to RI (97.2 vs. 97.0 %, P = 0.88), and the combination of both methods achieved a significant improvement compared with RI alone (99.8 vs. 97.0 %, P < 0.001). The detection rate for tumor-positive SLN was 93.3 % for ICG fluorescence and 90.0 % for RI, and the sensitivity of the ICG fluorescence method was 95.7 % (95 % CI 91.3-98.3, P = 0.11). The additional use of ICG significantly improved positive SLN detection for RI (97.2 vs. 90.0 %, P < 0.001). There were no serious adverse events related to hypersensitivity to ICG. CONCLUSIONS: The ICG fluorescence method may be an acceptable alternative to SLN detection using RI in breast cancer.

Which patients require or can skip biopsy for breast clustered microcysts? Predictive findings of breast cancer and mucocele-like tumor.

BACKGROUND: In order to determine the patients who require biopsy for breast clustered microcysts, we retrospectively investigated cases of clustered microcysts that were detected by ultrasonography (US) examinations. METHODS: We investigated 52 patients in whom clustered microcysts were detected by US and who underwent biopsy at our institution between January 2011 and March 2014. These patients were divided into two groups according to histopathological findings: those with invasive carcinoma (IC), ductal carcinoma in situ (DCIS), or mucocele-like tumor (MLT) (Group 1), and those with benign lesions (Group 2). Mammography (MG) and magnetic resonance imaging (MRI) findings were assessed in these two groups. RESULTS: There were 12 patients in Group 1 (IC:2, DCIS:6, and MLT:4) and 40 patients in Group 2. In 51 of the 52 patients, MG was performed before biopsy. Since 11 of 12 patients in Group 1 exhibited MG findings (mass, focal asymmetry, coarse heterogeneous calcifications and fine pleomorphic calcifications) at the same site as the clustered microcysts, and that MG findings had a significant probability of detecting clustered microcysts categorized into Group 1 with a sensitivity of 91.7 % and negative predictive value (NPV) of 96.8 % (p < 0.001). In contrast, MRI was performed in 39 of the 52 patients, and only 3 of the 9 Group 1 patients (33.3 %) for whom MRI was performed were detected as MRI Category 4 or 5 enhancement. CONCLUSION: The patients who exhibit clustered microcysts with MG findings (mass, focal asymmetry, coarse heterogeneous calcifications and fine pleomorphic calcifications) appear to require biopsy.

Sonographic and pathologic image analysis of pure mucinous carcinoma of the breast.

The aims of this study were to elucidate sonographic and histologic features of pure mucinous carcinoma (P-MC) of the breast using quantitative analysis and to evaluate the relationship between quantitative analysis and visual qualitative assessment. Eleven P-MCs (nine patients) were evaluated qualitatively and quantitatively. Three experts assessed these sonographic images using the Breast Imaging Reporting and Data System (BI-RADS) lexicon. For assessment of internal echoes and posterior echoes, quantitative measures were determined using ImageJ software. Histologic thin sections were stained for classification into separate parts of the tumor (stroma, mucin and cancer cells) and were digitized. Internal echoes were isoechoic in 7 of 11 (63.6%) tumors and hypoechoic in 4 of 11 (36.4%); all P-MCs were "enhanced" in qualitative evaluation. As internal echoes increased, the proportion of stroma increased and that of mucin decreased. The high level of internal echoes is correlated with reflection and back-scattering, which are caused mainly by the interface between mucin and stroma.

Effect of the menstrual cycle on background parenchymal enhancement in breast MR imaging.

PURPOSE: We assessed the influence of the menstrual cycle on background parenchymal enhancement (BPE) of the breast in the early and delayed phases of dynamic magnetic resonance (MR) imaging and the optimal timing of MR imaging of the breast in Japanese women. MATERIAL AND METHODS: We reviewed dynamic MR images of 165 consecutive women with regular menstrual cycles and divided the women into 4 groups by week of the menstrual cycle: 32 in Week One (Days 1 through 4 of the menstrual cycle); 46 in Week 2 (Days 5 through 12); 49 in Week 3 (Days 13 through 20); and 38 in Week 4 (Days 21 through 30). We qualitatively evaluated BPE of the whole breast in the early and delayed phases of MR imaging; categorized enhancement as minimal, mild, moderate, or marked; and calculated the rate at which signal intensity increased (=SI post-SI pre/SI pre) in regions of interest in from the early and delayed phase to the before contrast administration phase to assess BPE quantitatively. RESULTS: In both the early and delayed dynamic MR phases, BPE was significantly more extensive and stronger in Week 4 than Week 2 (P<0.01). Throughout the menstrual cycle, BPE was significantly stronger in the delayed phase than in the early phase in both qualitative (Week One, P=0.0002; Weeks 2 through 4, P<0.0001) and quantitative (Weeks One through 4, P<0.0001) assessments. CONCLUSION: The optimal time to perform dynamic breast MR imaging in premenopausal Japanese women was during Days 5 through 12 of the menstrual cycle.

