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Background: The pathogenesis of lymph node metastases in preinvasive breast cancer – ductal carcinoma in situ (DCIS) – remains controversial. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can assess a whole node and detect clinically relevant metastases. In this retrospective cohort study, we determined the performance of the OSNA assay in DCIS and the pathogenesis of node-positive DCIS.Methods: The subjects consisted of 623 patients with DCIS who underwent sentinel lymph node (SN) biopsy. Of these, 2-mm-sectioned nodes were examined using frozen-section (FS) histology in 338 patients between 2007 and 2009, while 285 underwent OSNA whole node assays between 2009 and 2011. The SN-positivity rate was compared between cohorts, and the characteristics of OSNA-positive DCIS were investigated.Results: The OSNA detected more cases of SN metastases than FS histology (12 out of 285, 4.2% vs 1 out of 338, 0.3%). Most of the metastases were micrometastases. The characteristics of high-risk DCIS (i.e., mass formation, size, grade, and comedo) and preoperative breast biopsy (i.e., methods or time to surgery) were not valid for OSNA assay–positive DCIS.Conclusion: The OSNA detects more SN metastases in DCIS than FS histology. Further examination of the primary tumours and follow-up of node-positive DCIS are needed to elucidate the pathogenesis. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (-/-) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf−/− mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (TNBC) (for example, pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f− quiescent cells and CD49f+cells. Contrary to our expectation, CD49f− quiescent cells had high tumor-initiating potential and CD49f+cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f− quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC. [ABSTRACT FROM AUTHOR]

Abstract Background Acquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance. Results Through genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR. Conclusion These findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.

Abstract Background The impact of sentinel lymph node biopsy on breast cancer mimicking ductal carcinoma in situ (DCIS) is a matter of debate. Methods We studied the rate of occurrence of sentinel lymph node metastasis in 255 breast cancer patients with pure DCIS showing no invasive components on routine pathological examination. We compared this to the rate of occurrence in 177 patients with predominant intraductal-component (IDC) breast cancers containing invasive foci equal to or less than 0.5 cm in size. Results Most of the clinical and pathological baseline characteristics were the same between the two groups. However, peritumoral lymphatic permeation occurred less often in the pure DCIS group than in the IDC-predominant invasive-lesion group (1.2% vs. 6.8%, p = 0.002). One patient (0.39%) with pure DCIS had two sentinel lymph nodes positive for metastasis. This rate was significantly lower than that in patients with IDC-predominant invasive lesions (6.2%; p < 0.001). Conclusions Because the rate of sentinel lymph node metastasis in pure DCIS is very low, sentinel lymph node biopsy can safely be omitted.

Abstract Background The impact of skin invasion in node negative breast cancer is uncertain. Methods We determined the prognosis in 97 node negative breast cancer patients (case group) who had tumors with skin invasion. Then we compared these patients with 4500 node negative invasive breast cancer patients treated surgically in the same period. Results Patients with skin invasion tended to be older, had more invasive lobular carcinoma and larger tumor size, and were less likely to have breast conserving surgery than those in the control group. The 5-year disease-free survival rate in the case group was 94.0%. There was no significant difference in the 10-year disease-specific overall survival rates in terms of skin invasion in node negative patients (90.7% in the case group, 92.9% in the control group; p = 0.2032). Conclusion Results suggest that skin invasion has no impact on survival in node negative invasive breast cancer patients. The adjuvant regimens which the individual institute applies for node negative breast cancer should be used regardless of skin invasion.

