Synthesis and Host-Guest Chemistry of Chiral Spirobifluorene-Based Macrocycles Soluble in Basic Aqueous Solution.

Synthesis and host-guest chemistry of water-soluble (pH 12.5) chiral spirobifluorene-based macrocycles 2-[n] were carried out. Cationic guests, such as quaternary ammonium salts, were accommodated well in the hosts. Cp2Co+ was especially strongly bound in 2-[4] (Ka of up to 3.0 × 105 M-1). Enantioselective recognition with (l)-carnitine was also achieved.

Pid3-I1 is a race-specific partial-resistance allele at the Pid3 blast resistance locus in rice.

KEY MESSAGE: The rice blast resistance QTL detected on chromosome 6 in MC276 is Pid3-I1, one of the multiple alleles at the Pid3 locus. Pid3-I1 shows race-specific partial resistance. Many of the quantitative trait loci (QTLs) for rice blast resistance reported to date remain unidentified. In the present study, we focused on qBRM6.2, a known blast-resistance QTL in experimental resistant rice line MC276. A CO39 near-isogenic line (NIL) carrying qBRM6.2 from MC276 was developed here, and we showed that qBRM6.2 resistance was partial but race specific to Japanese blast isolates using the NIL. Because defense genes in the NIL were expressed sooner than those in CO39 after inoculation with a blast isolate, qBRM6.2 resistance appeared to be an induced resistance. Next, we demonstrated that qBRM6.2 was located within a 123-kb interval on chromosome 6. Among the six genes annotated in the interval, only four genes appeared to be functional. Among these four, a polymorphism between CO39 and the NIL for qBRM6.2 at the amino acid sequence level was detected only in Os06g0330400 that encodes a fatty acid hydroxylase domain-containing protein and in Os06g0330100, the blast resistance locus Pid3, that encodes a nucleotide-binding site-leucine-rich repeat protein. Moreover, the allele at the Pid3 locus in the NIL was Pid3-I1, originally identified as a complete blast resistance gene in Kasalath. To clarify whether Pid3-I1 is qBRM6.2, we investigated the resistance phenotype of Pid3-I1 to Japanese isolates using Nipponbare transgenic lines that express Pid3-I1. The results showed that Pid3-I1 was a race-specific but partial-resistance allele at the Pid3 locus, suggesting strongly that Pid3-I1 is qBRM6.2. The discrepancy in the phenotype of Pid3-I1 between the present and previous reports is also discussed.

Construction of a System for the Strawberry Nursery Production towards Elimination of Latent Infection of Anthracnose Fungi by a Combination of PCR and Microtube Hybridization.

One of the major problems in strawberry production is difficulty in diagnosis of anthracnose caused by Colletotrichum acutatum or Glomerella cingulata in latent infection stage. We here developed a diagnostic tool for the latent infection consisting of initial culturing of fungi, DNA extraction, synthesis of PCR-amplified probes and microtube hybridization (MTH) using a macroarray. The initial culturing step is convenient to lure the fungi out of the plant tissues, and to extract PCR-inhibitor-free DNA directly from fungal hyphae. For specific detection of the fungi, PCR primers were designed to amplify the fungal MAT1-2 gene. The subsequent MTH step using the PCR products as probes can replace the laborious electrophoresis step providing us sequence information and high-throughput screening. Using this method, we have conducted a survey for a few thousands nursery plants every year for three consecutive years, and finally succeeded in eliminating latent infection in the third year of challenge.

[Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Multiple Metastatic Breast Cancer Patients].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)during fulvestrant therapyfor multiple metastatic breast cancer patients. IDO activitycan be measured using the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured using high-performance liquid chromatography(HPLC). The serum Trp/Kyn level in patients with multiple metastatic breast cancer was lower than in patients without metastases. IDO activityincreased after breast cancer metastases developed. IDO activitywas correlated with the number of metastatic lesions during toremifene and fulvestrant therapy. These results suggested that measurement of the Trp/Kyn ratio is useful to evaluate immunological metastatic status during endocrine therapy.

[Study of the Relationship between Obesity and Lymphocytes in Breast Cancer Patients Undergoing Chemotherapy].

Obesitychanges the regulatorymechanisms of the immune system, resulting in impaired immunity. In cancer immune mechanisms, the greater the degree of obesity, the lower the activity of the lymphocytes. Herein, we examined the relationship between obesity and lymphocytes in breast cancer patients undergoing chemotherapy. We recruited 10 recurrent or metastatic breast cancer patients who were administered eribulin. Using bodymass index(BMI), we classified these patients into a non-obese group(BMI<25)and an obese group(BMI>25). We measured the number of lymphocytes before chemotherapy and 8 days after eribulin administration. We examined the decreasing rates of lymphocytes before and after eribulin administration in the 2 groups. The average age was 63.1 years. Non-obese and obese groups comprised 6 and 4 cases, respectively. The average rates of lymphocyte decrease before and after eribulin administration were 13.3%and 12.3% in the non-obese and obese groups, respectively. There were no significant differences between the 2 groups.

