Relapsing bronchopneumonia due to community-associated methicillin-resistant Staphylococcus aureus: a case report.

BACKGROUND: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased the incidence of community-onset MRSA infection. Respiratory tract infections caused by MRSA has been noted for their severity; however, repeated relapses that require extended antibiotic therapy are rare. CASE PRESENTATION: We report a case of relapsing bronchopneumonia caused by CA-MRSA in a 56-year-old man. The patient responded to antibiotics, but repeatedly relapsed after stopping treatment. MRSA was consistently isolated from airway specimens during each relapse. Extended oral antibiotic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) for 6 months achieved infection control. Whole-genome sequencing of the isolated strain revealed that the causative agent was sequence type (ST)1/staphylococcal cassette chromosome mec (SCCmec) type IVa, a clone that is rapidly increasing in Japan. DISCUSSION AND CONCLUSIONS: This patient had an unusual course of MRSA bronchopneumonia with repeated relapses. Although the choice of antibiotics for long-term use in MRSA respiratory tract infections has not been well established, TMP/SMX was effective and well tolerated for long-term therapy in this case. The clinical course of infections related to the rapid emerging clone, ST1/SCCmec type IVa warrants further attention.

Pathology of human organic mercury poisoning: Lessons from an autopsy case.

We had an opportunity to perform a general autopsy of a case with chronic organic mercury toxicosis in 2017. He had been engaged in synthesizing a variety of organic mercury compounds throughout the four years from 1966 and developed chronic organic mercury poisoning in 1969. Almost forty years on, he still remained to complain of persistent paresthesia at finger tips and tongue, and of narrowed visual field. Neurological examinations clarified a rise of two-point discrimination thresholds, a systemic increase of touch thresholds, constriction of the visual field caused by general visual depression, and sensorineural hearing loss while primary modalities of his somatic, visual, and auditory sensations were preserved. These symptoms and signs are characteristic of human organic mercury poisoning. Furthermore, he had difficulty in processing a lot of visual and auditory information at a time. His two-point discrimination thresholds and systemic elevation of touch thresholds were comparable to those of mild organic mercury poisoning cases. He had slight sensory ataxia, but not cerebellar ataxia. Brain [18F]-2-fluorodeoxyglucose positron emission tomography analysis exhibited marked hypometabolism at bilateral postcentral gyrus, striate cortex, and superior temporal gyrus, but not the cerebellum. Histopathological studies revealed considerable decrease of granular neurons and neuronal networks in bilateral primary somatosensory, visual, and auditory cortices. Those characteristic brain lesions fairly explain increase of thresholds of somatic, visual, and auditory sensations, and degradation of integrating sensory information. It is noted that damages to the peripheral nervous system and the cerebellum were not detected and that his intellectual faculties were preserved.

Evaluating the potential of immunotherapy and chemoimmunotherapy in the treatment of elderly non-small cell lung cancer patients: A real-world study.

BACKGROUND: Immune checkpoint inhibitor (ICI) has become the standard therapy for metastatic non-small cell lung cancer (NSCLC) patients. However, no robust evidence on the efficacy and safety of ICI in elderly NSCLC patients has been established. MATERIALS AND METHODS: This retrospective study aimed to assess the efficacy and safety of ICI in elderly NSCLC patients. NSCLC patients treated with ICI monotherapy or chemoimmunotherapy (CIT) between 2016 and 2022 were divided into two cohorts according to the age: the Elderly cohort (patients aged ≥ 75 years) and the Nonelderly cohort (patients aged < 75 years). The progression-free survival (PFS), tumor response, and frequency of immune-related adverse events (irAEs) were compared between the two cohorts. RESULTS: A total of 111 NSCLC patients were included in this study (41 patients in the Elderly cohort and 70 patients in the Nonelderly cohort). The PFS (5.6 months vs. 6.3 months, P = 0.98), response rate (36.6% vs. 44.9%, P = 0.51), and disease control rate (80.5% vs. 76.8%, P = 0.83) were not significantly different between the two cohorts. In a subgroup analysis, stratified according to PD-L1 expression (low vs. high) and ICI treatment mode (ICI monotherapy vs. CIT), the PFSs of both cohorts were also not significantly different, regardless of PD-L1 expression. Moreover, the frequency of irAEs did not significantly differ between elderly and nonelderly NSCLC patients (21/41 [51.2%] vs. 38/70 [54.3%], P = 0.91). CONCLUSION: The efficacy and safety of ICI in elderly NSCLC patients were not inferior to those in younger patients.