Background: The OSNA (One Step Nucleic acid Amplification) assay is a semi-automated lymph node examination method using molecular biological technique. The OSNA assay has been validated for breast cancer patients without receiving preoperative systemic therapy (PST) by several clinical studies and has currently become more popular as sentinel lymph node (SLN) examination method with the following two main advantages; 1) to allow examination of the whole portion of a node, 2) to allow intraoperative judgment of metastasis positive or negative. However, the feasibility of the OSNA assay in breast cancer patients treated by PST has never been confirmed. In this multi-central clinical study, we compared the judgments of the OSNA assay and of pathological examination on lymph nodes dissected after receiving PST to evaluate the performance of the OSNA assay. Material & Methods: Three hundred two nodes dissected from the 80 breast cancer patients who received PST were examined. Each lymph node was divided at 2mm intervals and the slices were alternately applied to the OSNA assay and pathological examination with H&E staining and CK19 immunohistochemical staining of permanent-section. In pathological examination, judgments of metastasis positive or negative were determined by one central-review pathologist according to the criteria of AJCC 7th edition ("positive" if >0.2mm metastases were detected). Result: The overall concordance rate between the OSNA assay and pathological examination was 91.1% (275/302) with sensitivity of 88.3% (53/60) and specificity of 91.7% (222/242) (Table). These results are very similar to those of the Japanese clinical validation study in breast cancer patients without receiving PST which was conducted by the almost same protocol (Tamaki Y, et al. Clin Cancer Res, 2009, 15: 2879-2884). Conclusion & Discussion: These results indicate the OSNA assay can be applicable for breast cancer patients after receiving PST as well as breast cancer patients without receiving PST. The OSNA assay will enable to examine the whole portion of nodes, leading to more detection of metastases (especially micrometastases) and more exact nodal staging for breast cancer patients treated by PST. Also, for the patients who receive sentinel lymph node biopsy after PST, the OSNA assay will be useful as intraoperative examination method of SLNs because it is expected to provide more correct judgments than current intraoperative methods such as frozen-section or touch-print cytology. [ABSTRACT FROM AUTHOR]

Background: The standardized assessment of Ki-67 labeling index (LI) plays pivotal roles in identifying the patients (pts) with primary breast cancer who could benefit from systemic chemotherapy, in particular among pts with estrogen receptor(ER)-positive cancers. Therefore, in this study, we evaluated the inter-observer concordance of the assessment of Ki-67 LI in archival materials. Methods: Six surgical pathologists specializing in breast pathology from different Japanese institutions participated in this study. All slides were prepared from archival tissues of breast cancer fixed in 10% buffered formalin for 24 hours in a single institution (KU). Three independent studies were conducted. Study 1) Six consecutive slides were prepared from 5 cases. A slide from each case was stained with MIB-1 (DAKO, Denmark) in each institution according to their routine methods. Total of 30 stained slides were assessed for Ki-67 LI by each pathologist using two different modes of assessment. One is the scoring system in which the rate of positive cells was scored from 1 (0-9 %) to 10 (90-100%) without counting the cell number. The second one is the counting system in which approximately 1000 cells in total were counted in the hot spots and the positive rate was calculated. Study 2) Twenty tumors with Ki-67 LI ranging from 5 to 25 (15 ± 10) %, stained in a single institution (KU) were assessed by each pathologist by the counting system. Study 3) In order to avoid variations by assessment in varied microscopic fields and to further evaluate the variation of threshold of immunointensity interpreted as positive by different pathologists, fifteen printed photographs of Ki-67-stained slides were sent and assessed for Ki-67 LI by each participating breast pathologist. Results: Study 1) The counting system demonstrated a better correlation of Ki-67 LI among six pathologists than the scoring system {the intraclass correlation coefficient (ICC), 0.66 (95% confidence interval 0.52-0.78) for the counting system, 0.57 (0.42-0.72) for the scoring system}. The two assessment systems showed a moderate correlation {ICC, 0.68 (0.60-0.75)}. Study 2) The assessment of Ki-67 LI in 20 slides with Ki-67 LI of 5 to 25 % demonstrated a correlation similar to that in the specimens with an unrestricted range of Ki-67 LI in the study 1 {ICC, 0.68 (0.50-0.81) for the study 2, 0.66 (0.52-0.78) for the study 1}. Study 3) The assessment of Ki-67 LI in the same photographs yielded a considerably significant concordance among six pathologists {ICC, 0.94 (0.88-0.97)}. Conclusion: The counting system turned out better than the scoring system in terms of the inter-observer agreement of the Ki-67 LI assessment. The degree of concordance was by no means influenced by the range of Ki-67 LI. The concordance of the Ki-67 LI assessment among six participating pathologists was significantly high when the assessed field was fixed using the same photographs for evaluation, suggesting that the selection of the fields for evaluation is critical. These results suggest that identification of hot spots for evaluation is pivotal for obtaining the accurate Ki-67 LI of breast cancer and still images of these hot spots could provide reproducible results. [ABSTRACT FROM AUTHOR]

