Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.

Tolerogenic phenotype of dendritic cells is induced after hapten sensitization followed by attenuated contact hypersensitivity response in atopic dermatitis model NC/Nga mice.

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are common inflammatory diseases. We previously reported attenuated contact hypersensitivity (CHS) responses in AD model mice using 2,4-dinitrofluorobenzene, reflecting clinical experiments. However, previous studies have not addressed the commonality of findings across haptens and mechanisms focused on dendritic cells (DCs). Thus, this study evaluated CHS responses to fluorescein isothiocyanate (FITC) and DC migration and maturation in the sensitization phase of CHS in AD. CHS responses to FITC were compared between NC/Nga mice without and with AD induction (non-AD and AD mice, respectively). T-cell responses and DC migration and maturation after FITC-induced sensitization were examined in the draining lymph nodes of non-AD and AD mice. AD mice demonstrated reduced CHS responses to FITC under decreased T-cell proliferation following sensitization and interferon-γ production by hapten-specific T cells compared with non-AD mice. In addition, the number of FITC+CD11c+MHC class IIhigh migratory DCs 24 h after FITC sensitization was comparable between non-AD and AD mice. However, FITC+CD11c+MHC class IIhigh migratory DCs in AD mice exhibited lower expression levels of CD80 and CD86 and higher expression levels of PD-L1 and mRNA of transforming growth factor beta than non-AD mice. These findings suggest that attenuated CHS responses may be hapten-independent and the induction of the tolerogenic phenotype of hapten-bearing DCs can contribute to reduced T-cell proliferation after sensitization and CHS responses in AD.

CTLA-4 suppresses hapten-induced contact hypersensitivity in atopic dermatitis model mice.

Atopic dermatitis (AD) patients with skin barrier dysfunction are considered to be at a higher risk of allergic contact dermatitis (ACD), although previous studies showed that attenuated ACD responses to strong sensitizers in AD patients compared to healthy controls. However, the mechanisms of ACD response attenuation in AD patients are unclear. Therefore, using the contact hypersensitivity (CHS) mouse model, this study explored the differences in CHS responses to hapten sensitization between NC/Nga mice with or without AD induction (i.e., non-AD and AD mice, respectively). In this study, ear swelling and hapten-specific T cell proliferation were significantly lower in AD than in non-AD mice. Moreover, we examined the T cells expressing cytotoxic T lymphocyte antigen-4 (CTLA-4), which is known to suppress T cell activation, and found a higher frequency of CTLA-4+ regulatory T cells in draining lymph node cells in AD than in non-AD mice. Furthermore, the blockade of CTLA-4 using a monoclonal antibody eliminated the difference in ear swelling between non-AD and AD mice. These findings suggested that CTLA-4+T cells may contribute to suppressing the CHS responses in AD mice.

Incorporating integrated testing strategy (ITSv1) defined approach into read-across (RAx) in predicting skin sensitization potency: ITSv1-based RAx.

Recently, due to regulatory and ethical demands, new approach methodologies (NAMs), defined approaches (DAs), and read-across (RAx) have been used in the risk assessment of skin sensitization. Integrated testing strategy (ITS)v1 DA, adopted in OECD Guideline No. 497, can be used for skin sensitization potency categorization. However, ITSv1 DA alone is not used for further refinement of the potency prediction based on EC3 (the estimated concentration that produces a stimulation index of 3 in murine local lymph node assay) values. Moreover, there is no explicit approach to incorporating NAM/DA data into RAx to fill the data gap of EC3 values with high confidence. This study developed a strategy incorporating ITSv1 DA into RAx to predict skin sensitization potency: ITSv1-based RAx. To examine the reliability of this novel strategy, a case study with lilial, a fragrance material, was performed. Based on ITSv1-based RAx, the skin sensitization potency of lilial was determined by extrapolating the EC3 value of 9.5% for the suitable analogue bourgeonal, which was close to the historical EC3 value of 8.6%. The result suggested that the strategy can refine the prediction of EC3 values with high confidence and be useful for the risk assessment of skin sensitization.

