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Capsular contracture is the most common complication with smooth-type silicone implants. We investigated the preventive effect of an active metabolite of tamoxifen, 4-hydroxytamoxifen (4-OH TAM), on capsular contracture.A silicone sheet was implanted into the back of 28 female ICR mice. Mixtures of gel with 0.2% 4-OH TAM and 0.1% 4-OH TAM were administered transdermally once a day for 4 weeks. Saline was administered to the control. After killing the mice, capsular thickness was measured in HE-stained specimens. Estrogen receptor (ER), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β) expressions were immunohistochemically investigated in the capsules.The capsule was thinner in the 0.2% 4-OH TAM gel group than in the control group (control, 0.1% 4-OH TAM gel, 0.2% 4-OH TAM gel: 52.8 ± 3.4 µm, 54.2 ± 6.8 µm, 46.4 ± 3.3 µm, respectively). ER was found in most fibroblasts of all samples. α-SMA expression in the capsule was significantly lower in the 4-OH TAM gel groups than in the control group (control = 70.0 ± 3.4%, 0.1% 4-OH TAM = 57.0 ± 3.4%, 0.2% 4-OH TAM = 49.4 ± 4.9%). TGF-β expression was significantly reduced by the 4-OH TAM gel injections dose-dependently (control = 67.3 ± 2.2%, 0.1% 4-OH TAM = 52.4 ± 3.1%, 0.2% 4-OH TAM = 45.1 ± 2.4%).The transdermal administration of 0.1% and 0.2% 4-OH TAM gels inhibited capsule development. The inhibition of TGF-β expression is a mechanism by which 4-OH TAM suppresses fibroblast growth, preventing capsular formation.

Background With the introduction of dose-dense therapy, the use of primary pegfilgrastim (PEG-G) has been increasing in breast cancer treatment. A rare side effect of PEG-G is aortitis. We describe a case of PEG-G-induced aortitis. Case presentation The patient was a 43-year-old woman with stage IIA breast cancer. Due to the subtype of triple-negative breast cancer, preoperative dose-dense epirubicin–cyclophosphamide chemotherapy was started. PEG-G was administered on day 3 after the first cycle of epirubicin–cyclophosphamide chemotherapy. On day 11, she had a fever (39.4 °C) and an elevated C-reactive protein level (27.1 mg/dL). Emergency computed tomography revealed diffused wall thickening of the aortic arch without any other signs of infection. Despite administering antibiotics, her general condition and laboratory findings deteriorated until day 18. Based on these observations, she was diagnosed with PEG-G-induced aortitis. Antibiotics were discontinued, and she was treated with prednisolone thereafter. Subsequently, her clinical symptoms and laboratory findings improved around day 39. A second computed tomography scan revealed a decrease in the aortic arch wall thickening, and she was discharged on day 43. Conclusions We successfully treated PEG-G-induced aortitis using prednisolone. Although this side effect is rare, cancer patients receiving PEG-G for chemotherapy should be monitored for aortic inflammation.

Purpose Male breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers. Methods This retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes. Results The median patient age was 71 (range 31–92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7–88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1–100.0). Conclusion Japanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.

Three-dimensional (3D) culture reflects tumor biology complexities compared with two-dimensional (2D) culture. Thus, 3D culture has attracted attention in cell biology studies including drug sensitivity tests. Herein, we investigated differences in anticancer drug sensitivities between 2D and 3D culture systems in triple-negative breast cancer (TNBC) cell lines. Thirteen TNBC cell lines were maintained in 2D and 3D cultures for 3 days before drug exposure. Cell morphology in the 3D culture was examined by phase-contrast microscopy. Sensitivities to epirubicin (EPI), cisplatin (CDDP), and docetaxel (DTX) were investigated by cell viability assay in both cultures and compared. The IC50s of all 3 drugs were significantly higher in the 3D culture than in the 2D culture in most cell lines. Those were correlated between the 2D and 3D cultures in EPI (R = 0.555) and CDDP (R = 0.955), but not in DTX (R = 0.221). Round spheroid-forming cells were more resistant to agents than grape-like types. In conclusion, 3D culture was more resistant to all 3 drugs than 2D culture in most TNBC cell lines. Sensitivity to CDDP was highly correlated between the 2D and 3D cultures, but not to DTX. 2D culture may be acceptable for sensitivity test for DNA-damaging agents.