Lymphatic mapping with fluorescence navigation using indocyanine green and axillary surgery in patients with primary breast cancer.

The indocyanine green fluorescence (ICGf) navigation method provides real-time lymphatic mapping and sentinel lymph node (SLN) visualization, which enables the removal of SLNs and their associated lymphatic networks. In this study, we investigated the features of the drainage pathways detected with the ICGf navigation system and the order of metastasis in axillary nodes. From April 2008 to February 2010, 145 patients with clinically node-negative breast cancer underwent SLN surgery with ICGf navigation. The video-recorded data from 79 patients were used for lymphatic mapping analysis. We analyzed 145 patients with clinically node-negative breast cancer who underwent SLN surgery with the ICGf navigation system. Fluorescence-positive SLNs were identified in 144 (99%) of 145 patients. Both single and multiple routes to the axilla were identified in 47% of cases using video-recorded lymphatic mapping data. An internal mammary route was detected in 6% of the cases. Skip metastasis to the second or third SLNs was observed in 6 of the 28 node-positive patients. We also examined the strategy of axillary surgery using the ICGf navigation system. We found that, based on the features of nodal involvement, 4-node resection could provide precise information on the nodal status. The ICGf navigation system may provide a different lymphatic mapping result than computed tomography lymphography in clinically node-negative breast cancer patients. Furthermore, it enables the identification of lymph nodes that do not accumulate indocyanine green or dye adjacent to the SLNs in the sequence of drainage. Knowledge of the order of nodal metastasis as revealed by the ICGf system may help to personalize the surgical treatment of axilla in SLN-positive cases, although additional studies are required.

The role of breast MR imaging in pre-operative determination of invasive disease for ductal carcinoma in situ diagnosed by needle biopsy.

OBJECTIVES: To evaluate whether magnetic resonance (MR) imaging features can predict the presence of occult invasion in cases of biopsy-proven pure ductal carcinoma in situ (DCIS). METHODS: We retrospectively reviewed 92 biopsy-proven pure DCIS in 92 women who underwent MR imaging. The following MR imaging findings were compared between confirmed DCIS and invasive breast cancer (IBC): lesion size, type, morphological and kinetic assessments by ACR BI-RADS MRI, and findings of fat-suppressed T2-weighted (FS-T2W) imaging. RESULTS: Sixty-eight of 92 (74%) were non-mass-like enhancements (NMLE) and 24 were mass lesions on MR imaging. Twenty-one of 68 (31%) NMLE and 13 of 24 (54%) mass lesions were confirmed as IBC. In NMLE lesions, large lesions (P = 0.007) and higher signal intensities (SI) on FS-T2W images (P = 0.032) were significantly associated with IBC. Lesion size remained a significant independent predictor of invasion in multivariate analysis (P = 0.032), and combined with FS-T2W SIs showed slightly higher observer performances (area under the curve, AUC, 0.71) than lesion size alone (AUC 0.68). There were no useful findings that enabled the differentiation of mass-type lesions. CONCLUSIONS: Breast MR imaging is potentially useful to predict the presence of occult invasion in biopsy-proven DCIS with NMLE. KEY POINTS: MR mammography permits more precise lesion assessment including ductal carcinoma in situ A correct diagnosis of occult invasion before treatment is important for clinicians This study showed the potential of MR mammography to diagnose occult invasion Treatment and/or aggressive biopsy can be given with greater confidence MR mammography can lead to more appropriate management of patients.

Successful treatment of postoperative acute hepatic artery obstruction with mesenteric arterioportal shunt.

