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The prognosis of HER2-positive breast cancer has improved with the development of anti-HER2 therapies. In order to further improve the prognosis of HER2-positive breast cancer, it is essential to elucidate the cells that survive during the therapy (drug-tolerant persister DTP).Of the 2022 breast cancer patients operated at our institution during 2004-2018, 240 (12%) had HER2-positive breast cancer. Neo-adjuvant chemotherapy including trastuzumab (Tr-NAC) was administered to 94 of them. Forty-six of them were complete remission (CR), and 48 were non-CR. After 6.9 ± 3.7 years of follow-up, all 46 CR cases showed no recurrence (Cohort A), and 48 non-CR cases were divided into 31 cases with no recurrence (Cohort B) and 17 cases with recurrence (Cohort C). In addition to clinical backgrounds, we compared genomic profiles for 27 patients (Cohort A; 15/48, B; 7/31, and C; 5/17) who consented to genomic analysis.Genomic abnormalities of TP53 and PIK3CA were frequently observed in biopsy samples pre Tr-NAC, but we found no differences between CR (Cohort A) and non-CR (Cohorts B + C). Then, we examined both of pre and post Tr-NAC samples of Cohort B (7) and C (5) to see the relationship between recurrence and genomic abnormalities. TP53 mutations were significantly more prevalent in Cohort C (5/5, 100%) than cohort B (3/7, 43%) in the surgical sample after treatment (p = 0.04). PyClone analysis of TP53 mutations showed that the cellular frequency of TP53 clones increased in 4 of 5 patients in Cohort C and none of B. On the other hand, we found no enhancement of PIK3CA mutant clones in Cohort C.The DTP after Tr-NAC associated with subsequent relapse had TP53 mutations, suggesting that overcoming DTP with TP53 mutations is the most important clinical challenge.Not applicable.

Supplementary Figure 1 from Identification of Novel Isoforms of the EML4-ALK Transforming Gene in Non–Small Cell Lung Cancer

The genome of a subset of non–small-cell lung cancers (NSCLC) harbors a small inversion within chromosome 2 that gives rise to a transforming fusion gene, EML4-ALK, which encodes an activated protein tyrosine kinase. Although breakpoints within EML4 have been identified in introns 13 and 20, giving rise to variants 1 and 2, respectively, of EML4-ALK, it has remained unclear whether other isoforms of the fusion gene are present in NSCLC cells. We have now screened NSCLC specimens for other in-frame fusion cDNAs that contain both EML4 and ALK sequences. Two slightly different fusion cDNAs in which exon 6 of EML4 was joined to exon 20 of ALK were each identified in two individuals of the cohort. Whereas one cDNA contained only exons 1 to 6 of EML4 (variant 3a), the other also contained an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). The protein encoded by the latter cDNA thus contained an insertion of 11 amino acids between the EML4 and ALK sequences of that encoded by the former. Both variants 3a and 3b of EML4-ALK exhibited marked transforming activity in vitro as well as oncogenic activity in vivo. A lung cancer cell line expressing endogenous variant 3 of EML4-ALK underwent cell death on exposure to a specific inhibitor of ALK catalytic activity. These data increase the frequency of EML4-ALK–positive NSCLC tumors and bolster the clinical relevance of this oncogenic kinase. [Cancer Res 2008;68(13):4971–6]

Supplementary Figure 2 from Identification of Novel Isoforms of the EML4-ALK Transforming Gene in Non–Small Cell Lung Cancer

Background C3H/HeJ mouse models progress gradually in hair loss from acute to chronic phase and reflect the symptoms of patients with alopecia areata (AA). However, the underlying pathological characteristics alteration associated with disease progression and autoantigens remain unclear. Objective We aimed at elucidating the pathological differences between acute and chronic-AA in the C3H/HeJ mouse model. Methods We analyzed populations of PBMCs, skin-draining lymph node (SDLN) cells, and cutaneous cells of AA mice using flow cytometry. The cytokine and chemokine expressions in the serum and skin were determined using multiplex assay and qPCR. The antibody serum levels were determined using ELISA and the antigen-specific T cells were detected using the MHC class I tetramer. Results The CD8+NKG2D+ T and CD8+ TEM cell percentage in the chronic-AA SDLNs or among the unaffected and acute-AA mice PBMCs increased. The Th1 and CD4+ TEM cell percentage in the SDLNs and among PBMCs increased in the unaffected and AA mice. The percentage of CD8+ TEM/TRM cells and MHC class I expression increased in the lesions of acute-AA or the non-lesions and lesions of chronic-AA. The Th1 cells, dendritic cell-related cytokines, CD11c+ cells and MHC class II expression increased in the skin of AA mice. The antibody levels and TYRP2 and tyrosinase-specific CD8+ T cell percentages were upregulated in AA mice. Conclusion These results suggest that the CD8+ and CD4+ T cell subpopulations, cytokine and chemokine expressions differ between the disease phases. Moreover, TYRP2 and tyrosinase are potential autoreactive targets in the AA mouse model.