Older patients' experience of living with cognitive impairment related to hormone therapy for breast cancer: A qualitative study.

PURPOSE: Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients' experience of cognitive impairment related to hormone therapy for breast cancer. METHODS: A qualitative and descriptive design was used. Semi-structured interviews were conducted with 11 patients asking about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using the interview records. RESULTS: Three themes emerged from the patients' narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about the care burden of their family, concerns about progression of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function. CONCLUSION: Oncology nurses should assess cognitive function and complete a comprehensive evaluation of older patients receiving hormone therapy for breast cancer. An evaluation of cognitive function would enable a tailored approach to education and support to enhance coping ability in the longer term.

Hapten sensitization to vaginal mucosa induces less recruitment of dendritic cells accompanying TGF-ß-expressing CD206+ cells compared with skin.

INTRODUCTION: Contact hypersensitivity (CHS), a type of delayed-type hypersensitivity, is induced by hapten exposure to the skin and mucosa. We previously reported that, in a murine model of CHS, the vaginal mucosa (VM) sensitization showed lower T-cell responses as compared with the abdominal skin sensitization. To investigate mechanisms of impaired CHS by the VM sensitization, we compared migration of hapten-captured dendritic cells (DCs) in the draining lymph nodes (dLNs) and recruitment of DCs at the sensitized local sites. METHODS: Fluorescein isothiocyanate (FITC) or 2,4-dinitrofluorobenzene (DNFB) was used as hapten, and migration of FITC+ DCs in the dLNs and local recruitment of MHC class II+ and CD11c+ cells were compared between abdominal skin and VM sensitization by flow cytometric analyses and immunohistochemistry. Expression of tumor growth factor (TGF)-ß at mRNA and protein levels, and local recruitment of CD206+ cells were examined after VM sensitization. RESULTS: VM sensitization showed less numbers of FITC+ MHC class IIhigh CD11c+ migratory DCs in the dLNs at 6 and 24 h, as compared with skin sensitization. Both skin and VM sensitization induced the recruitment of dermal/submucosal DCs at 6 h, but the number of submucosal DCs in the VM was significantly decreased at 24 h. VM showed persistently higher mRNA levels of TGF-ß2/ß3 expression than those of the skin before and after sensitization. In the VM sensitization, increment of CD206+ MHC class II+ cells was observed especially at the deep lamina propria at 24 h. Most of CD206+ cells were also positive for the binding to Fc chimeric TGF-ß receptor that interacts with all TGF-ß isoforms, suggesting TGF-ß expression. CONCLUSION: DC migration to dLNs and localization of DCs at the sensitized sites are limited in the VM sensitization. Our results suggest that the existence of TGF-ß-expressing CD206+ cells may contribute less sensitization ability and CHS responses in the VM.

Adrenal function during long-term ACTH therapy for patients with developmental and epileptic encephalopathy.

Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long-term ACTH therapy (LT-ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT-ACTH. We evaluated the effectiveness of LT-ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin-releasing hormone (CRH) stimulation test during LT-ACTH, and those with peak serum cortisol below 15 µg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life-threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 µg/dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT-ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT-ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely.

Breast Cancer Treatment in a Patient with Decubitus Ulcer Infection Secondary to Spina Bifida: Surgical Resection versus Neoadjuvant Chemotherapy.

Spina bifida (SB) is a congenital neural tube defect that often presents with neurological disability and decubitus ulcers. A 66-year-old woman with SB presented to our hospital with decubitus ulcers and was treated by a plastic surgeon. She was referred to our department because of a mass measuring 5 × 4 cm in the superolateral quadrant of the right breast. The size of the right axillary lymph node (LN) was 2 × 1 cm. A core-needle biopsy revealed an invasive ductal carcinoma. Total mastectomy and axillary LN dissection were planned. However, 2 days prior to surgery, the size of the mass and the LN rapidly increased to 7 × 4 cm and 3 × 2 cm, respectively. Furthermore, the enlarged LN was close to the thoracodorsal artery. Since complete resection was difficult, neoadjuvant chemotherapy was also administered. On day 11 of neoadjuvant chemotherapy, the patient was febrile and developed a decubitus ulcer infection at the buttock. The neutrophil count was within normal limits; thus, she was not diagnosed with febrile neutropenia. Follow-up computed tomography revealed a shrinking of the mass to 5 × 4 cm after the first cycle of neoadjuvant chemotherapy. After 17 days of antibiotic therapy and drainage, total mastectomy and axillary LN dissection were performed. Due to the risk of recurrence of infection, adjuvant chemotherapy was discontinued and hormone therapy was initiated. In conclusion, indications for chemotherapy should be carefully evaluated in SB patients with lower limb paralysis and decubitus ulcers.