Fatal biliary complications and liver abscesses are likely in cases of acute hepatic arterial occlusion after hepatobiliary surgery with bilioenteric anastomosis. A 60-year-old man with hilar hepatic metastasis of gastric cancer underwent curative surgery. While the recurrent nodule was removed with the involved bile duct, vascular structures were preserved. Massive bleeding from the hepatic artery occurred suddenly on postoperative day 3, and the hepatic artery was ligated to stop bleeding. As Doppler ultrasonography indicated no arterial flow in the liver, a side-to-side mesenteric arterioportal shunt was created to prevent ischemic complications. Postoperative angiography showed fine patency of the shunt, and ischemic complications were avoided. However, the patient suddenly experienced massive hematemesis and fell into shock four months after the shunt operation. Upper gastrointestinal fiberoscopy showed serious varices throughout the whole esophagus. Angiographic examination indicated excessive shunt flow and markedly expanded mesenteric veins. The shunt was then occluded by coil embolization, but the patient did not recover from shock and eventually died. In the present case, the mesenteric arterioportal shunt appeared to be effective in relieving postoperative acute hepatic arterial occlusion. However, the shunt should be closed as soon as collateral blood flow is completed.

Distal gastrectomy with reconstruction of the right gastroepiploic artery for gastric cancer after coronary artery bypass grafting: report of a case.

A 61-year-old man was found to have anemia 3 years after an aortic valve replacement (AVR) and coronary artery bypass grafting (CABG) of the left intrathoracic artery to the left anterior descending artery and the right gastroepiploic artery (RGEA) to the right coronary artery (RCA) for aortic insufficiency and angina pectoris. A IIc gastric cancer in the antrum was subsequently diagnosed. Computed tomography (CT) and coronary angiography showed lymph node metastasis at the root of the RGEA, which perfused a large area of the inferoposterior wall of the heart. To prevent cardiac ischemia and perform complete #6 lymph node dissection, percutaneous intervention was carried out on the RCA before distal gastrectomy with D2 lymph node dissection, and the RGEA was reconstructed as a free graft to the left gastric artery. This procedure may be a surgical option for gastric cancer in patients who have undergone CABG using the RGEA.

Survival in nonocclusive mesenteric ischemia: early diagnosis by multidetector row computed tomography and early treatment with continuous intravenous high-dose prostaglandin E(1).

OBJECTIVES: The aim of the study was to establish a procedure for early diagnosis and treatment of nonocclusive mesenteric ischemia (NOMI). BACKGROUND: NOMI has a high mortality rate, and early diagnosis and treatment are important for improving survival in patients with this condition. METHODS: The subjects were 22 patients treated at our hospital over 13 years. Diagnostic criteria for NOMI were established based on the first 13 cases. In the 9 more recent cases, we performed abdominal contrast multidetector row computed tomography (MDCT) upon suspicion of NOMI based on these criteria. Imaging allowed definite diagnosis of NOMI, and continuous intravenous high-dose PGE1 administration was initiated immediately after diagnosis (dose, 0.01-0.03 microg/kg per min; mean administration period, 4.8 days). RESULTS: Nine of the first 13 patients died of multiple organ failure associated with multiple intestinal necrosis. These cases suggested that NOMI may develop when 3 of the following 4 criteria are met after cardiovascular surgery or maintenance dialysis in elderly patients: symptoms of the ileus develop slowly from abdominal symptoms, such as an unpleasant abdominal feeling or pain; a requirement for catecholamine treatment; an episode of hypotension; and slow elevation of the serum transaminase level. In the 9 recent cases, definite diagnosis was made from spasm of the principal arteries in arterial volume rendering and curved planar reformation MDCT images. Early treatment with PGE1 prevented acute-stage NOMI in 8 of the 9 cases. CONCLUSIONS: Early diagnosis of NOMI is possible using the above criteria and MDCT, and initiation of PGE1 treatment may increase survival in patients with NOMI.

Segment VI cholangiocholecystostomy for unresectable malignant obstruction at the hepatic hilum.

Anastomosis between the segment VI intrahepatic bile duct and the stump of the cystic duct was done to relieve obstructive jaundice caused by high biliary malignant obstruction. This procedure is considered to be a safe and easy method to provide good palliation in patients with unresectable hepatic hilar carcinoma.

Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF.

Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5' to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes.

Pushing the envelope: chromatin boundaries at the nuclear pore.

In a novel genetic screen, the nuclear-cytoplasmic transport system was found to reposition DNA to the nuclear pore and establish a barrier to the spread of heterochromatin. These data provide a mechanism for movement and attachment of DNA to a functional nuclear compartment.