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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Yoshimasa Kosaka,1– 3 Toshiaki Saeki,2 Toshimi Takano,4,5 Tomoyuki Aruga,6 Toshinari Yamashita,7 Norikazu Masuda,8,9 Yukio Koibuchi,10 Akihiko Osaki,2 Junichiro Watanabe,11,12 Ryu Suzuki13 1Department of Breast and Endocrine Surgery, Kitasato University School of Medicine, Sagamihara-shi, Kanagawa, Japan; 2Department of Breast Oncology, Saitama Medical University International Medical Center, Hidaka-shi, Saitama, Japan; 3Department of Breast Oncology, Japanese Red Cross Sagamihara Hospital, Sagamihara-shi, Kanagawa, Japan; 4Department of Medical Oncology, Toranomon Hospital, Minato-ku, Tokyo, Japan; 5Breast Medical Oncology Department, Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan; 6Department of Breast Surgery, Tokyo Metropolitan Center and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan; 7Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama-shi, Kanagawa, Japan; 8Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka-shi, Osaka, Japan; 9Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya-shi, Aichi, Japan; 10Department of Breast and Endocrine Surgery, National Hospital Organization Takasaki General Medical Center, Takasaki-shi, Gunma, Japan; 11Division of Breast Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan; 12Department of Breast Oncology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; 13Pharmaceuticals Group, Nippon Kayaku Co., Ltd, Kita-ku, Tokyo, JapanCorrespondence: Yoshimasa Kosaka, Department of Breast Oncology, Japanese Red Cross Sagamihara Hospital, 256 Nakano, Midori-ku, Sagamihara-shi, Kanagawa, 252-0157, Japan, Tel +81-42-784-1101, Email y-kosaka@med.kitasato-u.ac.jpBackground: NK105 is a paclitaxel (PTX)-incorporating “core-shell-type” polymeric micellar nanoparticle formulation composed of block copolymers (polyethylene glycol and a polyamino acid). The efficacy and safety of NK105 and paclitaxel in advanced or recurrent breast cancer have never been compared at equivalent dose levels.Patients and Methods: Patients were randomly assigned to either NK105 or PTX in a 1:1 ratio. The study drug was administered on Day 1, 8, and 15 of a 28-day cycle with 80 mg/m2. The primary endpoint was overall response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events.Results: A total of 123 patients (NK105, n=62; PTX, n=61) received one of the two drugs. There was no significant difference in ORR, the median PFS, or OS (NK105 group: 41.9%, 9.1, and 27.5 months, respectively; PTX group: 45.9%, 7.8, and 32.4 months, respectively). Neutropenia occurred more frequently in the NK105 group, but most patients did not require granulocyte-colony stimulating factor or dose-reduction. The median time to onset of peripheral sensory neuropathy (PSN) in the NK105 group was significantly longer than that in the PTX group (p=0.001), and PSN (≥ grade 3) was not observed in the NK105 group.Conclusion: Weekly NK105 administration was well-tolerated. Efficacy was similar in both groups. The PSN profile was better in the NK105 group.Keywords: polymeric micellar nanoparticles, chemotherapy-induced peripheral neuropathy, taxane, anti-polyethylene glycol antibodies, overall response rate

Tumor budding grade is a very useful histological prognostic indicator for colorectal cancer patients. Recently, it has been also reported as a significant prognostic indicator in invasive breast carcinoma patients. Our group and others have previously reported that the presence of a fibrotic focus in the tumor is a very useful histological finding for accurately predicting the prognosis in patients with invasive carcinoma of no special type (ICNST) of the breast. The purpose of the present study was to investigate whether a grading system incorporating tumor budding in a fibrotic focus is superior to the conventional grading system for tumor budding to accurately predict outcomes in patients with ICNST. According to our new grading system, we classified the tumors into grade I (164 cases), grade II (581 cases), and grade III (110 cases), and the results clearly demonstrated the significant superiority of the new grading system over that of conventional tumor budding alone for accurately predicting outcomes in patients with ICNST. Our findings strongly suggest that tumor cells and tumor-stromal cells interaction play very important roles in tumor progression rather than tumor cells alone.

Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders.Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769–78. ©2017 AACR.