Background/Aim: To investigate the utility of peripheral blood biomarkers – absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) – for predicting outcomes in eribulin-treated patients with metastatic human epidermal growth factor receptor type 2 (HER2)-negative breast cancer. Patients and Methods: ALC, NLR, and PLR were retrospectively obtained from pre-treatment blood sampling results of 120 patients and stratified according to means. Univariate and multivariate analyses were performed to investigate the association of clinicopathological factors, including these values, with overall survival (OS) and progression-free survival (PFS). Results: The ALC, NLR, and PLR cut-off points were 1,285/μl, 3.3, and 235, respectively. No biomarkers were associated with PFS. However, univariate analysis showed ALC (p=0.044) and PLR (p=0.044) to be significantly associated with OS. Conclusion: ALC and PLR can predict eribulin efficacy in terms of OS, reflecting the antitumour immune response in the microenvironment and indicating eribulin’s effectiveness.

A 52-year-old woman with a strong family history of breast cancer was diagnosed as having triple-negative breast cancer (TNBC) in her right breast. Neoadjuvant chemotherapy (NAC; four cycles of epirubicin/cyclophosphamide/5-fluorouracil) was performed, followed by breast-conserving surgery and axillary lymph node dissection. Histopathological analysis of the surgical specimens demonstrated a few focal tumor cells remaining in the stroma, but not a pathological complete response (pCR). Weekly paclitaxel was subsequently added to the treatment regimen. A total of 17 months after the adjuvant treatments, TNBC recurred in her left breast with massive lymph node metastasis. Because of the early recurrence after standard treatment, NAC was administered together with carboplatin and paclitaxel. Histopathological analysis of the partially resected breast and axillary lymph nodes demonstrated a pCR. No recurrent disease was found 2 years after the second TNBC treatment. This case underlines the importance of platinum-based chemotherapy and prophylactic mastectomy for patients with BRCA dysfunction.

Background Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. Case presentation We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. Conclusions Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

Using game theoretic modeling and multi-agent simulation, this study examines cooperation networks in business ecosystems. Business ecosystems generally involve various stakeholders, which develop complex and interdependent relations. Many related studies qualitatively assess these issues from actual case studies, but it is difficult to clarify the general mechanism that forms an ecosystem. In this study, particularly addressing cooperative behavior between agents in business ecosystems, we construct a game theoretic model of cooperation network formation based on Nowak's model of indirect reciprocity and Heider's balance theory. Multi-agent simulation demonstrates that in case agents have different abilities, a cooperation network is likely to collapse because low-ability agents leave the cooperative network. Furthermore, if the agents are able to imitate strategies, then simulation similarly demonstrates that cooperation is insufficiently constructed because of a delay of increasing evaluation values. However, the surviving cooperation network under the conditions of ability difference and strategy imitation forms strong cooperative relations. This result can be regarded as a strong coupling, whereas loosely coupled relations, as demonstrated by Iansiti and Levien, are desirable in terms of the health of ecosystems. Finally, we present discussion of how to form business ecosystems in terms of ability differences and strategy imitation.

Members of a series of macrocyclic bis(bibenzyl) riccardin-class derivatives were found to exhibit antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure–activity relationship (SAR) studies were conducted, focusing on the number and position of the hydroxyl groups. The minimum essential structure for anti-MRSA activity was also investigated.