Novel Strategy for the Management of Cervical Multicystic Diseases.

PURPOSE: To investigate the clinical practices of diagnosing multicystic cervical lesions as a means to develop a more appropriate diagnostic algorithm for gastric-type adenocarcinoma (GAS) and its precursors. METHODS: Clinical information for 159 surgically treated patients for multicystic disease of the uterine cervix was collected from 15 hospitals. We performed a central review of the MRI and pathological findings. The MRI findings were categorized into four types including two newly proposed imaging features based on the morphology and distribution of cysts, and the diagnosis accuracy was assessed. Among the four MRI types, types 1 and 2 were categorized as benign lesions that included LEGH; type 3 were precancerous lesions (with an assumption of atypical LEGH); and type 4 were malignant lesions. RESULTS: The central pathological review identified 56 cases of LEGH, seven with GAS, four with another form of carcinoma, and 92 with benign disease. In clinical practice, over-diagnosis of malignancy (suspicion of MDA) occurred for 12/19 cases (63.2%) and under-diagnosis of malignancy occurred for 4/11 (36%). Among the 118 patients who had a preoperative MRI and underwent a hysterectomy, type 3 or 4 MRI findings in conjunction with abnormal cytology were positively indicative of premalignancy or malignancy, with a sensitivity and specificity of 61.1% and 96.7%, respectively. CONCLUSIONS: Although the correct preoperative diagnosis of cervical cancer with a multicystic lesion is challenging, the combination of cytology and MRI findings creates a more appropriate diagnostic algorithm that significantly improves the diagnostic accuracy for differentiating benign disease from premalignancy and malignancy.

Ovarian high-grade serous carcinoma cells with low SMARCA4 expression and high SMARCA2 expression contribute to platinum resistance.

Platinum resistance is a major obstacle to the treatment of ovarian cancer and is correlated with poor clinical outcomes. Intratumor heterogeneity plays a key role in chemoresistance. Recent studies have emphasized the contributions of genetic and epigenetic factors to the development of intratumor heterogeneity. Although the clinical significance of multi-subunit chromatin remodeler, switch/sucrose nonfermenting (SWI/SNF) complexes in cancers has been reported, the impacts of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4/subfamily A, member 2 (SMARCA4/A2) expression patterns in human cancer tissues have not been fully elucidated. Here, we show that low expression of SMARCA4 and high expression of SMARCA2 are associated with platinum resistance in ovarian high-grade serous carcinoma (HGSC) cells. We used fluorescence multiplex immunohistochemistry (fmIHC) to study resected specimens; we examined heterogeneity in human HGSC tissues at the single-cell level, which revealed that the proportion of cells with the SMARCA4low /SMARCA2high phenotype was positively correlated with clinical platinum-resistant recurrence. We used stable transfection of SMARCA2 and siRNA knockdown of SMARCA4 to generate HGSC cells with the SMARCA4low /SMARCA2high phenotype; these cells had the greatest resistance to carboplatin. Bioinformatics analyses revealed that the underlying mechanism involved in substantial alterations to chromatin accessibility and resultant fibroblast growth factor (FGF) signaling activation, MAPK pathway activation, BCL2 overexpression, and reduced carboplatin-induced apoptosis; these were confirmed by in vitro functional experiments. Furthermore, in vivo experiments in an animal model demonstrated that combination therapy with carboplatin and a fibroblast growth factor receptor (FGFR) inhibitor promoted cell death in HGSC xenografts. Taken together, these observations reveal a specific subpopulation of HGSC cells that is associated with clinical chemoresistance, which may lead to the establishment of a histopathological prediction system for carboplatin response. Our findings may facilitate the development of novel therapeutic strategies for platinum-resistant HGSC cells. © 2023 The Pathological Society of Great Britain and Ireland.

