Pathology for severe inflammatory PML with PD1/PD-L1 expression of favorable prognosis: What's a prognostic factor for PML-IRIS?

A 72-year-old woman with dermatomyositis (DM) developed neurological manifestation, and magnetic resonance imaging (MRI) revealed multiple T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions predominantly in the deep white matter of the cerebral hemisphere. Punctate or linear contrast enhancement was observed surrounding the T1-hypointense area. Multiple T2/FLAIR-hyperintense lesions were aligned along with the corona radiata. Malignant lymphoma was first suspected, and a brain biopsy was performed. Pathological investigation suggested the provisional diagnosis of "suspicious of malignant lymphoma." Owing to emergent clinical conditions, high-dose methotrexate (MTX) therapy was conducted, and then T2/FLAIR-hyperintense lesions were dramatically reduced. However, the diagnosis of malignant lymphoma was concerning since multiplex PCR demonstrated clonal restriction of the Ig H gene for B cells and TCR beta genes for T cells. Histopathology revealed the infiltration of both CD4+ and CD8+ T cells, and the CD4+ /CD8+ ratio was 4.0. Moreover, prominent plasma cells were observed, in addition to CD20+ B cells. Atypical cells with enlarged nuclei were present, and they were not hematopoietic but found as glial cells. JC virus (JCV) infection was verified with both immunohistochemistry and in situ hybridization; the final diagnosis was progressive multifocal leukoencephalopathy (PML). The patient was treated with mefloquine and discharged. This case is informative in understanding the host anti-viral response. Variable inflammatory cells were observed, including CD4+ and CD8+ T cells, plasma cells, and a small amount of perivascular CD20+ B cells. PD-1 and PD-L1 expression was observed in lymphoid cells and macrophages, respectively. PML with inflammatory reactions was thought fatal, and autopsy cases of PML with immune reconstitution inflammatory syndrome (IRIS) demonstrated excessive infiltration of only CD8+ T cells. However, this case revealed infiltration of variable inflammatory cells, and a favorable prognosis would be expected under PD-1/PD-L1 immune-checkpoint regulation.

No evidence of bovine leukemia virus proviral DNA and antibodies in human specimens from Japan.

BACKGROUND: The potential risk and association of bovine leukemia virus (BLV) with human remains controversial as it has been reported to be both positive and negative in human breast cancer and blood samples. Therefore, establishing the presence of BLV in comprehensive human clinical samples in different geographical locations is essential. RESULT: In this study, we examined the presence of BLV proviral DNA in human blood and breast cancer tissue specimens from Japan. PCR analysis of BLV provirus in 97 Japanese human blood samples and 23 breast cancer tissues showed negative result for all samples tested using long-fragment PCR and highly-sensitive short-fragment PCR amplification. No IgG and IgM antibodies were detected in any of the 97 human serum samples using BLV gp51 and p24 indirect ELISA test. Western blot analysis also showed negative result for IgG and IgM antibodies in all tested human serum samples. CONCLUSION: Our results indicate that Japanese human specimens including 97 human blood, 23 breast cancer tissues, and 97 serum samples were negative for BLV.

Non-Destructive Measurement of Acetic Acid and Its Distribution in a Photovoltaic Module during Damp Heat Testing Using pH-Sensitive Fluorescent Dye Sensors.

An optical pH sensor that enables the non-destructive measurement of acetic acid and its distribution in a photovoltaic module during damp heat (DH) testing is reported. The sensor was fabricated by impregnating a solution of a pH-sensitive fluorescent dye into a fluororesin membrane filter, which was then dried. While conducting the DH test, fluorescence spectra from 20 pH sensors were periodically recorded and converted into pH values using a predetermined calibration curve. As a result, we succeeded in measuring changes in pH with a DH test time of up to 2000 h, and it was possible to obtain information on the pH distribution in the module. We also confirmed no change in pH in a module with a silicone encapsulant free from acetic acid, and revealed that the sensor that we developed does not respond to moisture and heat, but only to acetic acid.

Mantle cell lymphoma with EBV-positive Hodgkin and Reed-Sternberg-like cells in a patient after autologous PBSCT: Phenotypically distinct but genetically related tumors.

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed-Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5- , CD15+ , CD20- , CD30+ , PAX5+ , Bob.1- , Oct2- and EBER+ . The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein-Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.

Radiologic-pathologic association of tumor-like lesions with inflammation in cerebral white matter: Comparison of two cases with distinct clinical outcomes.