Therapeutic antibodies have many biopharmaceutical applications; however, characterization of their higher-order structures is a major concern in quality control. We have developed AF.2A1, an artificial protein, that specifically recognizes non-native, structured IgGs. We performed binding assays using various types of IgGs and fragments to investigate the mechanisms by which AF.2A1 interacts with the non-native IgG. AF.2A1 recognized the acid-stressed IgGs from human, mouse, and rat, but not rabbit. Binding assays using the human IgG1 fragments revealed that an interface emerged by deleting five C-terminal residues. We conclude that AF.2A1 recognizes an exposed hydrophobic core centered on the Trp417. Our results concur with those of the previous studies showing that C-terminal structural changes occur early during antibody denaturation and aggregation. Our findings explain the molecular rationale for using AF.2A1 in quality control of biopharmaceutical IgGs.

Neo-adjuvant chemotherapy (NAC) has become a standard treatment for advanced breast cancer because of the advantage of monitoring drug sensitivity and enabling breast-conserving therapy. The changes during NAC are also important to know the biological characteristics of the tumor. We experienced two cases with cystic degeneration and enhancement of the cyst wall during NAC for triple negative breast cancer (TNBC). They were diagnosed to have breast cancer with squamous metaplasia. In case 1, a 37-year-old woman with right breast cancer diagnosed as TNBC, T3N3M0, Stage 3b was treated with NAC. MRI showed a cystic degeneration with a diameter of 3.5 cm and enhancement of the cyst wall, and the other nodules were extinguished. The histopathological finding of the surgical specimen revealed solid tubular carcinoma with squamous metaplasia. In case 2, a 58-year-old woman with right breast cancer diagnosed as HER2 enriched subtype, T2N0M0 stage 2 was treated with NAC containing trastuzumab. The post-NAC MRI showed extinguishment of the mass in the right breast, but showed a cystic lesion with 24 mm in diameter and enhancement of its wall in the left breast. She underwent breast conserving surgery for bilateral breast cancer, and histopathological finding of the surgical specimen indicated complete remission of right breast cancer and squamous cell carcinoma developed in the left breast. These changes are impressive and remind us that there are metaplastic changes (especially for squamous metaplasia) with resistance to chemotherapy.

2020年度、日本は学校教育の一つの大きな転換期を迎えた。小学校から順次完全実施される改訂学習指導要領のスタート期であり、また、学校組織とともに教員の職務遂行のあり方そのものも変えていく「学校の働き方改革」の推進の渦中である。さらに、新型コロナウイルス感染症による未曾有の事態に直面し、「学校の新しい生活様式」を模索しながら教育課程のあり方そのものを抜本的に見直すことを迫られた。 そうしたなか、本稿執筆者の一人が、米国大学 “William & Mary School of Education”のJames H. Stronge教授から“International Beliefs and Practices of Teacher Effectiveness”のタイトルでの出版企画への参加依頼を受けた。米国、日本、中国など10か国の教員養成機関の関係者が参加し、各国の教員養成における質保証や教育施策の実際、またそれらが依拠する理念等について、それぞれの国の教育・文化的土壌や背景を含意しつつ検討を進めるとの趣旨であった。同書のテーマは2020年度に教職大学院に在籍した現職教員学生（リーダーコース）にとっても重要な関心事であった。そこで2 名の所属教職大学院の教員、5 名の現職教員学生によってプロジェクトチームが立ち上げられ、日本のチャプターを引き受けることになった。本稿はそれを大幅に加筆・修正したものである。