Amplitude of Somatosensory Evoked Potentials (SEPs) Recorded in Short-Latency SEP Condition Is 80% of That in Giant SEP Condition.

PURPOSE: Giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex (C-reflex) are useful to detect cortical motor hyperexcitability in patients with myoclonic epilepsy. The recording conditions of giant SEPs are different from those of short-latency SEPs (SSEPs). We investigated the waveform characteristics obtained for each condition. METHODS: Forty-eight upper limbs of 24 adult normal subjects (12 men, age 35.5 ± 9.7 years [mean ± SD]) were investigated. Somatosensory evoked potentials of each subject were recorded in both conditions on the same day. The main differences in recording conditions were reference electrodes (SSEP: Fz vs. giant SEP: the earlobe electrode ipsilateral to the stimulated limb), stimulus rate (5 vs. 1 Hz), and bandpass filter (20 Hz-3 kHz vs. 1 Hz-1 kHz). Somatosensory evoked potentials were elicited by unilateral percutaneous electrical stimulation of the median nerve at the wrist with intensity of 110% of the movement threshold and recoded at C3'/C4'. RESULTS: The amplitudes of N20 onset-N20 and N20-P25 were significantly larger in giant SEP condition than in SSEP condition (p < 0.001). The mean + 3SD of N20-P25 amplitude was 10.0 µV in giant SEP condition and 7.8 µV in SSEP condition. The N20-P25 amplitude was significantly correlated between giant SEP condition and SSEP condition (R = 0.64, p < 0.001). C-reflex was not elicited. CONCLUSIONS: The amplitude of SEPs in SSEP condition is equivalent to 80% of that in giant SEP condition. The information is useful for detecting cortical hyperexcitability in various neurological disorders including myoclonic epilepsy.

MRI of Borderline Epithelial Ovarian Tumors: Pathologic Correlation and Diagnostic Challenges.

Borderline epithelial ovarian tumors are a distinct pathologic entity characterized by increased epithelial proliferation and nuclear atypia, but without frank stromal invasion. Borderline tumor (BT) is now considered to represent an intermediate phase in the stepwise progression from benign to malignant ovarian epithelial tumor. Since BTs commonly manifest at early stages in women of reproductive age and are associated with a good prognosis, making the correct diagnosis is important in determining whether a patient is a candidate for fertility-sparing surgery. There are six histologic BT subtypes (serous, mucinous, seromucinous, endometrioid, clear cell, and Brenner), and each has different MRI features, reflecting their unique histologic architectures. Radiologists should be aware of the MRI features that can suggest BTs. These features include a hyperintense papillary architecture with hypointense internal branching, which can be observed with serous and seromucinous BTs on T2-weighted images; aggregates of microcysts that have hypointensity on T2-weighted images and reticular enhancement on contrast-enhanced T2-weighted images, which can be seen with mucinous BTs; and moderately high signal intensity on diffusion-weighted images along with relatively high apparent diffusion coefficient values, which can be observed regardless of the histologic subtype. Nevertheless, because the imaging features of BTs overlap with those of many benign lesions (eg, cystadenoma and cystadenofibroma, decidualized endometriosis, and polypoid endometriosis) and malignant tumors (ovarian cancers and metastases), histologic confirmation is required for the final diagnosis. Special emphasis is placed on the MRI features of BTs, pathologic correlation, and the challenges related to diagnosis. ©RSNA, 2022.

Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures.

BACKGROUND: The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. METHODS: Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. RESULTS: Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. CONCLUSION: The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Cerebellopontine angle metastasis of a neuroendocrine tumor mimicking vestibular schwannoma: A case report.