Here, we report two cases showing tumor-like white matter lesions; one case was diagnosed as having inflammatory disease, and the other was diagnosed as having astrocytoma. Their outcomes were completely distinct despite similar pathology. Prior to biopsy, perfusion computed tomography (CT) and magnetic resonance imaging (MRI) were conducted. The two mass-forming lesions were distinct in edema level and vascularity patterns on CT and MRI. However, pathological examination of brain biopsy specimens revealed commonalities, including (1) proliferation of glial cells, (2) perivascular lymphocytic infiltration, and (3) appearance of numerous macrophages. Although atypical astrocytes proliferated in both cases, nuclear atypia was more distinct in case 2 than in case 1. The immunohistochemical results were the same for both cases: isocitrate dehydrogenase 1 (IDH1) R132H mutation was negative, and alpha thalassaemia mental retardation X-linked (ATRX) was retained. Faint immunoreactivity for p53 was observed in a few glial cells, and Ki-67 immunoreactive cells were markedly reduced in numbers (< 1%). Inflammatory reactions were evident in both cases: T cells dominantly infiltrated over B cells in the perivascular area in case 1, whereas both T and B cells infiltrated in case 2. Molecular analysis revealed wild-type IDH1 and IDH2 in both cases. However, a telomerase reverse transcriptase (TERT) sequence mutation was detected in case 2 but not in case 1. Eventually, case 1 was diagnosed as having inflammatory lesions, whereas case 2 was diagnosed as having diffuse astrocytoma associated with inflammatory reactions. The prognosis was favorable for case 1, whereas case 2 died 10 months following biopsy. These data indicated the diagnostic value of molecular analysis, for example, a TERT mutation, in association with the radiological findings. Although in case 2, histopathological evidence did not suggest high-grade glioma, the case met the new diagnostic criteria: "diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma, World Health Organization (WHO) grade IV," according to cIMPACT-NOW, update 3. Thus, interdisciplinary approaches are essential for accurate diagnosis of newly categorized white matter diseases.

Development of demyelinating lesions in progressive multifocal leukoencephalopathy (PML): Comparison of magnetic resonance images and neuropathology of post-mortem brain.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by opportunistic infection of JC polyomavirus (JCV). Today, increased attention has been focused on PML development in multiple sclerosis (MS) patients under disease-modifying therapies (DMT). Although in the acquired immunodeficiency syndrome (AIDS) era, PML was thought to be a rapidly progressive disease with poor prognosis, drug-associated PML is relatively slow in progress, and a favorable outcome may be expected with early diagnosis. However, early PML diagnosis on magnetic resonance imaging (MRI) is frequently difficult, and JCV DNA copy number in cerebrospinal fluid (CSF) is usually low. To facilitate early PML diagnosis on MRI, the pre-mortem images were compared with neuropathology of the post-mortem brain, and underlying pathology corresponding to the MRI findings was evaluated. As a result, PML lesions of the autopsied brain were divided into three parts, based on the disease extension patterns: (A) Progressive white matter lesion in the right frontoparietal lobe including the precentral gyrus. Huge demyelinated lesions were formed with fusions of numerous small lesions. (B) Central lesion including deep gray matters, such as the putamen and thalamus. The left thalamic lesion was contiguous with the pontine tegmentum. (C) Infratentorial lesion of brainstem and cerebellum. Demyelination in the pontine basilar region and in cerebellar white matter was contiguous via middle cerebellar peduncles (MCPs). In addition, (D) satellite lesions were scattered all over the brain. These observations indicate that PML lesions likely evolve with three steps in a tract-dependent manner: (1) initiation; (2) extension/expansion of demyelinating lesions; and (3) fusion. Understanding of the PML disease evolution patterns would enable confident early diagnosis on MRI, which is essential for favorable prognosis with good functional outcome.

[A Case of Duplicated Cancer Simultaneously Causing Breast and Endometrial Cancer].

Recently, with the increase in the number of young cancer patients, we often encounter multiple primary cancer(MPC). In MPC, careful examination is necessary because the treatment order and policies change greatly depending on the stage and prognosis of each tumor. We report a case of synchronous MPC of endometrialcancer and breast cancer. The patient was a 40-year-old woman who underwent endometrial cytology by a previous doctor due to illicit bleeding. As a result of the diagnosis of classⅢB, she underwent gynecological examination in our hospital. Endometroid adenocarcinoma Grade 2 was diagnosed based on endoscopic findings. On pelvic MRI, a lesion adjacent to the neck showed a low signal in the uterine body compared to that in the endocardium. During the preoperative examination, CT showed contrast nodules in the right breast, and ultrasonography was performed at the department of breast surgery. Ultrasonography showed a low-echo mass of 23 mm in the right upper midline region. The needle biopsy results were papillotubular cancer(ER-negative, PgR-negative, HER2 1+, Ki-67 77%). Based on these findings, right breast cancer and endometrial cancer were diagnosed. Initially, we performed right mastectomy and sentinel lymph node biopsy; we then performed pancreatectomy in the gynecology department 2 weeks after discharge. After surgery, gynecology studied 6 courses of TC therapy, and currently, EC is undergoing breast surgery.