Survival impact of FDG-PET metabolic response Kaplan-Meier survival analysis demonstrated that metabolic responders (n = 18) as measured by serial FDG-PET/CT scans with a cut-off value of 20% reduction of SUVmax, had a favorable outcome of overall survival compared to non-responders (n = 10) (log-rank test, p = 0.1). Multivariate analysis using the COX regression model demonstrated hormonal receptor negativity (HR 7.6, 95%CI 1.0-57.2, p = 0.04) as an independent predictor of poor survival when compared to PET non-responders (HR 7.2, 95%CI 0.9-57.6, p = 0.06) and distant metastasis (HR 2.5, 95%CI 0.4-14.9, p = 0.3).

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Background and Aim Balloon‐occluded retrograde transvenous obliteration (BRTO) has been widely adopted for the management of gastric fundal varices (GVs). There are a few reports that BRTO leads to the improvement of mid‐term and long‐term hepatic functional reserve (HFR). We retrospectively investigated the long‐term effect on HFR and prognosis among patients who had undergone BRTO for GVs. Methods This single‐center, retrospective study included 57successful patients out of 60 patients who underwent BRTO for GVs from December 2005 to September 2018. We examined the indicators of HFR (e.g., encephalopathy and ascites statuses, serum total bilirubin and albumin levels, % prothrombin time, and Child–Pugh and albumin–bilirubin [ALBI] scores) during 3 years of follow‐up after BRTO. We analyzed survival using the Kaplan–Meier method and identified the independent prognostic factors via multivariate analyses. Results GVs disappeared in all patients who were successfully treated by BRTO. At 3 years after BRTO, serum albumin levels were significantly elevated (from 3.3 to 4.0 g/dL, P = 0.008), while Child–Pugh and ALBI scores were significantly decreased (from 7.0 to 5.7, P = 0.043, and from −1.94 to −2.60, P = 0.006, respectively). The median survival time among all patients was 2207 days; the survival rates after BRTO were 87.0% at 1 year, 81.8% at 3 years, 67.3% at 5 years, and 44.1% at 10 years. Multivariate analyses revealed that ascites, hepatic encephalopathy, and malignant neoplasms were independently associated with poor prognosis. Conclusion BRTO for GVs has a favorable effect on long‐term HFR., Balloon‐occluded retrograde transvenous obliteration (BRTO) is a very powerful treatment that eradicates gastric varices. BRTO improves hepatic reserve in the mid‐ to long‐term mainly by increasing albumin level. Survival analysis showed poor prognosis in patients with low liver reserve and those with malignant neoplasms.

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by an acute deterioration of liver function in cirrhotic patients. Since treatment of this condition is difficult, its prevention is of paramount importance. The predictors of ACLF are yet to be identified. To determine the prognosis of cirrhotic and ACLF patients, we conducted a retrospective study to analyze each parameter in ACLF patients. Cirrhotic patients with serum total-bilirubin level ≥5.0 mg/dL and prothrombin time (PT) value ≤40% after acute insults were diagnosed with ACLF, whereas patients who met one of the above criteria were diagnosed with extended type of ACLF (EX-ACLF). Overall, in this study, 18 ACLF and 16 EX-ACLF patients retrospectively investigated between 2008 and 2020, and each data was analyzed during and before acute insults. In the analysis during acute insults, renal and coagulation functions showed significant differences between the ACLF and EX-ACLF groups. Furthermore, the mortality rate in the ACLF group was higher than that in the EX-ACLF group. In the analysis before acute insults, aspartate aminotransferase (AST), Fibrosis-4 (FIB-4) index score, and AST to platelet ratio index (APRI) showed significant differences between the two groups. Among these, the FIB-4 index score correlated best with ACLF severity for identifying cirrhotic patients with poor prognosis. The FIB-4 index is the most useful predictor of ACLF severity. Careful management of cirrhotic patients with a high FIB-4 index score is considered beneficial to prevent ACLF occurrence.