[Study of the Immunological Stress Caused by Breast Surgery Methods].

To determine the role of immunosuppressive acidic protein(IAP)in the host defense of surgical patients, we investigated the kinetics of the post-operative elevation of IAP, as well as factors influencing the increase in serum IAP concentration, in 17 patients who underwent breast surgery. IAP was not increased in the pre-operation phase, post-operation phase, or 2 weeks after surgery, byvarious breast surgerymethods. In contrast, IL-6 was increased in the post-operation phase byall breast surgerymethods. IL-6 correlated with anesthesia time. These results suggest that breast surgical methods are less immunologicallyinvasive than other major surgery.

[Clinical Evaluation of Immunosuppressive Acidic Protein in the Serum of Patients with Locally Advanced Breast Cancer during Mohs Paste Treatment].

Locallyadvanced breast cancer lesions often compromise the patient's qualityof life(QOL). Mohs paste is a histopathological fixative containing zinc chloride as the main ingredient. It has been applied to perform chemosurgeryon skin tumors. In recent years, this paste has reportedlybeen veryeffective for controlling various symptoms of skin metastases in inoperable advanced cancer, such as pungent odor and hemorrhage, in the field of palliative care. We evaluated the clinical significance of immunosuppressive acidic protein(IAP)and C-reactive protein(CRP)in the serum of patients with locallyadvanced breast cancer duringMohs paste treatment. The tryptophan(Trp)/kynurenine(Kyn)ratio measures IDO activity. Trp and Kyn were measured byhigh performance liquid chromatography(HPLC). We took serum samples from 3 locallyadvanced breast cancer cases, in the pre-treatment phase, 2 times after the treatment phase, and 5 times after the treatment phase. Then, we measured IAP and CRP in these samples during Mohs paste treatment. Serum IAP values did not differ significantlybetween each of the phases; however, serum CRP values were decreased byMohs paste treatment. These results suggested that Mohs paste treatment for locallyadvanced breast cancer lesions was useful for enhancing the patient QOL, without immunosuppression.

[Indoleamine 2,3-Dioxygenase Activity in Intracystic Breast Tumors].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)in intra-cystic tumors of the breast. IDO activitycan be measured byusing the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured by high performance liquid chromatography(HPLC). We took liquid from 3 intra-cystic papilloma cases and 5 intra-cystic breast cancer cases. Then, we measured the Trp/Kyn ratio in these samples, and we evaluated the difference in the Trp/Kyn ratio between the papilloma group and the breast cancer group. The Trp/Kyn ratio was significantly lower in the breast cancer group than in the papilloma group. These results suggest that measuring the Trp/Kyn ratio in cystic liquid from intra-cystic breast lesions is useful to distinguish benign intra-cystic lesions from malignant intra-cystic lesions.

[Difficult Decision about a Surgical Margin for a Non-Invasive Apocrine Carcinoma in the Breast - Report of a Case].

We report a case of non-invasive apocrine carcinoma. In this case, we could not identifythe surgical margin. The patient was 39-year-old woman. Micro calcifications were discovered on her right breast during breast cancer screening. Stereotactic vacuum assisted core needle biopsywas performed and the pathological diagnosis was sclerosing adenosis. A low echoic lesion, 26mm in diameter, was discovered in the CDE area of her left breast byultrasonography . A contrast enhanced MRI showed a high intensityarea, 26mm in diameter, on her left breast. Ultrasonographyguided vacuum assisted core needle biopsywas conducted on the low echoic area. The pathological diagnosis was non-invasive ductal carcinoma. We checked her whole bodyand found no metastatic lesion. She underwent breast conserving surgeryplus sentinel lymph node biopsy. We had great difficultyin classifying the surgical margin. The pathological diagnosis from the resected surgical specimen was non-invasive apocrine carcinoma, negative for ER and PgR, and positive for HER2/neu protein expression. The Ki-67 labeling index was 20%, the surgical margins were negative, and the clinical Stage was 0(Tis, N0, M0). She was administered radiation therapy and endocrine therapy as adjuvant therapy. Two years and 6 months after surgery, she is well without metastasis.

[Axillary Lymph Node Dissection and Chemotherapy were Useful for Occult Cancer - Report of a Case].