Hemangiomas most commonly occur in the skin or mucosa and are rare in skeletal muscle. There have been almost no reports of their development in skeletal muscle of the head and neck region. A case of cavernous hemangioma of the temporalis muscle is reported along with a short discussion of the literature. A 69-year-old woman presented to our department with a chief complaint of swelling in the left temporal region. She had noticed a painless mass in this region around six months earlier and had consulted a local dental clinic, which had referred her to our department for further investigation and treatment. On general physical examination, she was of moderate build and well nourished. External oral examination showed a palpable, elastic-soft, semispherical mass in the left temporal region measuring 37 mm × 36 mm. Internal oral examination showed nothing of note. A clearly demarcated hyperintensity between the left temporalis muscle and the left temporalis fascia was visible on T2-weighted and short tau inversion recovery (STIR) magnetic resonance imaging (MRI), and this was clinically diagnosed as a tumor of the left temporal region. Thus, tumor enucleation of the left temporal region was scheduled and performed under general anesthesia. The histopathological diagnosis was cavernous hemangioma. The patient’s postoperative course has been good, with no recurrence nine months after surgery.

The benefit of home parenteral nutrition (HPN) for patients with malnutrition due to peritoneal metastasis depends on the type of cancer. During the period 1999–2020, we treated 460 patients with metastatic and stage 4 breast cancer, 23 of whom were invasive lobular carcinoma (ILC). Of the 23 patients with ILC, 13 (57%) developed peritoneal metastasis, and 11 died of progression of peritoneal metastasis. Among these 11 patients, 2 patients who underwent surgery due to bowel obstruction, had no improvement, and died 1–4 months after surgery. The prognosis of the other 7 patients under BSC alone was poor, survival time were ranging from 1 to 5 months. The remaining two patients who were able to continue outpatient chemotherapy under HPN were able to prolong their survival time by 18 months and 26 months, respectively. We need to recognize that HPN and chemotherapy may prolong survival time in patients with peritoneal metastasis of ILC, and determine the indication for HPN based on the non-peritoneal life-threatening metastasis, length of treatment, availability of support for HPN management and outpatient chemotherapy, and the patient's willingness to accept it.

Background Malignant lumbosacral plexopathy is caused by a direct extension of an intrapelvic malignancy to involve the plexus nerves. In this report, we describe the effect of radiotherapy on patients with malignant lumbosacral plexopathy. Patients and methods We performed a retrospective review of the medical records of patients who underwent radiation therapy for pain caused by malignant lumbosacral plexopathy between 2017 and 2020 at our institution. The pain was measured using a numeric rating scale (0-10) at initiation and completion of radiotherapy or at the time when the maximum response was observed. Results A total of 12 tumor sites in 11 patients were included. Eight of the tumors invaded the iliopsoas muscle, and the remaining four invaded or abutted the piriformis muscle. The mean duration of follow-up was 215 days (31-675 days). All patients achieved pain relief at the end of radiotherapy, with complete resolution of pain in nine patients. The maximum effect was seen at a mean of three weeks (1-12 weeks) after the initiation of radiotherapy. Toxicities related to radiotherapy included grade 1 diarrhea in four patients and grade 1 frequent urination in one patient. Two patients experienced a relapse of pain at one and two months, respectively, after achieving their maximal response. Conclusion Radiotherapy provides significant pain relief for patients with the malignant lumbosacral syndrome. The recognition and diagnosis of this syndrome, and the use of radiation therapy as a therapeutic option, are important. Patients should be offered all possible therapies, regardless of curative or palliative intent.

A chip-sized passively Q-switched laser is demonstrated, in which a solid-state gain medium is intra-cavity pumped and vertically integrated with a semiconductor laser. A laser chip volume of 1 mm3 and peak power of 50 kW are achieved simultaneously.

Lesson practice is often used as the main method for the in-school training programs.However, it is often the case that “Lesson Study” is not a part of in-school training.In otherwords, lesson study is done for the sake of lesson study.If that is the case, “Lesson Study” isfor teachers and not for school children.It is important to make “Lesson Study” work for inschooltraining.We propose three criteria to achieve it:First, we must always do “Lesson Study" with a focus on the study subject.Secondly, children should be the main focus on the “Lesson Study.”Thirdly, we must be prepared to update our “Lesson Study” at any time.