Background Eribulin is widely used in treating metastatic breast cancer (BC). Higher neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) are associated with higher mortality in several cancers. However, the association between BC prognosis and peripheral immune status remains controversial. We quantified the relative effects of NLR and PLR on survival in patients with recurrent/stage IV BC and evaluated their clinical prognostic value. Methods This retrospective study included 156 patients with recurrent/stage IV disease who received eribulin monotherapy at Saitama Medical University International Medical Center. We examined clinicopathological features (peripheral blood findings and biochemical liver and kidney function test results) and conducted univariate and multivariate analyses of the overall survival (OS). Results The 156 eribulin-treated patients had a median follow-up duration of 18.3 months. Before eribulin treatment, patients with absolute lymphocyte count (ALC) > 1500/uL, NLRs

Carney complex (CNC) is a rare multiple tumour syndrome characterized by cutaneous pigmented lesions, myxoma and endocrine tumours, among others, and is inherited as an autosomal dominant trait. Protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) is known to be the responsible gene. Breast myxomatosis and ductal adenoma, which are regarded as benign, are well-known mammary lesions of CNC and are included in the main diagnostic criteria. In this case, a 59-year-old woman with repeated cardiac myxoma was diagnosed with CNC with PRKAR1A mutation. She also had three multiple breast tumours bilaterally: breast cancer, adenomyoepithelioma and intraductal papilloma. In mammary lesions of CNC, attention should be paid to benign lesions, such as breast myxomatosis or ductal adenomas, and the development of breast cancer or breast tumours with malignant potential. Mammary lesions should be aggressively scrutinized and considered for resection, as required.

Introduction: U3-1402 is a novel, investigational ADC directed against HER3, which is widely expressed in breast cancer. Safety and preliminary antitumor activity of U3-1402 was previously reported in this ongoing, phase 1/2 clinical trial (NCT02980341/JapicCTI-163401). Here we report updated safety data from the dose escalation/dose finding (DE/DF) and phase 2 dose expansion parts, and we present for the first time efficacy data for patients in the expansion part with HR+/HER2− MBC with high or low levels of HER3 expression. Methods: In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2− MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg). Primary objectives included safety and efficacy of U3-1402; secondary objectives included correlative biomarker and pharmacokinetics analyses. Archival or pretreatment tissue obtained in the 6 months prior to U3-1402 treatment was analyzed by IHC for HER3 expression. Results: As of March 2020, all 4 expansion cohorts had completed enrollment. In the DE/DF and expansion parts combined, 172 patients received ≥1 dose of U3-1402 (114 [66%] had HR+/HER2− MBC). Median age was 56 y (range, 30-83 y); 123 (72%) and 49 (28%) patients had an ECOG PS of 0 or 1, respectively. Patients received a median of 6 (range, 1-14) prior systemic therapies. Median treatment duration of U3-1402 was 5 mo (range, 1-30 mo). 101 patients (59%) discontinued because of progressive disease, and 15 (9%) discontinued because of an AE. The most common grade ≥3 treatment-emergent AEs reported were decreased neutrophil count (43 patients [25%]), decreased platelet count (39 patients [23%]), decreased white blood cell count (28 patients [16%]), and anemia (31 patients [18%]). Nine patients (5%) experienced treatment-related interstitial lung disease according to central adjudication, including one grade 5 event. At data cutoff, 85 patients in the HR+/HER2− expansion part were evaluable for efficacy by blinded independent central review. Among 33 patients with HR+/HER2− HER3-high MBC treated with 4.8 mg/kg, 10 (30%) had a response (all partial responses [PRs]), with a clinical benefit rate (CBR; complete response + PR + stable disease for ≥6 mo) of 45% (15/33). Among 31 patients with HER3-high MBC treated with 6.4 mg/kg, 3 (10%) had a response (all PR) with a CBR of 16% (5/31). Among 21 patients with HER3-low MBC treated with 6.4 mg/kg, 6 (29%) had a response (all PRs) with a CBR of 33% (7/21). TNBC data are immature at the time of abstract data cutoff; efficacy by HR status will be provided in the presentation. Membrane HER3 expression levels were dynamic; they varied between archival and pretreatment biopsies and decreased on treatment with U3-1402. Across the doses evaluated, the U3-1402 AUC and Cmax of the total antibody, intact ADC, and released payload were approximately dose proportional, with minimal accumulation after multiple doses; the released payload Cmax was highest in cycle 1 and decreased in later cycles. Conclusions: In this heavily pretreated MBC population, U3-1402 demonstrated clinically meaningful antitumor activity in HR+/HER2− MBC with high or low levels of HER3 expression. The safety profile of U3-1402 was consistent with that previously reported, with 9% of patients discontinuing because of AEs. Clinical data pertaining to patients with TNBC and correlative analyses (including association of HER3 expression with response) will be presented. Citation Format: Ian Krop, Kan Yonemori, Shunji Takahashi, Kenichi Inoue, Takahiro Nakayama, Hiroji Iwata, Tatsuya Toyama, Yutaka Yamamoto, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O’Shaughnessy, Tiffany Traina, Shoichi Ohwada, Zhenhao Qi, Yang Qiu, Hiroshi Onuma, Om Sharma, Sabeen Mekan, Norikazu Masuda. Safety and efficacy results from the phase 1/2 study of U3-1402, a human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-09.