[Usefulness of Automated Breast Ultrasound for Deciding on a Surgical Approach in a Patient with Breast Cancer- A Case Report].

Since breast reconstruction has been covered by health insurance, we can choose a procedure that combines the cosmetic satisfaction of patients with curability. We report about a patient with breast cancer that who underwent nipple-sparing mastectomy after evaluating the intraductal spread by automated breast ultrasound system(ABUS), while hand held ultrasound( HHUS)showed only limited information on the intraductal spread of the lesion. A 52-year old woman with an abnormal screening finding was referred to our hospital. HHUS showed an irregular and poorly defined hypoechoic mass lesion with a lactiferous duct extending to directly under the nipple. A core needle biopsy revealed invasive ductal carcinoma. We performed ABUS to assess the intraductal spread in the lesion because the patient requested breast reconstruction. The coronal section of the breast in the ABUS did not showintraductal spread. We, therefore, decided to perform a nipple-sparing mastectomy and sentinel lymph node biopsy. Intraoperative evaluation by frozen and permanent sections showed negative margins. The ABUS findings helped in the evaluation of the intraductal spread of the lesion and in the choice of the optimal procedure for the patient.

[Usefulness of Breast Ultrasound in Follow-Up of Post-Operative Metachronous Contralateral Breast Cancer-A Case Report].

Mammography is the standard screening toolfor post-operative breast cancer, with annualcheck -ups recommended; however, it misses some cancers. We report a case a metachronous contralateral breast cancer detected by breast ultrasound 8 years and 6 months after operation. A 72-year-old women visited our hospital for follow-up 8 years and 6 months after the operation. She was diagnosed with right breast cancer at 63 years of age and underwent partial mastectomy with axially lymph node dissection. The pathological diagnose was scirrhous carcinoma. After chemotherapy and radiation therapy, she underwent screening with annual examinations. The mammography finding was normal, but an ultrasound showed a mass lesion in the contralateral breast. The pathological diagnosis of the biopsy specimen was mucinous carcinoma. A history of breast cancer is known to suggest an increased risk of metachronous contralateral breast cancer. Therefore, regular follow-up with breast ultrasound, not only mammography, is recommended.

[A Case of an Elderly Individual with Breast Cancer Diagnosed as Paget's Disease after Mastectomy].

We report here a case of a 78-year-old woman, who underwent mastectomy for breast cancer. Mammography showed a mass in the right MO area with an unclear boundary. Ultrasound examination revealed an irregular mass of 40×29×19mm in the right C region. Dynamic contrast-enhanced MRI showed a 34mm tumor with contrast effect in the C area of the right breast. We performed a core needle biopsy on the mass, and the histopathological diagnosis was apocrine carcinoma(ER-, PgR-, HER2 3+, and Ki-67 30%)of clinical T2N0M0, stageⅡA. Right mastectomy and sentinel lymph node biopsy were performed. In the postoperative pathological examination, the main lesion was apocrine carcinoma(ER-, PgR-, HER2 3+, Ki-67 20%)and Paget's disease(ER-, PgR-, HER2 3+, Ki-67 30%). After surgery, the patient was given trastuzumab therapy.

[A Case of Advanced Breast Cancer Effectively Treated with Bevacizumab and Letrozole].

We report a case of primary advanced breast cancer that was locally controlled by treatment with bevacizumab. A 69-yearold woman presented at our hospital complaining of left breast hemorrhage. Her left breast had a large mass with an ulcer, and there was bleeding. Breast ultrasonography showed a large tumor that involved the whole left breast, and some swollen axillary lymph nodes. Breast MRI showed a mass of 77mm and skin invasion around the medial area of the left breast. Histopathological examination indicated invasive ductal carcinoma, ER(+), PgR(+), HER2(-), Ki-67 20%. We diagnosed left breast carcinoma, T4bN1M0, stage III B. She received paclitaxel plus bevacizumab as first-line therapy. Breast MRI showed a reduction in the primary tumor and axillary lymph node swelling. Adverse events including hypertension(Grade 3) and peripheral neuropathy(Grade 2)were observed. She received letrozole as second-line therapy. After commencing letrozole, the tumor reduced further, and the local ulcer disappeared showing only induration. Four years from the start of treatment, the woman has obtained good local control and has not developed other metastases.

