Pneumocystis Pneumonia in Locally Advanced Breast Cancer Despite Prophylactic Use of Trimethoprim-Sulfamethoxazole During Prednisolone Treatment for a Pembrolizumab-Induced Immune-Related Adverse Event: A Case Report.

Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is insufficient information on PCP occurrence despite TMP-SMX prophylaxis. We encountered a 57-year-old woman with locally advanced breast cancer developing PCP despite prophylactic intake of TMP-SMX, during treatment with prednisolone for Stevens-Johnson syndrome (SJS) induced by pembrolizumab. This case underscores the need to pay attention to the possibility of PCP development even during TMP-SMX prophylaxis. Dosage and duration adjustments according to the patient's condition and weight may be required.

Endosomal protein expression of γ1-adaptin is associated with tumor growth activity and relapse-free survival in breast cancer.

BACKGROUND: γ1-Adaptin is a subunit of adaptor protein complex-1 (AP-1), which regulates intracellular transport between the trans-Golgi network (TGN) and endosomes. Since expression levels of AP-1 subunits have been reported to be associated with cell proliferation and cancer malignancy, we investigated the relationships between the immunohistochemical expression of γ1-adaptin and both clinicopathological factors and relapse-free survival (RFS) in breast cancer tissue. MATERIALS AND METHODS: SK-BR-3 cell line depleted of γ1-adaptin was used for cell proliferation, migration, and invasion assay. Intracellular localization of γ1-adaptin was examined with immunohistochemistry (IHC) using an antibody against γ1-adaptin, and with double immunohistofluorescence (IHF) microscopy using markers for the TGN and endosome. γ1-Adaptin intensities in IHC samples from 199 primary breast cancer patients were quantified and assessed in relation to clinicopathological factors and RFS. RESULTS: Cell growth, migration, and invasion of SK-BR-3 cells were significantly suppressed by the depletion of γ1-adaptin. Although the staining patterns in the cancer tissues varied among cases by IHC, double IHF demonstrated that γ1-adaptin was mainly localized in EEA1-positive endosomes, but not in the TGN. γ1-Adaptin intensity was significantly higher in the tumor regions than in non-tumor regions. It was also higher in patients with Ki-67 (high), ER (-), PgR (-), and HER2 (+). Among subtypes of breast cancer, γ1-adaptin intensity was higher in HER2 than in luminal A or luminal B. The results of the survival analysis indicated that high γ1-adaptin intensity was significantly associated with worse RFS, and this association was also observed in group with ER (+), PgR (+), HER2 (-), Ki-67 (high), or luminal B. In addition, the Cox proportional hazards model showed that high γ1-adaptin intensity was an independent prognostic factor. CONCLUSION: These results suggest that the endosomal expression of γ1-adaptin is positively correlated with breast cancer malignancy and could be a novel prognostic marker.

Long-term Experience on Breast Cancer-related Lymphedema in the Coastal Area of Fukushima, Japan After the 2011 Triple Disaster.

BACKGROUND/AIM: Disasters can jeopardize breast cancer care and Japan's triple disaster in 2011 (earthquake, tsunami, and nuclear accident) is no exception. However, detailed information is lacking regarding the care of breast cancer related lymphedema (BCRL) following the disaster. We aimed to explore the process by which local patients become aware of BCRL, the problems faced, and the support they require. We also aimed to clarify the effects of the 2011 disaster on experiences related to lymphedema in the target population. PATIENTS AND METHODS: Patients who developed BCRL after breast cancer treatment were recruited from Iwaki city, a municipality located in the southern coastal region of Fukushima (N=16). In-depth, semi-structured, face-to-face interviews were conducted, and the obtained data were appraised using thematic analysis. RESULTS: Five themes related to BCRL were identified: 1) the process of becoming aware of BCRL, 2) troubles or worries/concerns due to BCRL, 3) information sources regarding BCRL management, 4) strategies to cope with BCRL, and 5) the adverse impacts of the 2011 disaster on BCRL management. CONCLUSION: Except for the disaster context, the themes are in line with those of previous studies conducted in the non-disaster context. Nonetheless, there were limited but non-negligible adverse effects of the 2011 disaster on long-term local BCRL management. The findings of this study demonstrate the necessity for individualizing coping strategies against BCRL among healthcare professionals in the Fukushima coastal area and beyond.

The necessity of proactive measures from healthcare providers highlighted by delayed breast cancer diagnosis due to COVID-19: A case report.