Background: An exchange maneuver is useful for the delivery of devices to target vessels. However, hemorrhagic complications can occur due to vessel perforation during an exchange maneuver. In addition, the exchange is often challenging due to unfavorable anatomy. Center Wire is an exchange-length wire with a nondetachable stent that was developed to improve navigation and stability during exchange maneuvers. The aim of this study is to investigate the safety and efficacy of Center Wire of the anchor wire technique during neuroendovascular treatment., Methods: Ten patients with intracranial aneurysms were treated after signing a Certified Review Board-approved consent. Anchor wire technique was used in all patients to navigate catheters to the target vessel for aneurysm treatment., Results: Anchor wire technique was successfully applied in all 10 cases using Center Wire. One device-related incident of vasospasm occurred which was asymptomatic. No device-related dissection, perforation, or thromboembolic events occurred. One patient had intraoperative aneurysm rupture during coil placement which was treated immediately without clinical consequences. Two patients had postoperative ischemic strokes due to thrombotic occlusion of branches originating from the aneurysm which were unrelated to the device., Conclusions: This first-in-human trial of Center Wire demonstrated the safety and efficacy of the anchor wire technique for neuroendovascular treatment in a strictly regulated prospective registry trial.

Background: ER+HER2+ breast cancer requires most types of systemic therapies perioperatively. However, treatment resistance is often experienced. The current study investigated the predictive and prognostic value of intratumoral heterogeneity and conventional clinicopathological factors in patients with ER+HER2+ breast cancer., Methods: This research included two patient cohorts with ER+HER2+ breast cancer. Cohort A included patients who underwent surgery without neoadjuvant chemotherapy (NAC). Cohort B comprised patients who received NAC followed by surgery. Intratumoral heterogeneity was assessed via ER and HER2 double staining, and the number of cells stained with different patterns of ER and HER2 was counted., Results: In total, 11 of 92 tumors in cohort A and four of 45 tumors in cohort B consisted exclusively of double-positive (ER+ and HER2+) cells (homogeneous). The rest had different combinations of cells (heterogeneous). The pathological complete response (pCR) rates differed based on tumoral cell components but not intratumoral heterogeneity. The pCR rate of tumors with ER-HER2+ cells but without HER2- cells was higher than that of others (45.5% vs 4.3%; p = 0.0013). Low ER and PgR Allred scores indicated better pCR rates than high scores (p = 0.0005 and 0.024, respectively). Multivariate analysis showed that the ER Allred score and cell component of ER-HER2+ cells without HER2- cells were independent predictors of pCR (p = 0.0055 and 0.0081, respectively). In cohort B, posttreatment Ki67, but not pCR, was a prognostic factor of DFS and OS (p = 0.028 and 0.017, respectively). The prognostic value of combined posttreatment Ki67 and pCR was superior to that of either alone. Combined pCR and posttreatment Ki67 had an independent prognostic value for DFS and OS (p = 0.0068 and 0.0101, respectively)., Conclusions: In ER+HER2+ breast cancer, the presence of ER-HER2+ cells without HER2- cells was independently associated with pCR. Combined posttreatment Ki67 and pCR can be more precise in predicting prognosis than pCR alone., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Flow diverter or stent implantation to intracranial target lesion requires large inner diameter microcatheter navigation. The exchange method using stiff long wire is often necessary if it is difficult to navigate over the regular guidewire. However, this method has an intrinsic risk of vessel damage and may cause severe complications. We investigated the safety and efficacy of a new device, the Stabilizer device for navigation in a first-in-human clinical trial under the Certified Review Board agreement., Materials and Methods: The Stabilizer is a 320 cm length exchange wire with a stent for anchoring and is compatible with a 0.0165" microcatheter. The trial design is a prospective single-arm open-label registry. Inclusion criteria are elective flow diverter treatment or stent-assisted coiling, expected to be difficult to navigate a microcatheter with a regular micro guidewire, and obtained documented consent. The primary endpoint of the study was a hemorrhagic complication., Results: Five patients were enrolled in this trial. The median age is 52 years, ranges from 41 to 70, and all patients were female. Three aneurysms were located on the internal carotid artery, one on the vertebral artery, and one on the basilar artery. Basilar artery aneurysm was treated by stent-assisted coiling and others were treated by flow diverter deployment. All cases successfully navigate microcatheter for the treatment by the trial method using Stabilizer device without any adverse event., Conclusions: The results from this first-in-human consecutive five cases show the safety of the Stabilizer device in neuro-endovascular therapy for navigation of devices to the intracranial target lesion., Competing Interests: The authors declare the following conflict of interests: This trial received trial devices from Bolt Medical, without specific grant. Grant from Kobe City Medical Center General Hospital support this trial. The authors, NS, NK and ST, were consultants of Bolt Medical at the treatment, but declare that this trial was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. 10.13039/100007057NS received a research grant from Biomedical Solutions, 10.13039/501100002973Daiichi-Sankyo, and Terumo; lecturer's fees from Asahi-Intec, Biomedical Solutions, 10.13039/501100002973Daiichi-Sankyo, and Medtronic; membership on the advisory boards for Johnson&Johnson, 10.13039/100004374Medtronic and 10.13039/501100008645Terumo without related this manuscript. HI received lecturer's fee from 10.13039/100004374Medtronic. NK has been a consultant for Stryker and Medtronic. 10.13039/501100004347ST received research funds from Biomedical Solutions, Rapid Medical and Medtronic, and a consultant for TG Medical, 10.13039/100008476Irvine Neurovascular, Balt USA, Cerenovus, 10.13039/100004374Medtronic, Phenox GmbH, MicroVention, Kaneka USA, Century Medical Inc., EnCompass, NVMedTech, and 10.13039/100008894Stryker. The other authors have no personal or financial interest in any of the materials or devices described in this article., (© 2023 The Author(s).)

Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two-dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging-based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near-infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label-free MPM imaging is a promising method for the real-time automatic diagnosis of breast cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Vasospasm, initial neurological damage, rebleeding, and periprocedural complications are associated prognostic factors for clinical outcomes after aneurysmal subarachnoid hemorrhage (SAH). In this study, factors related to delayed ischemic neurological deficit (DIND) are evaluated using data from our institute for the last 18 years. Data from 2001 to 2018 of patients with aneurysmal SAH who underwent surgical clipping (SC) or endovascular coiling (EC) within 7 days of onset were retrospectively analyzed. Cases of mortality within 5 days after treatment were excluded. Multivariate analysis was used to identify the risk factors for DIND. In total, 840 cases of SAH were assessed; among these cases, 384 (45.7%) and 456 (54.3%) were treated with SC and EC, respectively. The frequency of DIND in the EC group was significantly less than that in the SC group (11.8% vs. 17.7%; p = 0.016). In the results of multivariate analysis, internal carotid artery (ICA) aneurysm and hemorrhagic complications were the risk factors for DIND. Cilostazol administration and EC were significant factors for vasospasm prevention after aneurysmal SAH (odds ratio of ICA aneurysm: 1.59, hemorrhagic complications: 1.76, SC: 1.51, and cilostazol administration: 0.51, respectively). Cilostazol administration was also a significant factor in patients who were treated with EC. ICA aneurysm, treatment strategy, hemorrhagic complications, and cilostazol administration were associated with DIND. Oral administration of cilostazol and avoiding hemorrhagic complications were effective in DIND prevention. If both treatments are available for ruptured aneurysms, clinicians should choose EC on the basis of its ability to prevent DIND.

Objective: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists., Methods: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics., Results: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753)., Conclusion: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: With the increasing use of the Pipeline Embolization Device for the treatment of aneurysms, predictors of clinical and angiographic outcomes are needed. This study aimed to identify predictors of incomplete occlusion at last angiographic follow-up., Materials and Methods: In our retrospective, single-center cohort study, 105 ICA aneurysms in 89 subjects were treated with Pipeline Embolization Devices. Patients were followed per standardized protocol. Clinical and angiographic outcomes were analyzed. We introduced a new morphologic classification based on the included angle of the parent artery against the neck location: outer convexity type (included angle,  <160°), inner convexity type (included angle,  >200°), and lateral wall type (160° ≤ included angle  ≤200°). This classification reflects the metal coverage rate and flow dynamics., Results: Imaging data were acquired in 95.3% of aneurysms persistent at 6 months. Complete occlusion was achieved in 70.5%, and incomplete occlusion, in 29.5% at last follow-up. Multivariable regression analysis revealed that 60 years of age or older (OR, 5.70; P  = .001), aneurysms with the branching artery from the dome (OR, 10.56; P  = .002), fusiform aneurysms (OR, 10.2; P  = .009), and outer convexity-type saccular aneurysms (versus inner convexity type: OR, 30.3; P  < .001; versus lateral wall type: OR, 9.71; P  = .001) were independently associated with a higher rate of incomplete occlusion at the last follow-up. No permanent neurologic deficits or rupture were observed in the follow-up period., Conclusions: The aneurysm neck located on the outer convexity is a new, incomplete occlusion predictor, joining older age, fusiform aneurysms, and aneurysms with the branching artery from the dome. No permanent neurologic deficits or rupture was observed in the follow-up, even with incomplete occlusion., (© 2021 by American Journal of Neuroradiology.)