Background: Neuroendocrine tumors (NETs) are uncommon neoplasms arising from neuroendocrine cells and are rarely associated with intracranial metastases. Case Description: We discuss the case of a 74-year-old woman with a right CPA tumor. She had a history of retroperitoneal NET, but was diagnosed with vestibular schwannoma due to a right-sided hearing loss and a right CPA tumor along the VII and VIII nerves. After a 3-year follow-up, she presented with repetitive vomiting, a 1-month history of gait instability, and a 3-month history of general fatigue. Brain imaging revealed tumor growth and edematous changes in the right cerebellum. She underwent retrosigmoid craniotomy and partial resection. Histopathological examination revealed metastatic NET. She underwent stereotactic radiosurgery for residual lesion and, at 11 months of follow-up, the lesion was confirmed to have shrunk on magnetic resonance imaging (MRI). Conclusion: This is the first case to report the natural course of cerebellopontine metastasis of a NET. The differential diagnosis of CPA tumors is diverse, and, in our case, we suspected a vestibular schwannoma because of the typical symptoms and imaging features. However, the tumor grew relatively faster than expected and showed intratumoral hemorrhage during the 3-year follow-up. Therefore, in patients with a history of a NET, a careful follow-up is advisable even for lesions highly suspected to be another benign tumor on MRI. Careful follow-up imaging and appropriate treatment strategies were useful to manage the brain metastasis. Although NETs metastasizing to the CPA are extremely rare, this possibility should be considered when patients with NETs have intracranial lesions.

Atypical preeclampsia before 20 weeks of gestation with multicystic placenta, hyperreactio luteinalis, and elevated sFlt-1/PlGF ratio as manifestations of fetal triploidy: A case report.

Preeclampsia is one of the most common as well as most severe complications of pregnancy, characterized by new-onset hypertension and proteinuria or other organ dysfunction. It predominantly occurs after 20 weeks of gestation. Very rarely, it can be triggered earlier in some specific situations. Here we report a case of fetal triploidy presenting as an extraordinarily early-onset preeclampsia. A healthy 36-year-old multiparous woman who had conceived naturally was hospitalized due to acute-onset severe hypertension accompanied by proteinuria at 18 weeks of gestation. Laboratory testing ruled out the presence of underlying maternal disease. Ultrasound findings, including multicystic large placenta and multiple fetal anomalies, strongly suggested fetal triploidy. Maternal ovaries showed hyperreactio luteinalis. The soluble fms-like tyrosine kinase-1/ placental growth factor (sFlt-1/PlGF) ratio was elevated, at 270. Medical abortion was carried out at 19 weeks of gestation; thereafter, her symptoms quickly resolved. Fetal triploidy was confirmed by genetic testing. We should be aware that fetal disorders including triploidy as well as pre-existing maternal diseases can provoke such very early-onset preeclampsia. Fetal ultrasound evaluation is critical and the sFlt-1/PlGF ratio is important for prompt diagnosis and management to prevent adverse maternal outcomes associated with atypical preeclampsia before 20 weeks of gestation.

Gastric-Type Adenocarcinoma of the Uterine Cervix Associated with Poor Response to Definitive Radiotherapy.

We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p < 0.05). Three-year overall survival and progression-free survival (PFS) rates of SCC were significantly higher than those of AC (88.6% vs. 74.1%, p < 0.05 and 76.3% vs. 59.3%, p < 0.05, respectively). Among the AC population, univariate and multivariate analyses were performed to examine prognostic factors associated with non-complete response (CR). In the multivariate analysis, gastric-type adenocarcinoma (GAS) was associated with non-CR in AC (adjusted odds ratio, 12.2; 95% confidence interval 1.0−145.6; p < 0.05). The 3-year PFS rate in patients with GAS was significantly lower than that in patients with other histological types of AC (44.4% vs. 66.7%, p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC.

The efficacy of human papillomavirus vaccination in young Japanese girls: the interim results of the OCEAN study.