Objective To determine an appropriate duration for a short course of oral steroids in cases of asthma exacerbations. Setting A 1, 000 bed city hospital in Kobe, Japan. Patients Patients with asthma exacerbations who needed hospital admission. Methods Following an initial treatment with a 3-day course of intravenous methylprednisolone, patients were allocated to either a 1-week (1W) or a 2-week (2 W) course of oral prednisolone (PSL, 0.5 mg/kg). Outcome measures Peak expiratory flow rate (PEF) and rate of unscheduled hospital visits and readmission. Results Twenty patients were enrolled (10 in 1 W, 10 in 2 W). Mean PEF just before starting oral PSL in 1W and 2 W were 51 and 58% of each patient's best value. PEF was significantly improved and to a similar degree over the course of time in both 1W and 2 W. The frequency of unexpected hospital visits during a 3-month period after discharge was similar (2 in 1W and 2 in 2 W). No readmission occurred during the same period. Conclusions Because both the 1-week and the 2-week course of oral PSL were equally effective in the treatment of asthma exacerbations, 1 week may be appropriate as the maximum duration of a short rescue course of oral steroids.(Internal Medicine 39: 794-797, 2000)

We prospectively investigated the etiology of community-acquired pneumonia among adult patients admitted to three general hospitals over one year. Antibody titers to Chlamydia pneumoniae were also measured by ELISA method to investigate the incidence and clinical pictures of C. pneumoniae pneumonia in Japan. Two hundred and fourteen patients were enrolled in the study. Seventeen patients (7.9%) satisfied the criteria for diagnosis of acute infection due to C. pneumoniae by ELISA method. C. pneumoniae was the 3rd leading causative agent following Streptococcus pneumoniae (21.5%) and Haemophilus influenzae (8.4%). Preexisting antibodies were detected in 62.1% of the patients. Most of the patients with C. pneumoniae pneumonia were aged, and had comorbidities of respiratory system. Superinfection with bacterial pneumonia was recognized in some patients. Though there are several problems, ELISA method is thought to be useful to diagnose C. pneumoniae pneumonia, and is suitable for screening tests.

血清カルシウム (Ca) が12mg/dl以上の中等症ないし重症の高Ca血症をきたした肺癌患者の臨床病態とその予後について検討した. 対象: 1990年8月～1998年4月の入院肺癌症例1126例のうち高Ca血症を呈した43例 (頻度3.8%).結果: 組織型は扁平上皮癌23例 (7.4%), 大細胞癌3例 (6.3%), 腺癌14例 (2.4%), 小細胞癌3例 (2.0%) で, 扁平上皮癌に多かった (p

縦隔腫瘍に対する超音波ガイド下針生検 (UGNB) の有用性を当科入院症例で検討した.対象は1995年4月から1998年4月の間に当科に初回入院した縦隔腫瘍の31例.病変が超音波で確認されたのはうち18例.前縦隔が最も多く15例であった.18例中3例では安全な穿刺が困難と判断し, UGNBを行わなかった.各生検時の穿刺回数は平均3.2回であった.UGNBを施行した15例中, 確定診断が得られた症例は9例 (60.0%) であった.悪性リンパ腫と胸腺癌の各1例では吸引細胞診でもclass Vと診断された.嚢腫の3例と胸腺腫7例中3例では, UGNBによる確定診断は得られなかった.合併症は2例で生じたが, 一過性なものであった.結論として, 嚢腫や胸腺腫の一部では診断がつかない場合もあったが, UGNBは概して安全で容易に施行でき, 有用と考えられた.