Objective: The efficacy and safety of acute percutaneous transluminal angioplasty or stenting (PTA/PTAS) for vertebrobasilar artery occlusion with atherothrombotic brain infarction (ATBI) have not been confirmed despite the resistance to medical therapy alone. There are few reports about this disease and its treatment. Therefore, the treatment outcomes at our hospital were summarized to evaluate the efficacy and safety., Methods: This was a retrospective study of acute PTA/PTAS for vertebrobasilar artery occlusion due to atherosclerotic change in 19 consecutive patients with a modified Rankin Scale (mRS) score of 0-2 before stroke between March 2010 and December 2018. The factors related to prognosis were investigated. Outcomes were assessed at 90 days of follow-up., Results: Of 19 patients with acute vertebrobasilar artery occlusion treated by PTA/PTAS, 8 had good outcomes (mRS 0-2) and 11 had poor outcomes (mRS 3-6). There were no differences in the clinical or patient background except for the National Institutes of Health Stroke Scale (NIHSS) score between groups. The good outcome group had a lower NIHSS score than the poor outcome group (median: 9.5 vs 35, p <0.001). The Thrombolysis in Cerebral Ischemia (TICI) 2b-3 group had a slightly more favorable outcome than the TICI0-2a group (p = 0.10). There were no differences in outcome between PTA and PTAS groups (p = 0.65)., Conclusion: Reperfusion of the posterior circulation by PTA/PTAS may be necessary for a good outcome. Although acute stenting must be performed under careful observation, a stent can be placed when recurrence in the early phase is estimated with high probability., Competing Interests: Hirotoshi Imamura received rewards as lecture fees from Stryker Japan and Medtronic Japan. Nobuyuki Sakai received research funds from Terumo Corporation, and rewards as lecture fees from Biomedical Solutions, Johnson & Johnson, Medtronic Japan, Penumbra, Stryker Japan, and Terumo Corporation. The remaining authors declare no conflicts of interest regarding the publication of this article., (©2021 The Japanese Society for Neuroendovascular Therapy.)

Background: Internal mammary and/or supraclavicular (IM-SC) lymph node (LN) recurrence without distant metastasis (DM) in patients with breast cancer is rare, and there have been few reports on its clinical outcomes., Methods: We enrolled 4237 patients with clinical stage I-IIIC breast cancer treated between January 2007 and December 2012. Clinicopathological features of patients with IM-SC LN recurrence and patients with DM were retrospectively reviewed., Results: With a median follow-up time 78 (range, 13-125) months after the primary operation, 14 (0.3%) had IM-SC LN recurrence without DM and 274 (6.5%) had DM at the first recurrence among 4237 patients. No statistical differences were found in the baseline characteristics of the primary tumor between the two groups. The 5-year overall survival (OS) rate after recurrence in patients with IM-SC LN recurrence was 51% compared with 27% in patients with DM (P = 0.040). In patients with IM-SC LN recurrence, clinically positive axillary LN at diagnosis and pathologically positive axillary LN at primary surgery were poor prognostic factors for distant disease-free survival (DDFS) (P = 0.004 and 0.007, respectively). Clinical and pathological axillary nodal status at primary surgery was associated with OS (P = 0.011 and 0.001, respectively)., Conclusions: Patients with IM-SC LN recurrence without DM who had no clinical and pathological axillary LNs involved at primary surgery had a favorable prognosis. A larger validation study is required.

Background: It is unknown whether patients with cytologically proven axillary node-positive breast cancer who achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have comparable prognosis to patients with axillary pathological node-negative disease (pN-) without NAC., Methods: We retrospectively reviewed the data of patients with cytologically proven axillary node-positive disease who received NAC and those with axillary pN- without NAC for control between January 2007 and December 2012. We compared outcomes according to response in the axilla to NAC and between patients with axillary pCR and matched pairs with axillary pN- without NAC using propensity scores., Results: We included 596 patients with node-positive breast cancer who received NAC. The median follow-up period was 64 months. Patients with axillary pCR showed significantly better distant disease-free survival (DDFS) and overall survival (OS) than patients with residual axillary disease (both p < 0.01). There was no significant difference in DDFS and OS between patients with axillary pCR and matched pairs with axillary pN- without NAC., Conclusion: Axillary pCR was associated with improved prognosis. Patients with axillary pCR and matched pairs with axillary pN- without NAC had comparable outcomes. This information will be useful when considering the intensity of follow-up and adjuvant therapy.