Portal-systemic encephalopathy is a hepatic encephalopathy caused by portosystemic shunts and is a poor prognostic factor for cirrhotic patients. Percutaneous transhepatic obliteration is an option for controlling portal-systemic encephalopathy. We report two cases of portal-systemic encephalopathy that were successfully controlled with percutaneous transhepatic obliteration.(Case 1) A 70-year-old woman experienced repeated portal-systemic encephalopathy due to a mesocaval shunt and a paraumbilical vein. She underwent percutaneous transhepatic obliteration with coils and 5% ethanolamine oleate-iopamidol. After treatment, portal-systemic encephalopathy became controllable. (Case 2) A 60-year-old man experienced repeated portal-systemic encephalopathy due to a left gastric vein shunt, a shunt from the posterior branch of the intrahepatic portal vein to the inferior phrenic vein, and a paraumbilical vein. He underwent percutaneous transhepatic obliteration of three portosystemic shunts with coils, 5% ethanolamine oleate-iopamidol, and N-butyl-2-cyanoacrylate. After treatment, the portal-systemic encephalopathy became controllable.Percutaneous transhepatic obliteration is particularly effective in cases involving multiple and complex portosystemic shunt pathways; however, percutaneous transhepatic obliteration is an invasive treatment, and its indications should be carefully considered. These cases will serve as a reference for successful treatment in the future cases.

AIM Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P

Breast cancer is the most common malignancy in women and has a risk of late recurrence. We report a case of metastasis to the stomach and colon 23 years after surgery, with characteristic findings. A 74-year-old woman underwent breast cancer resection at the age of 51. At the time, no additional therapy was performed despite the histological diagnosis of invasive lobular carcinoma with lymph node metastasis. Upper gastrointestinal endoscopy, which was performed as a follow-up for her chronic gastritis, revealed multiple erosions. Histology revealed diffuse proliferation of signet ring cell-like atypical cells, that were positive for cytokeratin CAM5.2 and estrogen receptor. These findings suggested metastasis from the invasive lobular breast carcinoma. Positron-emission tomography revealed sternal and vertebral metastases. Colonoscopy also performed to screen for intestinal metastasis revealed several lesions that resembled hyperplastic polyps. Although these lesions were not strongly suspected of metastasis, histology surprisingly revealed the same findings as the gastric metastasis. This case involved gastric and colorectal superficial metastases that were synchronously detected 23 years after primary treatment. We report that early-stage colorectal metastasis may resemble hyperplastic polyps, and biopsy should always be considered in patients with a history of breast cancer, regardless of years elapsed since treatment.

Secretory breast carcinoma constitutes the majority of breast cancers in children and young people less than 20 years of age. Noninvasive examination is particularly necessary for the diagnosis of breast carcinoma in children. Herein, we report a case of secretory breast carcinoma in a 6-year-old girl with psychomotor retardation. She was referred to our outpatient clinic for evaluation of a palpable mass in her left breast. A hard mass, rather than the increase in size typical of premature thelarche, was palpated. An excision biopsy was performed. Pathological findings revealed an invasive secretory breast carcinoma. We performed a retrospective review of the preoperative findings of this case, and compared it to the pathological diagnosis. Elastography, which can be performed without deep sedation or general anesthesia and without causing pain, resulted in a stiffness score of 4; however, the distinction between benign and malignant tumors on elastography, which is important to decide the intra-operative procedures, was not sufficient according to the Japanese breast cancer society clinical guidelines. This is the first report of secretory breast carcinoma in a child with a stiffness score determined by tissue elasticity imaging. A breast mass in a child with a high stiffness score of more than 4 on elastography should be referred for invasive diagnostic procedures, such as fine needle aspiration or excisional biopsy. According to our experience, an accurate preoperative diagnosis could be possible for malignant breast tumors in children. Such parameters as stiffness score on elastography are practical, noninvasive, and objective diagnostic tools for the accurate preoperative diagnosis of breast tumors in children.