During the 7 years from 1990, thirty-two patients (20 in male and 12 in female, mean age; 53 years old) were diagnosed as having pulmonary cryptococcosis. To clarify the essential points for early diagnosis of pulmonary cryptococcosis, we reviewed the clinical records and chest images. Three patients had a past history of pulmonary tuberculosis and eleven patients had underlying disorders such as malignancy, chronic pulmonary diseases and so on, but no HIV infection, which would affect this disease. Eighteen patients did not have any past history nor complications. The symptoms such as cough, sputum, chest pain and fever were generally of low-grade, 14 patients had no symptom at diagnosis. Except of some patients with severe infections and severe underlying disorders, laboratory findings such as inflamatory and nutritious markers were almost within near the normal range. On plain chest X-ray films the distribution of lesions was almost in proprtion to the volume of the lobes. The multifocal nudular and/or infitrative shadows wer observed in about 2/3 cases and single lesion in about 1/3. The width of lesions were minimal except of one case with interstitial pneumonia and two cases with multifocal segmental pneumonia. The cavity lesions were observed in 7 cases and hilar lymphadenopathy in 3 cases. On CT images, the lesions were almost located in the outer zone, the lesions which were adjacent to the pleura were observed in 15 cases. Cavitary lesions were almost smooth in edge and ubiquitous, the walls were also thick. The peripheral air-bronchogram in the nodular/infitrative shadows were observed in three cases. Pulmonary cryptococcosis is air-borne and almost a chronic infection except in AIDS patients, so careful planning for examination is essential with considerations of the characteristics of clinical and imaging features of this infection.

BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers. It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present. STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases. For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required. This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed. Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT126.

A 46-year-old woman was referred to our hospital because of abnormal findings of 18F-fluorodeoxyglucose-PET (FDG-PET) scan at a medical check-up. Her chest radiography and CT showed nodular shadows distributed along the broncho-vascular bundle. The 1st FDG-PET showed a high FDG uptake in the pulmonary nodules, and the hilar, mediastinal and supraclavicular lymph nodes. Although sarcoidosis was suspected, diagnosis was not obtained by bronchoscopy. Thoracoscopic lung biopsy was performed in order to exclude malignancy, resulting in a definite diagnosis of sarcoidosis. No treatment was given and subsequently spontaneous regression was obtained. The follow-up FDG-PET showed no abnormal uptake at all. FDG-PET has been widely used in the assessment of malignancy, however recent reports have indicated that sarcoid lesions could have increased FDG activity. FDG-PET may be useful for diagnosis and monitoring in sarcoidosis.

This multi-institutional phase II study was designed to assess the feasibility, efficacy, toxicity, and long-term survival of induction chemoradiotherapy followed by surgery in previously untreated patients with advanced stage III non-small cell lung cancer. Chemotherapy regimen included cisplatin 20 mg/m2 on days 1-5 and 29-33, and VP-16 40 mg/m2 on days 1-5 and 29-33. Radiotherapy (50 Gy in 25 fractions) began on day 1. Clinically downstaged patients underwent thoracotomy 3-5 weeks after the completion of radiotherapy. Forty-two eligible patients (ten stage IIIA and 32 IIIB) were followed for a median period of 64 months. The response rate was 81%, and 20 patients had a clinically good response. Twenty-one patients underwent thoracotomy. Nineteen patients had complete resections and there were seven pathologic complete responses. There were four treatment related deaths (all stage IIIBs). There were significant survival differences between stage IIIA versus IIIB patients (P = 0.028; median survivals, 24.9 vs. 11.1 months; 5-year survival rates, 20% vs. 8.3%), and patients that achieved pathologic complete response (CR) versus those that did not (P = 0.045; median survivals 30.1 vs. 11.1 months; 5-year survival rates, 28.6% vs. 8.3%). Although the induction chemoradiotherapy employed in this study was not appropriate for stage IIIB patients, it proved feasible in stage IIIA patients in whom it resulted in good 5-year survival rates. It also provided good survival rates in patients achieving pathologic CR.

A 52-year-old male gardener, who traveled to Guam Island several days ago, was admitted to our hospital with fever, cough and dyspnea. His chest X-ray showed bilateral infiltration and he was severely hypoxic and hypotensive on admission. He died of multiple organ failure in spite of intensive treatment with mechanical ventilation antibiotics including erythromycin. Legionella longbeachae serotype 1 was isolated from his sputum and was regarded as the etiologic agent. Legionella longbeachae was not isolated from the same type of leaf mold that he used as potting soil. This is the first case of Legionella longbeachae pneumonia from whom the organism was isolated in Japan.