Protein-protein interactions that can be controlled by environmental triggers have immense potential in various biological and industrial applications. In the current study, we aimed to engineer a pH-dependent protein-protein interaction that employs intramolecular electrostatic repulsion through a structure-guided histidine substitution approach. We implemented this strategy on

Colletotrichum species cause diseases on many plants and are among the 'top 10' fungal plant pathogens. Species of the C. gloeosporioides and C. acutatum complexes are particularly important because they infect temperate fruit crops, but their control relies largely on chemical fungicides. In this study, differences in intrinsic fungicide sensitivity were determined in vitro using isolates of the C. gloeosporioides sp. complex (C. fructicola, C. siamense, and C. tropicale) and the C. acutatum sp. complex (C. fioriniae and C. nymphaeae), which had never been exposed to fungicides. Mycelial growth of all isolates was sensitive to the QoI azoxystrobin, the SDHI benzovindiflupyr, and the new DMI fungicide mefentrifluconazole. The isolates of C. nymphaeae were highly sensitive to the phenylpyrrole fungicide fludioxonil. The isolates of C. gloeosporioides sp. complex were sensitive to the bis-guanidine fungicide iminoctadine-albesilate, whereas those of C. acutatum sp. complex were inherently insensitive. These results are valuable when sensitivity of field populations is monitored in resistance management. Although SDHI fungicides are largely not effective against diseases caused by Colletotrichum species, benzovindiflupyr controlled anthracnose disease of various crops such as kidney bean, garland chrysanthemum, and strawberry, caused by C. lindemuthianum, C. chrysanthemi, and C. siamense, respectively, demonstrating this fungicide to be unique among SDHIs and having a broad control spectrum against anthracnose. To help understanding the reason for differential activity of benzovindiflupyr and boscalid, sdhB gene sequences were analyzed but those of C. lindemuthianum, C. chrysanthemi, and C. scovillei revealed no known mutations reported to be responsible for SDHI resistance in other fungi, indicating that other mechanism(s) than target-site modification may be involved in differential sensitivity to benzovindiflupyr and boscalid, found in Colletotrichum species.

We developed TSV fabrication process using the anisotropic wet etching of Si assisted by noble metal catalyst and electroless plating of CoWB barrier and Cu seed layers. These methods are essentially low cost as compared to conventional dry etching and CVD methods which use high vacuum chamber systems. Controllability of anisotropic Si etching is improved with the use of catalytic Au disk with nanopores and adequate choice of a mixing ratio of HF and H 2 O 2 in etching solutions. Conformal deposition of CoWB barrier film is possible even for a high aspect ratio TSV with choice of adequate temperature. We have developed equipment of 8 inch processes for both Si etching and electroless plating.

Large developing odontoma is a rare odontogenic tumor showing proliferation of both odontogenic epithelium and ectomesenchyme, with enamel and dentin formation. A case of large developing odontoma affecting the lower molar region to the mandibular ramus of a 14-year-old girl is reported. Panoramic and computed tomography images showed a clearly demarcated, multilocular radiolucency extending from the left lower molar region to the mandibular ramus, containing a tooth-like radiopacity. With the patient under general anesthesia, the mass was removed. The histopathological diagnosis was developing odontoma. There was no sign of recurrence at 1 year after tumor removal.

Oncoplastic breast conserving surgery had been challenged to achieve both of local control and the cosmetic appearance of preserved breast. We developed the lateral thoracoaxillar dermal-fat flap (LTDF) as an oncoplastic procedure to fill the defect of breast-conserving surgery in 1999. A total of 2338 breast cancer patients underwent surgery from January, 2000 to December, 2017. Mastectomy was performed in 706 patients (30%), and breast conservative surgery (BCS) was performed in 1634 patients (70%). The LTDF was adopted in 487/1634 (30%) of BCS cases to fill the large defect left by partial resection. we divided all patients into 3 groups: breast total mastectomy (BT group), the breast partial resection (BP) with LTDF (LTDF group), and Bp without LTDF (BP group) and compared the clinical characteristics, and recurrence rate. The Indications for LTDF increased up to 40% in 2010, while they decreased to 20%–30% in the most recent period, in accordance with the frequency of breast reconstruction increased. Patients who underwent BP + LTDF (LTDF group) included significantly higher proportions of stage II diseases and cases treated by neoadjuvant chemotherapy than those in BP or BT groups.. We found no marked difference of local recurrence and distant metastases between the LTDF and Bp groups. However, the rate of distant metastasis was significantly higher in BT group than in the Bp or LTDF group. Concerning the complications of LTDF, we experienced a few complications of Grade 3–4 requiring surgical management, namely one case of dislocation of the LTDF, three cases of bleeding, and five cases each of skin necrosis and fat necrosis. We reported satisfying long-term outcomes of 487 cases treated by LTDF. LTDF is a suitable oncoplastic technique for BCS.