Since generalized peritonitis is a fatal disease, accurate diagnosis and treatment are important. In this paper, we report a case of recurrent generalized peritonitis associated with spontaneous urinary bladder rupture (SBR). A 65 year old woman, who underwent radiotherapy 21 years prior, was diagnosed with generalized peritonitis. Although the cause of the generalized peritonitis could not be identified, the patient recovered with conservative treatment in short period. However, recurrent episodes of generalized peritonitis occurred four times. We diagnosed the patient with urinary ascites due to SBR, based on a history of radiotherapy and dysuria. No recurrence of generalized peritonitis had occurred after accurate diagnosis and treatment with long-term bladder catheter placement. Since SBR often occurs as a late complication after radiotherapy, it is difficult to diagnose SBR, which leads to delayed treatment. This case and literature review of similar cases suggest that the information of the following might be helpful in the diagnosis of SBR: (i) history of recurrent generalized peritonitis, (ii) pseudo-renal failure, (iii) history of radiotherapy, (iv) dysuria, and (v) increase or decrease of ascites in a short period. It is important to list SBR in the differential diagnosis by knowing the disease and understanding its clinical features. This case and literature review will serve as a reference for future practices.

Occult breast cancer is rare in practice. We studied the clinical outcomes of 5 occult breast cancers, including 2 with Luminal and 3 with non-Luminal subtypes, for which the primary site was not detected in the breast-by-breast MRI. The percentage of occult breast cancers that we encountered at our hospital was 0.11%. The mean age was 54 years. The Ki-67 labeling index value was 30% or higher for all the patients except one. Four patients were administered neoadjuvant chemotherapy and all but one patient received non-mastectomy and axillary dissection plus radiotherapy. We observed recurrent cases in one example each of the Luminal and HER2 subtypes, and both patients were less than 40 years old. The estimates of the probability of 5 year recurrence-free survival and 5 year overall survival were 40.0% and 66.7%, respectively. One recurrence case was a patient negative for ER and positive for HER2 wherein a breast cancer lesion appeared in the breast during post-treatment follow-up. Intrabreast relapse, which is itself rare in occult breast cancer, was observed 4 years postoperatively after standard treatment. Although there was no deviation according to subtype rate, the Ki-67 labeling index value was high and the prognosis was poor in our 5 cases.

Breast cancer arising from fibroadenoma (FA) is rare, in which almost all reported cases are human epidermal growth factor receptor 2 (HER2)-negative. This is the first report to describe a case of HER2-positive breast cancer arising from FA that was treated with chemotherapy plus anti-HER2 therapy. In this early case, upfront surgery outcomes guided the selection of appropriate systemic therapy. A 31-year-old woman previously diagnosed with FA experienced tumor growth. Core needle biopsy and imaging studies confirmed a diagnosis of stage IIA HER2-positive invasive ductal carcinoma (IDC) with no evidence of lymph node metastasis (cT2N0M0). Breast-conserving surgery was performed. Pathological diagnosis revealed stage IA IDC with a predominant intraductal component (pT1aN0M0), arising from FA. In conclusion, we encountered an extremely rare case of HER2-positive breast cancer arising from FA in which pathological infiltration was difficult to predict based on preoperative imaging.

Bone-modifying agents (BMAs), including bisphosphonate and anti-receptor activator of NF-κB ligand (RANKL) antibodies, are effective in treating bone metastases. The present study is a case report on the efficacy and side effects of long-term treatment with zoledronic acid, a BMA, in a 57-year-old woman. The patient was diagnosed with concurrent stage IV triple-negative breast cancer and stage II colon cancer. The patient experienced complete remission of both these cancers following chemotherapy, zoledronic acid treatment and irradiation for breast cancer and surgery for colon cancer. The patient received long-term zoledronic acid treatment and has survived >7 years after her initial diagnosis. The patient subsequently reported bilateral hip pain that was diagnosed as osteonecrosis of the femoral head, after the presence of bone metastases was ruled out using magnetic resonance imaging. The patient underwent bilateral artificial hip joint replacements. After orthopedic surgery, the multiple distant metastases, including a brain metastasis, remained in complete remission. It is well established that BMAs, such as zoledronic acid, increase the risk of osteonecrosis of the jaw, but it is not well understood if they can increase this risk in other anatomical locations. The findings of the present case study suggested that while long-term use of BMAs may be effective in managing bone metastases, it may increase the risk of osteonecrosis in anatomical locations other than the jaw.