Until recently, inhaled corticosteroids have not been recognized as a first-line drug mainly because of the traditional polypharmaceutical approach to asthma in Japan. To examine the trend more precisely following the introduction of inhaled corticosteroids, we retrospectively analysed the relation between the number of prescriptions for anti-asthma drugs including inhaled corticosteroids and the number of hospitalizations due to asthma exacerbation, near fatal episodes and deaths from asthma for a period of 11 years from 1986 to 1996 at Kobe City General Hospital (KCGH). A marked decline in these actual indices in patients attending KCGH, which shows the improvement in asthma control, started coincidentally with the increased use of inhaled corticosteroid, which was followed by both a discontinuation of the trend for increased use of inhaled beta-agonists and the decreased use of oral anti-asthma agents. There was no significant difference in the mean duration of hospital stays between 1988 and 1996. Although the intensification of patient education is likely to play an important role in enhancing the protective effect of inhaled corticosteroids, we highly suspect that the major contributory factor in the great decline in hospitalizations is the increased use of inhaled corticosteroids.

Although the influence of high dose inhaled steroids on hypothalamo-pituitary-adrenal (HPA) function in patients with asthma has been extensively studied worldwide, there has been limited information on Japanese asthmatics, especially in terms of a prospective analysis of HPA function in the course of time. We analyzed the changes in HPA function using 2 serial short tetracosactrin tests (STT) separated by an interval of one year in 11 Japanese asthmatics who were treated with high dose inhaled steroids alone [beclomethasone dipropionate (BDP); mean dose 982 micrograms/day] during the period between 2 STTs. Mean values of plasma cortisol before administration of ACTH, maximum cortisol and the rise in cortisol in response to ACTH in the 2 STTs were 7.8, 20.5 and 12.7 micrograms/dl for the 1st test, and 8.9, 23.6 and 14.7 micrograms/dl for the 2nd test, respectively. Overall, there was no significant change in the course of time in each of these 3 values. Although the results of the 1st STT proved to be abnormal in 3 patients who had been receiving systemic steroids before their 1st STT, they improved uniformly in their 2nd STT. In the remaining 8 patients, who had never received systemic steroids, 4 patients showed improvements while the other 4 showed deterioration in HPA function in their serial STTs over the course of time. The dose of BDP was 800 micrograms/day in the former 4 patients, while it was 1,200 micrograms/day in the latter 4. Furthermore, only one patient, in whom BDP had been increased from 800 micrograms/day to 1,200 micrograms/day between the 2 tests, developed an abnormal response in the 2nd STT. On the other hand, one patient whose BDP dose was increased from 800 micrograms/day to 1,600 micrograms/day showed an improvement in HPA function in the 2nd test. These results indicate that the threshold dose of BDP which may cause HPA suppression in Japanese asthmatics lies between 800-1,200 micrograms/day, although there is a large inter-individual variation in terms of such doses.

We retrospectively studied the use of inhaled corticosteroids in patients who experienced near fatal episodes (NFE) to determine whether such therapy reduces the risk of death. Forty-eight patients who had near fatal episodes of asthma between January 1981 and December 1989 were divided into two groups. Group A comprised 19 patients who received beclomethasone dipropionate (BDP) daily (mean dose of BDP: 687 μg/day: 200-2, 000) following NFE, and Group B, 28 patients who did not take BDP or who took less than 6 mg BDP/month. During the follow-up period (Group A: 82.9 months, Group B: 66.2 months), no patients in Group A died, but eight deaths occurred in Group B (mean period between near fatal episode and death was 31.5 months: 12-66). These results suggest that the regular use of inhaled corticosteroids, even at low doses, may reduce the risk of death in patients who experience NFE.(Internal Medicine 34: 77-80, 1995)