This retrospective study investigated factors influencing the portal vein thrombosis (PVT) volume and recurrence in 52 cirrhosis patients with PVT from November 2008 to September 2018. All patients were treated with danaparoid sodium with or without additional antithrombin III. Blood platelet counts significantly correlated with the PVT volume (r 2 = 0.17; P < 0.01). Computed tomography confirmed recurrence as PVT aggravation was reported in 43 patients, with ≥50% PVT volume reduction following anticoagulation therapy. In 43 patients, recurrence significantly correlated with the pretreatment PVT volume ( P = 0.019). Factors influencing recurrence included a Child-Pugh score >8 ( P = 0.049) and fibrosis index ≤7.0 based on four factors (FIB-4) ( P = 0.048). Moreover, the relationship between recurrence and correlating factors showed that 15 patients who received warfarin experienced recurrence more often when Child-Pugh scores were >8 ( P = 0.023), regardless of maintenance treatment. For patients who did not receive warfarin, a PVT volume ≥3.0 mL significantly influenced recurrence ( P = 0.039). Therefore, the platelet count influences the PVT volume. The pretreatment PVT volume correlated with recurrence after anticoagulation therapy. According to the Kaplan-Meier curve, risk factors for PVT recurrence after anticoagulation therapy included Child-Pugh scores >8 and FIB-4 ≤7.0. Therefore, the FIB-4 is a unique factor that shows trends opposing other liver function markers.

Dendritic cell (DC)-based immunotherapies are believed to help eradicate residual tumor cells, including hepatocellular carcinoma (HCC). Here, we assessed the safety and clinical response to OK432-stimulated monocyte-derived DCs (MoDCs) in treating HCC after radiofrequency ablation (RFA). MoDCs were derived from 30 HCC patients in the presence of interleukin-4 and granulocyte-macrophage colony stimulating factor for 5 days and then cultured for 2 more days in the medium (basic protocol) or stimulated with OK432. On day 7, DCs were harvested and percutaneously injected into HCC tumors after RFA. We observed no grade 3 or 4 National Cancer Institute Common Toxicity Criteria adverse events. Kaplan-Meier analysis indicated that patients treated with RFA + OK432-stimulated DCs transfer had longer recurrence-free survival than those treated with RFA + basic-protocol DCs (median: 24.8 vs 13.0 months; P = .003). RFA with DC infusion can enhance various tumor-associated antigen (TAA)-specific T-cell responses. Additionally, the 5-year RFS rate for patients with significantly increased TAA-specific T-cell responses was much higher than for other patients (50.0% vs. 7.7%; P = .030). Our study provides useful information for development of HCC immunotherapies (trial registration: UMIN000001701)., Competing Interests: Conflict of Interest The authors have declared no conflict of interest exists., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Portal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis., Methods: This retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1-5 and days 8-12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT., Results: All patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis., Conclusions: Danaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.

The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up-regulated in advanced chronic hepatitis C (CHC). We found miR-10a regulated various liver metabolism genes and was markedly up-regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR-10a was rhythmic and down-regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 ( Bmal1 ) by directly suppressing the expression of RA receptor-related orphan receptor alpha ( RORA ). Overexpression of miR-10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [ SREBP ] 1 , fatty acid synthase [ FASN ], and SREBP2 ), gluconeogenesis ( peroxisome proliferator-activated receptor gamma coactivator 1 alpha [ PGC1α ] ) , protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis-related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR-10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C-related liver cirrhosis, liver tissue miR-10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C-related hepatocellular carcinoma recurrence. Conclusion : MiRNA-10a is involved in abnormal liver metabolism in cirrhotic liver through down-regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR-10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis., (© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Background: This study aimed to evaluate the impact of previous local treatment on lymphatic drainage patterns in ipsilateral breast tumor recurrence (IBTR) based on our data on re-operative sentinel lymph node biopsy (re-SLNB) for IBTR., Methods: Between April 2005 and December 2016, re-SLNB using lymphoscintigraphy with Tc-99 m phytate was performed in 136 patients with cN0 IBTR. Patients were categorized into two groups: the AX group included 55 patients with previous axillary lymph node dissection; the non-AX group included 69 patients with previous SLNB and 12 patients with no axillary surgery. The whole breast irradiation (RT) after initial surgery had performed in 17 patients in the AX group and 27 patients in the non-AX group., Results: Lymphatic drainage was visualized in 80% of the AX group and 95% of the non-AX group (P < 0.01). The visualization rate of lymphatic drainage was associated with the number of removed lymph nodes in prior surgery. In the non-AX group, lymphatic drainage was visualized in 96% of patients without RT and 93% with RT. Lymphatic drainage was observed at the ipsilateral axilla in 98% of patients without RT and in 64% with RT (P < 0.0001). Aberrant drainage was significantly more common in patients with RT than without RT (60% vs. 19%, P < 0.001); it was observed mostly to the contralateral axilla (52% vs. 2%, P < 0.0001). In the AX group, patients with previous RT showed decreased lymphatic drainage to the ipsilateral axilla compared to those without RT (29% vs. 63%, P < 0.05) and increased aberrant drainage to the contralateral axilla (64% vs. 5%, P < 0.0001)., Conclusion: Lymphatic drainage patterns altered in re-SLNB in patients with IBTR and previous ALND and RT were associated with alterations in lymphatic drainage patterns.