[Study of the Therapeutic Effect and Neutrophil Lymphocyte Ratio in Breast Cancer Patients Who Received Eribulin].

BACKGROUND: The neutrophil lymphocyte ratio is reported to be a poor prognostic factor in each carcinoma, and the possibility of predicting the therapeutic effect of chemotherapy, for example, is being studied. In this study, we measured the NLR before and after administration of eribulin and the NLR before and after the final administration in breast cancer patients and examined the relationship with the therapeutic effect. METHODS: Eleven primary breast cancer patients were examined after eribulin was administered; PD was confirmed eventually, and administration was discontinued. The NLR was determined before the first administration of eribulin and 7 days after the administration; the NLR before the final administration and after the last administration were each tested with p<0.05 as the significance level and using the t test. RESULTS: The average value of NLR before initial administration was 4.07±2.11, and the average value after 7 days of administration was 2.47±1.97. The NLR before initial administration tended to be higher, and a significant difference was observed(p<0.05). The average NLR value before the final administration was 4.02±2.04, and the average value of the NLR after the final administration was 3.19 ±1.76, showing no significant difference(p=0.27, NS).

[Indoleamine 2,3-Dioxygenase Activity during Long-Term Letrozole Therapy for Hormone Receptor-Positive Breast Cancer].

Endocrine therapy is effective for elderly patients who are diagnosed with estrogen receptor-positive breast cancer and cannot receive surgical treatment or chemotherapy because of advanced age. The duration of response in patients receiving letrozole is approximately 10.3 months. There are few cases with more than 3 years of response. We evaluated the significance of indoleamine 2,3-dioxygenase(IDO)during letrozole therapy in long-term response. We measured IDO activity based on the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn levels were measured using high-performance liquid chromatography(HPLC). The Trp/Kyn ratio decreased along with tumor reduction after letrozole therapy. These results suggest that measuring the Trp/Kyn ratio may be useful for evaluating immunological status during endocrine therapy in elderly patients with locally advanced breast cancer.

[Synchronous and Unilateral Breast Cancers(Invasive Lobular Carcinoma and Non-Invasive Ductal Carcinoma) - A Case Report].

We report a case of synchronous and unilateral breast cancers in a 51-year-old female.A focal asymmetric right breast density was detected on breast cancer screening mammography.Ultrasonography showed a low echoic mass, 9mm in diameter, in the B area, and a second low echoic mass in the CD area of her right breast.A core needle biopsy of the B area mass led to a diagnosis of an invasive lobular carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), and negative for HER2/neu.One -percent of the tumor cells were Ki-67 positive.Her preoperative diagnosis was Stage I (T1N0M0).She underwent muscle-preserving mastectomy plus sentinel lymph node biopsy.The pathological diagnosis from the resected surgical specimen was invasive lobular carcinoma(B area), positive for ER, and negative for PgR and HER2/neu protein expression.From this, she was additionally diagnosed with non-invasive ductal carcinoma(CD area)that was posi- tive for ER, and negative for PgR and HER2/neu protein expression.The surgical margins were negative, and there were no sentinel lymph node metastases.These tumors were independent.She was given adjuvant endocrine therapy.Two years and 6 months after surgery, the patient was doing well and without metastases.

[Long-Term Effect of Fulvestrant for Locally Advanced Breast Cancer in an Elderly Patient - A Case Report].

We report an elderly patient with locally advanced breast cancer who received long-term fulvestrant therapy.The patient was a 75-year-old woman who presented with a right breast lump.She noticed the tumor 4 years and 6 months ago, but she had not visited any hospital.However, her daughter brought her to our hospital.The tumor was 73mm in diameter.A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), and negative for HER2/neu.The Ki-67 positive cell index was 20%.We performed a whole- body checkup, and confirmed the diagnosis as T4cN1M0, Stage III B.She initiated endocrine therapy by letrozole(2.5 mg/ day).After 1 year and 6months, tumor marker levels increased.We changed the endocrine therapy to fulvestrant(500mg/ month).For the next 2 years and 6 months, this therapy was effective.Her axillary lymph node metastases disappeared and tumor size decreased(60%).She underwent muscle-preserving mastectomy plus axillary lymph node dissection.The pathological diagnosis from the resected surgical specimen was confirmed as invasive ductal carcinoma, positive for ER and PgR, and negative for HER2/neu protein expression.The surgical margins were negative, and there was no metastasis in the lymph nodes.She was administered adjuvant endocrine therapy.Four years after surgery, she was well without metastasis.