Key Clinical Message: During disasters, multiple factors can cause significant delays in medical visits. Regular patient monitoring, high-risk individual alerts, and telemedicine enhancements can potentially alleviate these issues and ensure timely interventions. Abstract: During the COVID-19 pandemic, a Japanese woman in her 70s delayed her regular breast cancer checkup for over 2 years. During disasters, health priorities tend to decline, necessitating proactive measures from healthcare providers, such as augmenting collaboration among healthcare professionals and identifying high-risk individuals.

Claudin-4-adhesion signaling drives breast cancer metabolism and progression via liver X receptor ß.

BACKGROUND: Cell adhesion is indispensable for appropriate tissue architecture and function in multicellular organisms. Besides maintaining tissue integrity, cell adhesion molecules, including tight-junction proteins claudins (CLDNs), exhibit the signaling abilities to control a variety of physiological and pathological processes. However, it is still fragmentary how cell adhesion signaling accesses the nucleus and regulates gene expression. METHODS: By generating a number of knockout and rescued human breast cell lines and comparing their phenotypes, we determined whether and how CLDN4 affected breast cancer progression in vitro and in vivo. We also identified by RNA sequencing downstream genes whose expression was altered by CLDN4-adhesion signaling. Additionally, we analyzed by RT-qPCR the CLDN4-regulating genes by using a series of knockout and add-back cell lines. Moreover, by immunohistochemistry and semi-quantification, we verified the clinicopathological significance of CLDN4 and the nuclear receptor LXRß (liver X receptor ß) expression in breast cancer tissues from 187 patients. RESULTS: We uncovered that the CLDN4-adhesion signaling accelerated breast cancer metabolism and progression via LXRß. The second extracellular domain and the carboxy-terminal Y197 of CLDN4 were required to activate Src-family kinases (SFKs) and the downstream AKT in breast cancer cells to promote their proliferation. Knockout and rescue experiments revealed that the CLDN4 signaling targets the AKT phosphorylation site S432 in LXRß, leading to enhanced cell proliferation, migration, and tumor growth, as well as cholesterol homeostasis and fatty acid metabolism, in breast cancer cells. In addition, RT-qPCR analysis showed the CLDN4-regulated genes are classified into at least six groups according to distinct LXRß- and LXRßS432-dependence. Furthermore, among triple-negative breast cancer subjects, the "CLDN4-high/LXRß-high" and "CLDN4-low and/or LXRß-low" groups appeared to exhibit poor outcomes and relatively favorable prognoses, respectively. CONCLUSIONS: The identification of this machinery highlights a link between cell adhesion and transcription factor signalings to promote metabolic and progressive processes of malignant tumors and possibly to coordinate diverse physiological and pathological events.

E3 Ubiquitin Ligase NEDD4 Affects Estrogen Receptor α Expression and the Prognosis of Patients with Hormone Receptor-Positive Breast Cancer.

Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.

Myeloid-derived suppressor cells: Cancer, autoimmune diseases, and more.

Although cancer immunotherapy using immune checkpoint inhibitors (ICIs) has been recognized as one of the major treatment modalities for malignant diseases, the clinical outcome is not uniform in all cancer patients. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells that possess various strong immunosuppressive activities involving multiple immunocompetent cells that are significantly accumulated in patients who did not respond well to cancer immunotherapies. We reviewed the perspective of MDSCs with emerging evidence in this review. Many studies on MDSCs were performed in malignant diseases. Substantial studies on the participation of MDSCs on non-malignant diseases such as chronic infection and autoimmune diseases, and physiological roles in obesity, aging, pregnancy and neonates have yet to be reported. With the growing understanding of the roles of MDSCs, variable therapeutic strategies and agents targeting MDSCs are being investigated, some of which have been used in clinical trials. More studies are required in order to develop more effective strategies against MDSCs.

The molecular heterogeneity of the precancerous breast affects drug efficacy.

In the therapeutic domain, targeted therapies have been shown to be generally more effective when given to patients with tumors that harbor the targeted aberration. This principle has not been tested in cancer prevention despite evidence that molecular heterogeneity accompanies the multi-step progression to invasive disease. We hypothesized that efficacy of agents targeting the precancerous state varies based on timing of the treatment relative to the underlying molecular changes. MCF10A cell line-based model of the multi-step progression to TNBC was used. Global proteomic patterns were obtained and growth-inhibitory effects of selected agents were correlated with the underlying molecular stage of progression. These analyses revealed that most protein alterations were acquired in the normal-to-atypia (preneoplasia) transition, with only handful aberrations acquired hereafter. The efficacy of small molecule inhibitors of the AKT/MEK pathway was associated with the underlying pathway levels. Similarly, fluvastatin was more effective in inhibiting cell proliferation earlier in the progression model. However, the nonspecific inhibitors, aspirin and metformin, were equally ineffective in inhibiting proliferation across the progression model. Our data provides proof-of-principle that in the prevention domain, treatment with agents developed to target specific pathways, will need to consider the molecular heterogeneity of the precancerous breast in order to achieve maximum efficacy.