We report a case of occult cancer. In this case, axillaryly mph node dissection and chemotherapywere useful treatments. The patient was a 71-year-old woman who had left axillaryly mph node swelling. Mammographyshowed the swollen axillary lymph nodes, but there was no lesion in either breast. Ultrasonographyalso showed the swollen axillaryly mph nodes, but there was no malignant lesion in her breasts. CT showed swollen axillaryand mediastinal lymph nodes. We checked her entire body, but could not find a malignant lesion, so we diagnosed an occult cancer. She underwent axillary lymph node dissection. The pathological diagnosis from the resected surgical specimen was metastatic carcinoma, negative for ER and PgR, and negative for HER2/neu protein expression. She was given TC chemotherapyand her CEA value decreased. After 8 cycles of TC chemotherapy, she was well without metastasis.

[Effectiveness of Lenvatinib for Thyroid Cancer with Lung Metastases - Report of a Case].

A 73-year-old woman visited our hospital 1 year 4 months ago because of multiple lung masses that were incidentally detected on CT. We subsequently conducted a whole body examination. Ultrasonography revealed multiple masses in her thyroid. We performed fine needle aspiration biopsy cytology(ABC), and the cytological diagnosis was papillary carcinoma. Total thyroidectomy and modified radical neck dissection were performed. Two months after the operation, cervical lymph nodes were enlarged, and she received I -131 radioisotope therapy. However, the lung masses became enlarged. Five months after operation, she was stared on lenvatinib therapy. The lung lesions did not progress during the 10 months after starting this therapy. In this case, lenvatinib was effective against metastatic thyroid cancer.

[Breast Cancer with Microinvasion and Lymph Node Metastasis Diagnosed by Microdochectomy - Report of a Case].

We report a case of breast cancer with microinvasion and lymph node metastasis. The patient was a 72-year-old woman who had spontaneous nipple discharge from her left breast. There was no detectable lesion on mammographyor duct endoscopy. Ultrasonography showed a low echoic lesion, 23×15mm in diameter, in the CD area of her left breast. Contrastenhanced MRI showed a high intensityarea, 25mm in diameter, in her left breast, so microdochectomywas performed. The histopathological diagnosis was invasive ductal carcinoma(invasion of 2mm)and the surgical margin was positive. Therefore, she underwent breast conserving surgeryplus axillaryly mph node dissection. The pathological diagnosis from the resected surgical specimen was invasive ductal carcinoma with micro lymph node metastasis, positive for ER and PgR and negative for HER2/neu protein expression. The Ki-67 labeling index was 10% and the surgical margins were negative. She was treated with radiation and endocrine therapy as adjuvant therapy. One year and 6 months after surgery, she was well without metastasis.

[Intra-Cystic Mucinous Carcinoma of the Breast - A Case Report].

A 75-year-old woman consulted our hospital for a lump on her left breast. The tumor was 5 cm in diameter and was palpable in the ABE area. The tumor was identified as an intra-cystic tumor using ultrasonography. Contrast-enhanced magnetic resonance imaging showed a tumor with cystic components that were slowly stained in a dynamic study. A fine needle aspiration biopsywas performed, and the pathological diagnosis was class V. Metastatic work-up revealed no evidence of metastasis. Therefore, we determined the clinical stage as T3N0M0, stage II B. Breast reduction surgeryand sentinel lymph node biopsywere performed on the left breast. The histopathological findings from the surgicallyresected specimens showed mucinous components with some invasive ductal components. Therefore, the pathological diagnosis was mixed mucinous carcinoma of the breast. The tumor size was 8 cm in diameter. Here, we report a case of mucinous carcinoma that showed a huge intra-cystic tumor, which is rarely described in the literature.

[Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy.

[Examination of the Response Rate of Paclitaxel and Bevacizumab Therapy for Metastatic Advanced Breast Cancer According to the Lymphopenia Grade].

Bevacizumab is a well-established anti-VEGF monoclonal antibody that inhibits angiogenesis. Herein, we examined the response rates according to the grade of lymphopenia in metastatic breast cancer patients treated with bevacizumab+paclitaxel therapy. The objective responses were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guideline v1.1. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Twenty study patients were divided into group A (grade 2-4 lymphopenia) and group B (grade 1 lymphopenia or no decreased lymphocyte count) and compared. The mean progression-free survival (PFS)was 77.7 days in group A (n=7) and 56.8 days in group B (n=13). There was no significant difference between both groups (p=0.67, logrank test). The response rate (RR) was 14.3% (CR=0, PR=1, SD=3, PD=3) in group A, while in group B, it was 23.0% (CR=0, PR=3, SD= 6, PD=4). Furthermore, the clinical benefit rate (CBR) bwas 57.1% in group A and 69.2% in group B.