Granulomatous mastitis is a rare breast disease that is categorized as a benign tumor with chronic inflammation. Since the cause of the chronic inflammation is usually unknown, it is sometimes called idiopathic granulomatous mastitis (IGM). Although imaging modalities, such as ultrasound, magnetic resonance imaging and mammography can detect tumors, they are sometimes unable to differentiate between benign and malignant tumors. In such cases, biopsy is needed to make a correct diagnosis. We experienced three cases of IGM after breast conserving surgery in breast cancer patients in whom we needed to rule out recurrence of breast cancer. In our cases, tumorectomy was performed in two cases for pathological diagnosis, since neither biopsy nor cytology was able to reveal a conclusive pathological diagnosis. Our management of these three cases might suggest the appropriate management of granulomatous tumors after breast conserving surgery in breast cancer survivors.

Objective Netupitant is a novel, selective neurokinin-1 receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting, a distressing side effect of chemotherapy. This double-blind, randomized, Phase II study investigated the dose-response of oral netupitant in Japanese patients receiving highly emetogenic chemotherapy. Methods Chemotherapy-naive patients were randomized (1:1:1) to a single oral netupitant 30-, 100- or 300-mg dose before chemotherapy initiation. Patients received concomitant palonosetron (0.75 mg intravenously [i.v.] Day 1) and dexamethasone (9.9 mg i.v. Day 1, 8 mg orally Days 2-4). Results Overall, 402 patients (30 mg: 134; 100 mg: 135; 300 mg: 133) were treated and evaluable for efficacy and safety. The primary endpoint of overall (0-120 h after chemotherapy administration) complete response (CR) rate (no emesis, no rescue medication) was 64.2%, 60.0% and 54.9% in the 30-, 100- and 300-mg arms, respectively, without statistical significance for dose-response. The safety profile of netupitant was comparable in the three arms. The plasma concentrations of netupitant and its metabolites increased with the dose increase from 30 mg to 300 mg. Conclusions No dose-response relationship of netupitant in terms of overall CR rate was observed in this study. Netupitant was well tolerated at all doses without clinically harmful safety signals observed. Clinical trial registration JapicCTI-142 483.

Rupture of gastric varices (GVs) can be fatal. Balloon-occluded retrograde transvenous obliteration (BRTO), as known as retrograde sclerotherapy, has been widely adopted for treatment of GVs because of its effectiveness, ability to cure, and utility in emergency and prophylactic treatment. Simplifying the route of blood flow from GVs to the gastrorenal shunt is important for the successful BRTO. This review outlines BRTO indications and contraindications, describes basic BRTO procedures and modifications, compares BRTO with other GVs treatments, and discusses various combination therapies. Combined BRTO and partial splenic embolization may prevent exacerbation of esophageal varices and shows promise as a treatment option.

Severe stenosis rarely occurs with radiation esophagitis after irradiation. We report our recent experience of a case of recurrent breast cancer in which the patient developed severe esophageal stenosis after receiving combined bevacizumab (Bev)-paclitaxel(PTX)therapy following radiotherapy for a thoracic vertebral metastasis. A 59-year-old woman with Stage ⅢB left breast cancer had undergone total mastectomy with axillary lymph node dissection after receiving neoadjuvant therapy. Elevated carcinoembryonic antigen levels were observed 23 months postoperatively, and multiple bone metastases were detected on PET-CT. After 5 sessions of irradiation with 20 Gy at the Th8-L1 level, combined Bev and PTX plus zoledronic acid was administered. The patient developed dysphagia at the end of the 4 cycles of combined Bev and PTX therapy, and her condition exacerbated subsequently. Therefore, upper gastrointestinal endoscopy was performed, which revealed a circumferential stenosis 31-37 cm from the incisors. We decided to perform the endoscopic treatment. After 3 balloon dilatations, her condition improved, and oral ingestion was possible. The esophageal stenosis might have been caused by the exacerbation of esophagitis because of the delayed wound healing effect of Bev in addition to radiation.