Systemic therapy and prognosis of older patients with stage II/III breast cancer: A large-scale analysis of the Japanese Breast Cancer Registry.

AIM: This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC). METHODS: This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients. RESULTS: In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes. CONCLUSIONS: Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.

Clinicopathological characteristics, practical treatments, prognosis, and clinical issues of older breast cancer patients in Japan.

BACKGROUND: Minimal data are available to support the clinical management of older breast cancer patients. Consequently, the standard of care remains unclear. Our aim was to clarify the clinicopathological characteristics, practical treatments, and prognosis of older Japanese breast cancer patients and discuss clinical issues. METHODS: We reviewed 132,240 cases, diagnosed between 2004 and 2011, from the Japanese Breast Cancer Registry. Focusing on older patients, we compared data among three age groups: 75 years and over (n = 27,385), 65-74 years (n = 43,839), and 55-64 years (n = 61,016). RESULTS: Data revealed the proportions of mucinous and apocrine carcinoma were higher in older patients, and they more frequently had clinical stage II and III cancer. Their ER-positive rates were higher, in contrast to the lower HER2-positive, breast-conserving surgery (BCS), post-BCS irradiation, and adjuvant chemotherapy rates. Almost half of the older patients who underwent chemotherapy received CMF or oral 5FU, during hormone therapy, Tamoxifen was administered more frequently. The overall survival rate decreased with age, but the breast cancer-specific survival (BCSS) at 5 years remained similar. The rate of other cause of death in the oldest group was about a half, and more than double that in those aged 55-64 years. CONCLUSIONS: We showed clinical data of older breast cancer patients in Japan. Their disease was more advanced at the time of diagnosis, post-BCS irradiation and primary systemic chemotherapy were omitted more frequently, and overall, BCSS was similar among age categories, although the rate of other causes of death was higher.

Differential susceptibility between skin and vaginal mucosa in sensitization phase of allergic contact dermatitis in mice.

INTRODUCTION: Mechanisms underlying skin sensitization in allergic contact dermatitis have been actively studied using the murine contact hypersensitivity (CHS) model. However, much less is known about sensitization at the vaginal mucosa (VM). METHODS: We developed a CHS model with VM sensitization and epicutaneous elicitation at the ear. We then examined the proliferation activity of lymphocytes, the frequencies of T cells and the differentiation of hapten-specific T cells in draining lymph nodes (dLNs) after sensitization. RESULTS: Hapten-specific CHS responses to 2,4-dinitrofluorobenzene (DNFB), 2,4,6-trinitrochrolobenzene, and oxazolone assessed by ear swelling suggested that the VM would be an inductive site of CHS to haptens. In the comparisons of CHS responses to each of the three haptens examined, the lower responses in VM-sensitized mice were observed than skin-sensitized mice (e.g., DNFB-induced responses, -56%; p < .001, at 48 h after challenge). Consistent with the CHS responses, the DNFB-induced proliferation of cells in dLNs examined by 5-bromo-2'-deoxyuridine assay was lower (-62%; p < .001) in VM-sensitized mice than skin-sensitized mice. On the other hand, between skin and VM sensitization, no significant differences were observed in the frequencies of interferon-γ-producing CD4+ and CD8+ effector, and regulatory T cells in dLNs after sensitization. We also observed no significant differences with respect to differentiation of hapten-specific T cells based on the examination of cytokine production from dLN cells stimulated in vitro with 2,4-dinitrobenzene sulfonate. CONCLUSION: These findings suggested that the lower T cell proliferation after VM sensitization is important for the lower CHS responses with VM sensitization than skin sensitization.

Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening.

PURPOSE: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood. METHODS: We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity. RESULTS: We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group. CONCLUSIONS: The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.

Erratum: Author Correction: Bcl11b controls odorant receptor class choice in mice.

[This corrects the article DOI: 10.1038/s42003-019-0536-x.].

Bcl11b controls odorant receptor class choice in mice.

Each olfactory sensory neuron (OSN) expresses a single odorant receptor (OR) gene from the class I or class II repertoire in mice. The mechanisms that regulate OR class choice in OSNs remain unknown. Here, we show that the transcription factor Bcl11b determines the OR class to be expressed in OSNs. Both loss- and gain-of-function analyses demonstrate that class I is a default fate of OSNs and that Bcl11b dictates a class II OR choice by suppressing the effect of the J-element, a class I-OR enhancer. We further demonstrate that OSN-specific genetic manipulations of Bcl11b bias the OR class choice, generating mice with "class I-dominant" and "class II-dominant" noses, which display contrasting innate olfactory behaviors to two distinct aversive odorants. Overall, these findings reveal a unique transcriptional mechanism mediating a binary switch for OR class choice that is crucial to both the anatomical and functional organization of the olfactory system.

A Single Pheromone Receptor Gene Conserved across 400 My of Vertebrate Evolution.

Pheromones are crucial for eliciting social and sexual behaviors in diverse animal species. The vomeronasal receptor type-1 (V1R) genes, encoding members of a pheromone receptor family, are highly variable in number and repertoire among mammals due to extensive gene gain and loss. Here, we report a novel pheromone receptor gene belonging to the V1R family, named ancient V1R (ancV1R), which is shared among most Osteichthyes (bony vertebrates) from the basal lineage of ray-finned fishes to mammals. Phylogenetic and syntenic analyses of ancV1R using 115 vertebrate genomes revealed that it represents an orthologous gene conserved for >400 My of vertebrate evolution. Interestingly, the loss of ancV1R in some tetrapods is coincident with the degeneration of the vomeronasal organ in higher primates, cetaceans, and some reptiles including birds and crocodilians. In addition, ancV1R is expressed in most mature vomeronasal sensory neurons in contrast with canonical V1Rs, which are sparsely expressed in a manner that is consistent with the "one neuron-one receptor" rule. Our results imply that a previously undescribed V1R gene inherited from an ancient Silurian ancestor may have played an important functional role in the evolution of vertebrate vomeronasal organ.

Overcalling low-risk findings: grouped amorphous calcifications found at screening mammography associated with minimal cancer risk.

BACKGROUND: Because of the increasing availability of screening mammography and spread of information about its benefits, the incidence of early breast cancer has been increasing in Japan. However, screening mammography can result in overdiagnoses or false positives, causing in some subjects undergoing unnecessary invasive procedures. The current mammography guidelines recommend further investigation of subjects with grouped amorphous calcifications; this recommendation may have resulted in overdiagnoses or false positives. METHODS: We retrospectively reviewed the charts of patients who had undergone screening mammography in the screening unit of our institution from January 2011 to December 2012 and been found to have grouped amorphous calcifications. Of the 233 such cases, 17 had been lost to follow-up, whereas whether the lesions were actually benign or malignant had been determined in the remaining 216 (92.7%). RESULTS: Six (2.8%) of 216 subjects with grouped amorphous calcifications were diagnosed as having malignancy and the remaining 210 (97.2%) as having benign lesions. Four of the six cases (1.9%) with malignancy had ductal carcinoma in situ and two (0.9%) 3 and 4 mm diameter invasive cancers of luminal type and nuclear grade 1. CONCLUSIONS: Grouped amorphous calcifications identified on screening mammography contribute minimally to detection of breast cancer and are not thought to be associated with any identifiable improvement in prognosis; present recommendations concerning this finding may result in false positives and overdiagnoses.