We report a case in which an odontogenic infection developed into a deep neck abscess and descending necrotizing mediastinitis (DNM). The patient was a 43-year-old man with a chief complaint of swelling extending from the right submandibular region to the neck. He had experienced repeated episodes of swelling and pain in the right mandibular molar region starting 1 year prior to the initial visit. He was emergently transported to our department from the Dental and Oral Surgery Department of a general hospital. He was febrile with a temperature of 38.3 °C and exhibited obvious swelling and redness from the right submandibular region to the anterior part of the chest. The maximum opening of the mouth was 1 fingerbreadth, and swelling, redness and pus drainage were observed in the right mandibular molar region. Laboratory tests showed a leukocyte count of 15,590/μL and a C-reactive protein level of 21.6 mg/dL. Computed tomography scans showed periapical lesions at the right mandibular second and third molars, as well as a gas pattern extending from the area around the right submandibular gland to the common carotid artery and anterior mediastinum. The clinical diagnosis was a right-sided deep neck abscess and DNM. At the initial visit, tracheotomy was performed under general anesthesia, with incision and drainage of the deep neck abscess and extraction of the right mandibular second and third molars. In consultation with the Department of Respiratory Surgery, thoracoscopic cleaning and drainage were performed. The patient was discharged in comfortable condition on Day 38.

We experienced an extremely rare case of recurrent esophageal adenosquamous carcinoma showing cutis, bone and adrenal gland metastases. Furthermore, the patient showed complete remission by chemotherapy and irradiation, with a long-term survival of over 8 years. A 46-year-old man with esophago-gastric junction cancer of clinical stage II was administered two cycles of neo-adjuvant chemotherapy with FP (5FU 800 mg/mm(2) Cisplatin 80 mg/mm(2) every 3 weeks), subsequently, underwent esophagectomy and mediastinal and celiac lymph node dissection. However, at 1 month after the surgery, he was admitted again due to a 1 cm cutaneous metastasis at the anterior chest wall and left side adrenal gland metastasis. Furthermore, magnetic resonance imaging showed bone metastasis at the second cervical vertebra. He was administered weekly docetaxel at 40 mg/body (3 times every 4 weeks) for 27 cycles. Irradiation therapy (liniac 36 Gy/16Fr) was performed for the vertebral metastasis. The cutaneous and adrenal metastases were diminished and complete remission persisted for over 8 years.

This chapter analyzed how Japanese teachers' qualifications and abilities, as well as educational policies, have been promoted since the postwar period to the present day and summarized these results. There are discrepancies between the needs of students' families and the real world and the ideas and contents required by the Course of Study. Teachers have tried to play a positive role in bridging the gap and in merging the reality and the ideals. In order to bridge the “difference” faced by school sites, it is necessary to start by examining the contents of the reforms required from the bottom and reforms required from the top. As an initiative from below, in most elementary schools in Japan, groups of teachers have voluntarily gathered, and “Jugyo-Kenkyu” have been conducted for many years to analyze the challenges of their own school's students as a team. Although Jugyo-Kenkyu has achieved some positive results, the way to measure the effectiveness of the research is still an issue.

To our knowledge, highly detailed findings of flexible hysterofiberscopy in patients with adenofibroma have not been described. A 75-year-old nulliparous asymptomatic woman presented with a uterine polyp, which exhibited punctate heterogeneous hyperintensity or islands of isointense-to-hypointense signals on T2-weighted magnetic resonance imaging (MRI), hypointense signals on T1-weighted images (T1WI), and a little enhancement on contrast-enhanced T1WI. Flexible hysterofiberscopy revealed a red-pink polyp with a white-yellow, cobblestone-like surface easily deformed by perfusion fluid. The tumor was diagnosed histologically as an adenofibroma. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The tumor in the uterus was necrotic macroscopically and histologically, and a residual adenofibroma could not be confirmed. At present, two years after surgery, the patient remains healthy. MRI and hysterofiberscopy can reveal the histological features of uterine adenofibromas and be useful for their diagnosis.