Breast cancer is the most common malignancy in women and has a risk of late recurrence. We report a case of metastasis to the stomach and colon 23 years after surgery, with characteristic findings. A 74-year-old woman underwent breast cancer resection at the age of 51. At the time, no additional therapy was performed despite the histological diagnosis of invasive lobular carcinoma with lymph node metastasis. Upper gastrointestinal endoscopy, which was performed as a follow-up for her chronic gastritis, revealed multiple erosions. Histology revealed diffuse proliferation of signet ring cell-like atypical cells, that were positive for cytokeratin CAM5.2 and estrogen receptor. These findings suggested metastasis from the invasive lobular breast carcinoma. Positron-emission tomography revealed sternal and vertebral metastases. Colonoscopy also performed to screen for intestinal metastasis revealed several lesions that resembled hyperplastic polyps. Although these lesions were not strongly suspected of metastasis, histology surprisingly revealed the same findings as the gastric metastasis. This case involved gastric and colorectal superficial metastases that were synchronously detected 23 years after primary treatment. We report that early-stage colorectal metastasis may resemble hyperplastic polyps, and biopsy should always be considered in patients with a history of breast cancer, regardless of years elapsed since treatment.

Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan. A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010–2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively. A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066–4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702–1.726). This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.

A 69-year-old man consulted a local doctor because of a chief complaint of fever and anorexia. CT showed a giant liver mass of the right hepatic lobe and multiple pulmonary nodules. The patient was admitted to our hospital. We punctured the liver mass, obtaining pus, and as gram-negative bacilli were detected from both blood and pus cultures, a liver abscess with septic pulmonary embolism was diagnosed. Following a positive string test, we identified the pathogenic bacteria as hypermucoviscous Klebsiella pneumoniae, which is highly invasive to the tissues. The patient showed improvement following the administration of an antimicrobial agent (Meropenem) and multiple abscess drainage procedures.

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients’ condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

[Background] Many of the tripartite motif (TRIM) proteins, like Efp/TRIM25 which was identified by our group previously (Nature 417, 871-875, 2002), function as E3 ubiquitin ligases, and are thought to be involved in various physiological and pathological processes such as immunity and oncogenesis. In regard to tripartite motif containing 44 (TRIM44), which is an atypical TRIM family protein lacking RING finger domain, some evidences suggest that it is implicated in the progression of several human malignancies. But its pathophysiological significance in breast cancer remains unknown. [Methods] In the present study, immunohistochemical analysis using anti-TRIM44 antibody was performed in clinical breast cancer tissues from 129 patients with the approval of institutional ethical committees (approval number: 845). We then explored the pathophysiological role of TRIM44 in breast cancer by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. [Results] TRIM44 strong immunoreactivity was significantly associated with nuclear grade, distant disease-free survival and overall survival of the breast cancer patients. With multivariate analysis it was shown that the TRIM44 status was an independent prognostic factor for distant disease-free survival and overall survival. The proliferation of MCF-7 and MDA-MB-231 cells was significantly decreased by siRNA-mediated TRIM44 knockdown. TRIM44 knockdown also suppressed migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR revealed that TRIM44 knockdown upregulated CDK19 (Cyclin Dependent Kinase 19), which is reported to be a tumor suppressor gene, whereas downregulated MMP1 (Matrix Metallopeptidase 1) in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. [Discussion] Our clinical study showed that prognosis of breast cancer patients is correlated with the immunoreactivity detected by anti-TRIM44 antibody. This result suggested that expression of TRIM44 protein could be used as a potential biomarker of breast cancer. We demonstrated that NF-κB signaling pathway is modulated by TRIM44. Since NF-κB augmentation is shown to be related to aggressive character of breast cancer, stimulation of NF-κB signaling with TRIM44 might be underlying mechanism of poor prognosis. Our in vitro study showed TRIM44 knockdown caused attenuated proliferation and migration of breast cancer cells, raising the possibility of TRIM44 as a potential therapeutic target for breast cancer. These findings provide new clues to develop alternative effective strategies for breast cancer management. Citation Format: Kawabata H, Azuma K, Ikeda K, Sugitani I, Kinowaki K, Fujii T, Osaki A, Saeki T, Horie-Inoue K, Inoue S. TRIM44 is a possible poor prognostic factor for breast cancer patients and positively regulates NF-κB signaling pathway [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-06.