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The value of assessing tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive/human epidermal growth factor receptor type 2 (HER2) negative breast cancer has yet to be determined. In the present study, a total of 184 cases with early distant recurrence detected within 5 years following the primary operation, 134 with late distant recurrence diagnosed following 5 years or longer and 321 controls without recurrence for >10 years following starting the initial treatment for ER-positive/HER2 negative breast cancer, registered in 9 institutions, were analyzed. The distributions of TILs and their clinical relevance were investigated. TIL distributions did not differ significantly among the early, late and no recurrence groups, employing a 30% cut-off point as a dichotomous variable. In those who had received adjuvant chemotherapy as well as endocrine therapy, a trend toward higher TIL proportions was detected when the early recurrence group was compared with the no recurrence group employing the 30% cut-off point (P=0.064). The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group). High TIL distributions also predicted shorter survival time following the detection of recurrence (P=0.026). However, these prognostic interactions were not significant in multivariate analysis (P=0.200). The present retrospective study demonstrated no significant interaction between TIL proportions and the timing of recurrence. However, higher TIL proportions were observed in breast cancer patients with aggressive biological phenotypes, which tended to be more responsive to chemotherapy. The clinical relevance of stromal TILs for identifying patients who would likely benefit from additional therapies merits further investigation in a larger patient population.

Background & Aims: The modest consumption of alcohol has been reported to decrease the incidence of fatty liver or prevalence of steatohepatitis. In this study, we investigated the effect of light alcohol consumption on liver function and gene expression in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: The study group was formed of 178 patients diagnosed with non-alcoholic fatty liver disease, subclassified into two groups for analysis based on the daily alcohol consumption: non-alcohol group and light alcohol consumer group (≤20 g of ethanol/day). Clinical characteristics, liver histological features, gene expression, comprehensively analyzed using microarrays (BRB-Array tools), and molecular network were evaluated and compared between the two groups., Results: No significant differences in steatosis or inflammation score were noted among the groups. However, the ballooning and fibrosis scores were significantly lower in the light alcohol consumer group than in the non-alcohol group. Gene expression analysis revealed a marked inhibition of the pathways involved in the immune response in the light alcohol group compared to that in the non-alcohol group., Conclusions: Light alcohol consumption might suppress activity of non-alcoholic steatohepatitis by reducing gene expression levels involved in the immune response. This inhibition in gene expression was associated with a lowering of liver fibrosis and hepatocellular injury.

Background: Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel therapy for patients with metastatic breast cancer. We performed a retrospective analysis assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel., Patients and Methods: Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively., Results: Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD ≥ 6 months) was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the EPN group (median 11.2 months, 95% CI: 9.5-12.9) was significantly longer than that of the non-EPN group (5.7 months, 95% CI: 4.6-6.8) (p<0.001). Multivariate analysis demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for TTF., Conclusion: The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel.

The present case is the first report in Japan in which a breast cancer was discovered as a result of prospective magnetic resonance imaging (MRI) screening study for BRCA1/2 mutation carriers who were free of breast or ovarian cancer. This case is significant and it verifies the importance of MRI screening in breast or ovarian cancer-free BRCA1/2 mutation carriers who do not exhibit positive mammographic or ultrasonographic findings.