Human papillomavirus (HPV) vaccine has been used to prevent chronic HPV infection, which accounts for cervical cancer. Japanese Ministry of Health, Labor and Welfare (MHLW) conducted an HPV vaccination campaign in 2010 and the Obstetrical Gynecological Society of Osaka initiated a multicenter, prospective cohort study in Osaka, Japan - OCEAN (Osaka Clinical resEArch of HPV vacciNe) study - to investigate the oncogenic HPV prevalence and the long-term protection rate of HPV vaccine. A total of 2814 participants were enrolled on their visit for HPV vaccination between 12 and 18 years old. Among them, 102 participants received HPV/Pap co-test as primary cancer screening at the age of 20-21. We compared the prevalence in two groups (the vaccinated and the unvaccinated group). HPV infection ratio was significantly lower in the vaccinated group compared to the unvaccinated (12.9% vs. 19.7%; p = .04). In particular, HPV 16 and 18 were not detected in the vaccinated group, while 4.9% of participants in the unvaccinated group were infected (p = .001), suggesting that vaccination provided effective protection against high-risk types of HPV. The cross-protection effect of HPV vaccines was also observed against HPV 31, 45, and 52. Although HPV vaccines were not contributed to the reduction of cervical intraepithelial neoplasia 1 (CIN) (p = .28), CIN2 or worse was not observed in vaccinated group. Our research showed that at the age of 20-21, HPV vaccine inhibited the infection of high-risk HPV and had impacted on the development to CIN2 or worse in Japan.

Strong expression of PD-L1 in invasive front of MELF pattern in endometrioid carcinoma.

Endometrioid carcinoma (EC) is classified into 3 histological subtypes; Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3). Although the prognosis is relatively good in G1, some G1 cases are more aggressive, which are called G1 with MELF (microcystic, elongated, and fragmented) pattern. Current therapy, such as radiotherapy and chemotherapy, is not effective in MELF, and more effective treatment is needed. The Cancer Genome Atlas (TCGA) performed an integrated genomic, transcriptomic, and proteomic analysis and classified EC into 4 groups: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high, in which MELF was associated with microsatellite instability hypermutated. Microsatellite instability is detected in a wide variety of cancer, and PD-1 (programmed cell death 1) and PD-L1 (programmed cell death-ligand 1) are received a lot of attention as a therapeutic target. To date, no studies have been focused on PD-L1 expression in EC with MELF pattern. Then we performed immunohistochemical analysis of the distribution of PD-L1 expressing cells in G1 with MELF pattern. In cases of G1 with MELF pattern, tumor cells expressed PD-L1 significantly higher in invasive front area than in surface area. We often found lymphovascular invasion of PD-L1 expressing tumor cells. PD-L1 expressing tumor cells in MELF would be the cause of recurrence or lymph node metastasis. Moreover, in most G1 cases with MELF pattern, PD-L1 was expressed in inflammatory cells as well as tumor cells in invasive front area. PD-L1 expression in both tumor and immune cells contribute to immune suppression and both cells could be sensitive to therapeutic agents targeting the PD-L1/PD-1 axis. Therefore, significant therapeutic effect can be expected by applying PD-1/PD-L1 immunotherapy to the treatment of G1 with MELF.

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma.

Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation-response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N-methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial-mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S-adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

Prognostic factors for bone metastases from head and neck squamous cell carcinoma: A case series of 97 patients.

Although bone is the second-most frequent site of distant metastases of head and neck squamous cell carcinoma (HNSCC), variable prognostic factors in patients with bone metastases from HNSCC have not been fully investigated. The aim of the present study was to assess the prognostic factors affecting overall survival (OS) in these patients. The medical records of 97 patients at two institutions who developed bone metastases from HNSCC between January 2010 and December 2020 were retrospectively reviewed. A multivariate analysis using a Cox proportional hazards model was performed to identify potential clinical predictive factors for longer OS. The median OS was 7 months, and the 1- and 2-year OS rates for all patients were 35.4 and 19.2%, respectively. The independent predictive factors for longer OS were single bone metastasis, good performance status and administration of systemic chemotherapy. The median OS with each predictor was 10, 10 and 10.5 months, respectively. In a selected group of patients with these three factors, the OS was 14.5 months. In conclusion, single bone metastasis, a good performance status and systemic chemotherapy were independent predictors of longer OS in patients with HNSCC, but their contributions were limited.

Polycythemia Vera Associated with Pulmonary Hypertension and Diffuse Large B-Cell Lymphoma: A Case Report.