[A Case of Emergency Radiotherapy for Intramedullary Spinal Cord Metastasis from Breast Cancer].

Intramedullary spinal cord metastasis(ISCM)is rare. However, with advances in diagnostic imaging, the incidence of ISCM is increasing. We herein present a case of breast cancer metastasis in the lower thoracic spinal intramedullary area in a patient who was then successfully treated with emergency radiotherapy. A 56‒year‒old woman with breast cancer was admitted to our hospital due to rapidly progressing weakness in both legs and bladder and rectal disturbance. Spinal MRI revealed a gadolinium‒enhancing intramedullary lesion. The patient was treated with emergency radiotherapy and oral steroids. Although the prognosis of ISCM is extremely poor, emergency radiotherapy could be an effective treatment for ISCM to improve the patient's quality of life(QOL).

[A Case Report of Uterine Metastasis Four Years after Breast Surgery for Breast Cancer].

We report a case of uterine metastasis of the breast cancer. The patient was diagnosed with invasive ductal carcinoma of the breast and underwent partial right mastectomy and sentinel lymph node biopsy. Tamoxifen was administered as adjuvant endocrine therapy. Four years after the surgery, she had irregular genital bleeding, and was referred to our hospital for cytological diagnosis of uterine cancer. Postoperative pathological diagnosis showed uterine metastasis of breast cancer, and it was decided to treat the recurrence of breast cancer with aromatase inhibitors and CDK4/6 inhibitors, a molecular targeted therapy. The patient has been progression-free for 5 months.

The relationship between BRCA-associated breast cancer and age factors: an analysis of the Japanese HBOC consortium database.

BRCA1/2 pathogenic variant prevalence in Japanese breast cancer is unclear. Here, we analyzed BRCA1/2 pathogenic variant prevalence with a particular focus on age factors, using the Japanese HBOC consortium database. All registered subjects were Japanese individuals who underwent BRCA1/2 genetic testing from January 1996 to July 2017 according to the Japanese HBOC consortium database. Cases were extracted and analyzed for each evaluation item. Overall BRCA1 and BRCA2 pathogenic variant prevalence was 11.2% and 9.0% in the cohort of 2366 proband patients, respectively. The age at onset of breast cancer for patients with BRCA1/2 pathogenic variants was significantly lower than that for patients without a BRCA1/2 pathogenic variant. In both BRCA1/2 patients, ages at onset were not statistically significantly different between two subtype groups (ER-positive vs. TNBC). We analyzed the BRCA1/2 pathogenic variant prevalence among age groups in patients with no family history of breast or ovarian cancer. In the TNBC group, the rate of genetic variants was more frequent among younger patients. Our results demonstrated that early breast cancer onset is associated with a BRCA1/2 pathogenic variant in the Japanese population. Younger TNBC patients were more likely to have a BRCA1/2 pathogenic variant irrespective of a family history of breast or ovarian cancer.

Cluster of differentiation 8 and programmed cell death ligand 1 expression in triple-negative breast cancer combined with autosomal dominant polycystic kidney disease and tuberous sclerosis complex: a case report.

BACKGROUND: Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8+ in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden. CASE PRESENTATION: A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient's breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity. CONCLUSIONS: Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.

Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis.

Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data were obtained from The Cancer Genome Atlas (TCGA, n = 1079) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1904). TNBC patients had significantly higher levels of ANXA1 expression compared to the other subtypes in both TCGA and METABRIC cohorts (p < 0.001). ANXA1 protein expression was assessed by immunohistochemistry in Japanese TNBC patient cohort (n = 48), where 17 cases (35.4%) had positive ANXA1 staining, and their overall survival was significantly shorter compared with negative staining group (p = 0.008). The CIBERSORT algorithm was used to calculate immune cell infiltrations. ANXA1 high tumors were associated with activated mast cells and M2 macrophages (p > 0.01), but did not show any association with tumor heterogeneity nor cytolytic activity. High expression of ANXA1 group enriched inflammation, epithelial-to-mesenchymal transition (EMT), and angiogenesis-related genes in a gene set enrichment assay in both cohorts. To our knowledge, this is the first study to demonstrate that ANXA1 is associated with infiltration of mast cells and inflammation that is associated with the aggressive phenotype of TNBC, such as EMT and angiogenesis.

Prognostic impact of interleukin-6 and C-reactive protein on patients with breast cancer.