[A Case of Advanced Breast Cancer with Liver Metastasis Successfully Treated with Multi-Disciplinary].

We report a case of advanced breast cancer with liver metastasis(T2N1M1, Stage IV )achieving a significant improvement of QOL by multi-disciplinary therapy. The patient was 37-year-old woman who had breast lump and axillary lymph nodes swelling with liver metastasis. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma, negative for estrogen receptor and progesterone receptor, and positive for HER2/neu protein expression. The Ki-67 positive cell index was 40%. She received 16 courses of DOC plus HER plus PER(docetaxel 75mg/m / 2, trastuzumab 6 mg/kg, pertu- zumab 450mg/body, and received 4 courses of EC(epirubicin 90mg/m / 2, cyclophosphamide 600 mg/m2). The breast lesion and liver metastatic lesion disappeared after chemotherapy. We checked up whole body. There was no metastatic lesion. Therefore, we diagnosed a clinical complete response. We performed muscle preserving mastectomy and axillary lymph nodes dissection. The pathological diagnosis from resected specimens were pathological complete response. The surgical margin was negative. She was started the endocrine therapy by tamoxifen(20mg/day). Three years after surgery, she was well without metastases. Multi-disciplinary therapy can improve patient QOL and the clinical outcomes in Stage IV advanced breast cancer.

[Successful Breast Conserving Surgery for Simultaneous and Ipsilateral Multiple Breast Carcinomas of Young Patient - A Case Report].

We report a case of a simultaneous and ipsilateral multiple breast carcinoma.The patient was 35-year-old woman.She was noticed a breast lump on her right breast, and visited our hospital.Mammography showed a tumor accompanied by spiculation on her right breast.Ultrasonography revealed 2 tumors with irregular margins, 23mm in diameter and 12mm in diameter, and were observed on C area of her right breast.The continuity of the 2 tumors was not clear.Core needle biopsies for each breast tumors led to a diagnosis.The pathological diagnosis was invasive ductal carcinoma.We checked up whole body. There was no metastatic lesion.We performed breast conserving surgery and sentinel node biopsy.The pathological diagnosis was invasive ductal carcinoma, positive for estrogen receptor and progesterone receptor, negative for HER2/neu.The Ki-67 positive cell index was 30%.The surgical margin was negative.We diagnosed T2N0M0=Stage II A.She was started the endocrine therapy by LH-RH agonist and tamoxifen.Four years after surgery, she was well without metastases.

[Diagnosis of a Non-Invasive Ductal Carcinoma, Assisted by Long-Term Follow-Up of Spontaneous Nipple Discharge - A Case Report].

We report a case of a non-invasive ductal carcinoma revealed on long-term follow-up of spontaneous nipple discharge. The patient, a 36-year-old woman, had noticed spontaneous nipple discharge from both breasts over a 3-year period. Mammography and ultrasonography did not reveal any lesions in the breasts. The nipple discharge from her left breast stopped 36 months after initial clinical assessment. However, the nipple discharges from her right breast transformed into a bloody discharge from a single duct. Ultrasonography showed a tumor, 6mm in diameter, in the upper-outer quadrant of her right breast. A core needle biopsy for breast tumor led to a pathological diagnosis of non-invasive ductal carcinoma. We conducted a whole-body clinical examination but no metastatic lesions were detected. Subsequently, we performed breastconserving surgery and sentinel lymph node biopsy. The pathological diagnosis was non-invasive ductal carcinoma in situ. The tumor was positive for estrogen and progesterone receptors, but negative for HER2/neu. The Ki-67 labeling index was 5%. The surgical margin was negative. We diagnosed the tumor as TisN0M0=Stage 0. Endocrine therapy comprising tamoxifen (20mg/day)was initiated. Four years after surgery, she was well without any metastases.

[Treatment Experience of Palbociclib as a New Checkpoint Inhibitor].

We encountered a case of multiple metastases from breast cancer. The patient was administered palbociclib, which was a new checkpoint inhibitor. The patient received various chemotherapies and endocrine therapies. We observed episode of care, a harm phenomenon, and tolerability. We did not recognize adverse events more severe than Grade 3 during the 6 weeks after initiating palbociclib therapy. Diagnostic imaging showed that the metastatic lesions maintained stable disease during the 6 weeks after initiating palbociclib therapy. This case suggested that palbociclib therapy is useful for patients with metastatic breast cancer.