BACKGROUND Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), are associated with pulmonary hypertension (PH) and malignant lymphomas. Although the underlying mechanisms have not been completely clarified, it has been suggested that the Janus kinase 2 (JAK2) mutation, which is frequently identified in PV, can be involved in the development and/or progression of these distinct diseases in patients with MPNs. However, no reports have described the coexistence of PH and malignant lymphoma in patients with MPNs. CASE REPORT A 79-year-old man being treated for PV for 27 years and PH for 5 years was hospitalized due to severe dyspnea at rest. His soluble interleukin-2 receptor levels gradually increased and the chest computed tomography showed remarkable progression of the lung lesions and an enlargement of the mediastinal and axillary lymph nodes. A lymph node biopsy was performed and the patient was diagnosed with diffuse large B-cell lymphoma (DLBCL). Owing to his poor condition, chemotherapy was not initiated, and he died on the 89th day of hospitalization. The pathological autopsy revealed the destruction of alveolar structures with neoplastic space-occupying lesions of DLBCL. Multifactorial features of PH associated with MPNs, including the intimal thickening of pulmonary arteries accompanied by megakaryocytes and obstructed pulmonary arteries with organized thrombi in the lung tissue specimens, were observed. We found a JAK2 mutation based on a genetic analysis of the patient's bone marrow. CONCLUSIONS We present the rare case of a patient who had PV with a JAK2 mutation, which coexisted with PH and DLBCL, and he developed severe refractory respiratory failure.

Inverse association between hypertension treatment and COVID-19 prevalence in Japan.

OBJECTIVES: Cell entry of SARS-CoV-2 depends on angiotensin-converting enzyme II. Angiotensin-converting enzyme II is homologous with, but acts antagonistically to, angiotensin-converting enzyme and has the critical function of protecting the lungs. Angiotensin-converting enzyme inhibitors are major antihypertensive agents. Thus, we aimed to analyze the impact of the prevalence of preexisting hypertension on the local spread of COVID-19. METHODS: Data on SARS-CoV-2 infection and the estimated number of patients who received medical treatment on the basis of disease classification using the International Statistical Classification of Diseases and Related Health Problems (10th Revision) in each prefecture were obtained from the official Japanese notifications database. We analyzed the association between the proportion of patients with each disease and SARS-CoV-2-infection prevalence. RESULTS: The ratio of patients treated for diseases of the circulatory system, especially hypertensive disorders, per population demonstrated the most significant negative correlation with SARS-CoV-2-infection prevalence (Spearman's rank correlation, P < 0.01). Age group analysis revealed a significant negative correlation in age groups 35-44, 45-54, 55-64, 75-84, and ≥85. CONCLUSIONS: Our findings suggest that hypertension treatment may play a protective role against the local spread of SARS-CoV-2 infection.

CD70 antibody-drug conjugate as a potential therapeutic agent for uterine leiomyosarcoma.

BACKGROUND: Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma. OBJECTIVE: This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70-antibody-drug conjugate treatment in uterine leiomyosarcoma. STUDY DESIGN: Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models). RESULTS: CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70-antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70-antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70-antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm3; relative reduction, 54.5%; P<.001) and patient-derived xenograft mouse model (tumor volume, 128.1 vs 837.7 mm3; relative reduction, 84.7%; P<.001). CONCLUSION: Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70-antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.

Active direct current (DC) shifts and "Red slow": two new concepts for seizure mechanisms and identification of the epileptogenic zone.

An accurate identification of the epileptogenic zone is essential for patients with intractable epilepsy who are candidates to neurosurgery. EEG recordings can provide predictive biomarkers of the epileptogenic zone. Wide-band EEG makes it possible to record from infraslow (including DC shifts) to high frequency (HFO, over 300 Hz) oscillations for diagnostic purposes in patients with epilepsy. Although the presence of HFOs have been proposed to sign the epileptogenic zone, DC-like recordings demonstrate that DC shifts precede HFOs at seizure onset. This led to the proposal that "ictal active DC shifts" are causally related to seizure onset as opposed to "ictal passive DC shifts". Thus, active DC shifts may constitute predictive biomarkers of the epileptogenic zone in epilepsy. Since DC shift is commonly associated to a rise in extracellular potassium, potassium homeostasis regulated by Kir4.1 channels in astrocytes may play an key role at seizure onset. In addition, we hypothesize that, during the interictal period, the co-occurrence of slow events and interictal HFOs, so-called "Red slow", may also delineate an epileptogenic zone, even if a seizure would not be actually recorded.