The prognostic impacts of preoperative C-reactive protein (CRP) and interleukin (IL)-6 expression levels in patients with breast cancer remain controversial. A total of 55 female patients with invasive breast cancer were enrolled, and preoperative prognostic parameters including IL-6 and CRP were analyzed. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and candidates' prognostic factors were examined using a Cox proportional hazard model. Using receiver operating characteristic curve analysis, IL-6 at 10.0 pg/ml and CRP at 0.12 mg/dl were determined as threshold values to predict OS and RFS, respectively. Patients with IL-6 ≥10.0 pg/ml had poorer OS compared with those with IL-6 <10.0 pg/ml (P=0.003), and patients with CRP ≥0.12 mg/dl had poorer RFS compared with those with CRP <0.12 mg/dl (P<0.001). Serum IL-6 level (hazard ratio, 13.230; 95% confidence interval, 1.285-136.214; P=0.030) and triple-negative subtype (hazard ratio, 11.739; 95% confidence interval, 1.415-97.362; P=0.023) were independent prognostic factors for OS, and CRP expression level was an independent prognostic factor for RFS in patients with breast cancer (hazard ratio, 18.571; 95% confidence interval, 2.240-153.949; P=0.007). In patients with invasive breast cancer, preoperative serum IL-6 and triple-negative subtype may be independent prognostic factors for OS, while for RFS, preoperative CRP may be a more accurate prognostic factor compared with those currently established.

[A Case of Synchronous Bilateral Neuroendocrine Ductal Carcinoma In Situ].

Neuroendocrine ductal carcinoma in situ(NE-DCIS)is a unique subtype of ductal carcinoma in situ(DCIS)that is not described in the general rules for clinical and pathological recording of breast cancer. NE-DCIS is described as an unusual variant of DCIS in the 2012 World Health Organization(WHO)classification. The chief complaint in NE-DCIS is hemorrhagic nipple discharge. The histological characteristics of NE-DCIS are solid growth of cancer cells with granular and spindle-shaped nuclei. Histologically, NE-DCIS is suggestive of low malignancy but a poor prognosis of neuroendocrine carcinoma of the breast has been reported. The report by Honami et al was the only other report of synchronous bilateral neuroendocrine ductal carcinoma in situ. We report the second case of NE-DCIS diagnosed synchronously in both breasts in a patient who had visited our outpatient clinic with hemorrhagic nipple discharge.

Abscopal effect following radiation monotherapy in breast cancer: A case report.

Radiotherapy has been found to be valuable for the control and eradication of local foci in various malignant tumors. The abscopal effect is determined as a systemic antitumor response at a distance from the irradiation site invoked by local irradiation. We herein present an extremely rare case of breast cancer in a 64-year-old woman, in whom the abscopal effect was observed after radiotherapy induced an antitumor response in all metastatic lesions, without any combination therapy. The patient was admitted to our hospital complaining of a breast mass and pain at the left hip, and was diagnosed with breast cancer with multiple bone, lung and lymph node metastases. She received treatment with local radiotherapy delivered to the breast tumor and some of the bone metastases but did not receive chemotherapy due to her poor performance status. However, 10 months after radiotherapy, spontaneous regression was observed, not only within the irradiated field, but also in the non-irradiated areas. All signs of cancer throughout the body disappeared, and the patient's performance status drastically improved. To the best of our knowledge, there have been no reports of advanced breast cancer cases in which the abscopal effect was observed after radiation monotherapy; therefore, this case report is extremely rare and highly valuable.

Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis.

Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes.Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis.Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen.Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468-81. ©2018 AACR.

[Indication for Radiotherapy for Breast Cancer Metastasis to the Skull Base Accompanied by Cranial Nerve Palsies].

Distant metastasis to the skull base region frequently manifests various cranial nerve symptoms and reduces patients' quality of life(QOL). We report a 62-year-old woman with skull base metastasis of breast cancer, whose condition clinically improved following palliative radiotherapy. The patient presented to our hospital with hoarseness. CT screening revealed a tumor in the right breast, axial lymph node swelling, and osteoblastic change at multiple sites. A core needle biopsy of the breast tumor revealed invasive lobular carcinoma. She also had nausea, anorexia, vertigo, lower left angle of the mouth, apraxia of lid closing, and dysphagia owing to several cranial nerve palsies. MRI T1- and T2-weighted images showed a diffuse low-signal intensity of the skull base region, and the patient was diagnosed as having breast cancer with symptomatic skull base metastases. Her cranial nerve symptoms improved after 1 week of palliative irradiation to the skull base. We conclude that, even among terminal-stage patients, palliative radiotherapy to the skull base region is an effective treatment option to improve patients' QOL.