[Indoleamine 2,3-Dioxygenase Activity during I131-Radioisotope Therapy for Metastatic Thyroid Cancer].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during I131-radioisotope therapy for metastatic thyroid cancer. The IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by using high performance liquid chromatography (HPLC). The serum Trp/Kyn levels of were lower in thyroid cancer patients with lung metastases than in patients without metastases. The IDO activity increased after the development of lung metastases from thyroid cancer. The IDO activity was correlated with the number of metastatic lesions during I131-radioisotope therapy. These results suggest that measurement of the Trp/Kyn ratio is useful in the evaluation of the immunological metastatic status during I131-radioisotope therapy.

[Study of the Response Rate and Neutrophil Lymphocyte Ratio in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy].

The neutrophil lymphocyte ratio (NLR) is associated with the outcomes of some cancer patients such as those with digestive cancer. Herein, we examined the relationship between the response rate following neoadjuvant chemotherapy and NLR in breast cancer patients. We recruited 19 primary breast cancer patients who were administered neoadjuvant chemotherapy. We evaluated the effects of this treatment and classified the patients into responder (CR and PR) and non-responder (SD and PD) groups. We measured the value of NLR before or at the start of nab-PTX treatment, and 7 days after nab-PTX (1-1) and nab-PTX (4-3) treatment. The average age was 58.6 years. The responder and non-responder groups comprised 14 and 5 cases, respectively. The average values of NLR before or at the start of the nab-PTX phase were 4.33 and 5.05 in the responder and non-responder groups, respectively. The average NLR values 7 days after nab-PTX (1-1) were 6.72 and 5.60 in the responder and non-responder groups, respectively. The NLR values 7 days after nab-PTX (4-3) were 2.40 and 2.65 for the responder and non-responder groups, respectively. There were no significant differences between the responder and non-responder groups for each treatment phase.

[Usefulness of Local Therapy in Elderly Breast Cancer Patients with Distant Metastases].

We investigated the usefulness of local therapy in elderly breast cancer patients with distant metastases. Sixty-four elderly breast cancer patients were encountered during 10 years. Fifty-one patients had complications. The proportion of endocrine receptor-positive tumors was 95.2%. Patients who had metastases at the first visit represented 22.6% of the study group. Advanced-stage cancers were recognized in elderly patients than other patients. The mean observation time for all the patients was 7.4 years. The mortality from cancer was 6.5%, and the mortality from other diseases was 58.1%. We divided the patients into 2 groups, the non-metastases group (group A, n=48), and the metastases group (group B, n=14). There were no significant differences between groups A and B in the rates of endocrine receptor-positive tumors, surgery rate, and survival rate. These results suggest that endocrine therapy without surgery should be considered in elderly breast cancer patients with endocrine receptor-positive tumors.

[Examination of the Cases Given Primary Tumor Resection after Systemic Therapy for Metastatic Breast Cancer].

We examined the records of patients with stage Ⅳ breast cancer who underwent primary tumor resection after systemic therapy. In our department, in 2013, there were 8 such cases. The average local tumor diameter was 59 mm. There was 1 case of metastases to the liver, 2 cases to the lung, 3 cases to the bone, and 1 case to the kidney. Three cases had lymph node metastases. Two cases were treated with hormonal therapy, and 6 cases received chemotherapy as preoperative systemic therapy. All cases underwent Bt plus Ax. Approximately 2 years after the surgery, 5 of the 8 patients were alive. The postoperative local control was good and we were able to continue systemic treatment for the distant metastases in all cases. We think that resection of the primary tumor improved the quality of life of the patients. However, for 1 fatal case, a brain metastasis was detected shortly after surgery. Therefore, we need to consider the patient's condition carefully before we operate.

[Interval Breast Cancer with Neuroendocrine Differentiation].

We report a case of interval breast cancer that was an invasive ductal carcinoma of the breast with neuroendocrine differentiation. The patient was a 66-year-old woman who had a breast lump. She had received breast cancer screening every other year. The last screening was 1 year and 6 months prior to diagnosis. A core needle biopsy for breast tumor led to a diagnosis of invasive ductal carcinoma. Breast conserving surgery plus sentinel lymph node biopsy was performed. The pathological diagnosis from the resected surgical specimen was invasive ductal carcinoma with neuroendocrine differentiation, positive for ER and PgR, and negative for HER2/neu protein expression. The surgical margins were negative, and there was no metastasis in the sentinel lymph node. She was administered radiation therapy and adjuvant endocrine therapy. Two years after surgery, she is well without metastasis.