Journal of Nippon Medical School最新文献

Background: Acoustic trauma is a common cause of acute sensorineural hearing loss associated with tinnitus; however, the underlying molecular mechanisms remain unclear. Extracellular signal-regulated kinase 2 (ERK2), a member of the mitogen-activated protein kinase family, is crucial in cellular signaling, especially in the nervous system, where it helps regulate neuroprotection, neurogenesis, and neuronal plasticity. ERK2 is activated in the cochlea by acoustic stimuli and plays a protective role in cochlear hair cells (HCs), which are the primary sensory receptors for hearing. However, the significance of ERK2 expression in HCs associated with development and etiology of tinnitus is largely unexplored.

Methods: To investigate the role of ERK2 in tinnitus development, the gap detection test (GAP) was used to evaluate HC-specific ERK2-conditional knockout mice (HC-E2CKO) exposed to moderate acoustic stimuli.

Results: Both control and HC-E2CKO mice showed normal prepulse inhibition levels (<0.6) before and after auditory damage, indicating normal functioning of sensorimotor gating pathways, excluding gross sensorimotor deficits. This confirmed that the animals were eligible for the GAP. HC-E2CKO mice showed a transient increase in the GAP ratio, indicating tinnitus development, 1 week after noise exposure, although the hearing threshold was not significantly elevated. The GAP ratio returned to normal after 2 weeks. In contrast, control mice did not exhibit elevation in hearing threshold and the GAP ratio remained normal.

Conclusion: Our findings suggest that ERK2 in the inner ear plays a role in tinnitus onset or perception after acoustic stress, potentially through inhibitory mechanisms.

Background: Prostate cancer (PCa) significantly contributes to male cancer mortality. Triplet therapy shows promise for metastatic castration-sensitive prostate cancer (mCSPC), but real-world data are limited. This study aimed to evaluate the clinical outcomes of triplet therapy in real-world patients with mCSPC at an academic hospital in Japan.

Methods: We retrospectively analyzed the efficacy and safety of triplet therapy, comprising androgen deprivation therapy, docetaxel, and darolutamide, in patients with mCSPC at Nippon Medical School Hospital. Clinical outcomes, adverse events (AEs), prostate-specific antigen (PSA) responses, and progression to castration-resistant prostate cancer were assessed.

Results: Between January 2023 and June 2024, we identified 14 Japanese patients with mCSPC who received triplet therapy. All patients presented with synchronous high-volume metastases as defined by the CHAARTED criteria. The median follow-up period was 7.9 months. In terms of efficacy, all 14 patients achieved PSA reduction of > 90%, while 13 of them achieved reductions of > 99%. AEs were reported in all patients, with grade 3 or higher AEs occurring in 10 patients. One patient permanently discontinued treatment and 4 patients temporarily interrupted therapy due to AEs. During follow-up, biochemical progression was observed in 2 patients and radiological progression in 2 patients. Subsequent therapies were selected based on each patient's clinicopathological and genetic characteristics, with considerable variability in treatment approaches following progression.

Conclusions: While PSA responses were favorable and tolerability was generally high, progression patterns and subsequent therapies varied widely, highlighting the need for close monitoring and individualized treatment in patients with mCSPC receiving triplet therapy.

Shaggy aorta refers to an aorta with intimal roughening due to atheromatous aortic plaques. Catheterization and anticoagulation therapy can result in cholesterol emboli, potentially leading to systemic organ infarction. Contrast-enhanced computed tomography (CT) and transesophageal echocardiography are commonly used to diagnose shaggy aorta. A patient in his ninth decade of life had a history of right occipital lobe ischemic stroke, bilateral internal carotid artery stenosis, and shaggy aorta syndrome related to transfemoral cerebral angiography. Dysarthria occurred immediately after the procedure. Brain magnetic resonance imaging (MRI) confirmed cerebral infarction, and anticoagulant therapy was administered. Four days later, after observing numbness of the left 5th finger and purplish discoloration of the tips of the 2nd and 5th fingers, we performed contrast-enhanced CT and diagnosed shaggy aorta. There was no renal impairment or eosinophilia and the patient was discharged 16 days after the examination. Aortic MRI performed 1 month later revealed an unstable plaque in the vessel wall. Although we report our experience with a single patient, we recommend that patients scheduled for cerebral angiography, especially those with severe arteriosclerosis, undergo preprocedural aortic fast spoiled gradient echo MRI screening to avoid shaggy aorta syndrome.

Background: Both ultraviolet B (UVB) phototherapy with 308-nm excimer light and excimer laser devices are widely used to treat vitiligo. While the devices share the 308-nm wavelength, they have distinct characteristics. Notably, the excimer laser exhibits laser properties (monochromatic coherent light) and unique device specifications (a high frequency of 400 Hz and a remarkably high irradiance of 83 million mW/cm²). This study compared excimer light and laser irradiation, focusing on the depth of penetration into hair follicles and the effects on activation of melanocyte lineage cells, including melanocyte stem cells (McSCs) and melanoblasts.

Methods: We irradiated the dorsal skin of mice with both devices at 1,000 mJ/cm². Samples taken at 15 min and 3, 24, and 72 h after irradiation were used for immunostaining analysis. We evaluated penetration depth by using the staining pattern of cyclobutane pyrimidine dimers (CPDs), induction of apoptosis by using a terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling (TUNEL) assay, and activation of melanocyte lineage cells by using fluorescent double immunostaining for TRP2 and β-catenin.

Results: The excimer laser induced significantly more CPDs in the deeper regions of hair follicles while causing significantly faster removal of CPDs and less apoptosis in the epidermis. Moreover, the percentage of TRP2-positive cells with nuclear β-catenin in the follicles was significantly higher with the excimer laser.

Conclusions: As compared with excimer light, the excimer laser penetrated more deeply into hair follicles, resulted in fewer epidermal side effects, and activated significantly more melanocyte-lineage cells.

Background: Current guidelines lack recommendations for serum tumor markers in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). This study assessed the potential of the postoperative serum C-terminus of cytokeratin 19 (CYFRA21-1, CYFRA) level, hereafter referred to as poCY, as a predictor of early progression in patients treated with RNU.

Methods: Overall, 117 patients were categorized into the high group (HG) or low group (LG) based on a poCY cutoff level of 3.5 ng/mL after excluding those who did not meet the inclusion criteria. Kaplan-Meier curves and log-rank tests were used to measure cancer-specific survival (CSS) and progression-free survival (PFS) rates. Multivariate analysis was performed using the Cox proportional hazards model.

Results: During a median follow-up of 34 months, the 5-year CSS and PFS rates were 79% and 66%, respectively. The HG had a significantly worse CSS and 2-year PFS than the LG. Multivariate analyses identified poCY and lymph node involvement (LNI) as independent prognostic factors. Regarding the 2-year PFS, poCY, LNI, and resection margin status (RM) emerged as independent prognostic factors.

Conclusions: poCY, LNI, and RM predicted early progression following RNU in patients with UTUC. Patients with elevated poCY may benefit from adjuvant chemotherapy, irrespective of their pathological findings.

Background: Triple-negative breast cancer (TNBC) comprises subgroups with distinct characteristics and histological types. Tumor-infiltrating lymphocyte (TIL) concentration and programmed death-ligand 1 (PD-L1) expression are prognostic factors for TNBC. We analyzed the association of immune cell PD-L1 expression, in relation to histological type and TIL concentration, with TNBC outcomes.

Methods: Data from 86 patients with TNBC treated between 2008 and 2014 were analyzed. Those treated with immune-checkpoint inhibitors (ICIs) were excluded. PD-L1 expression in immune cells was assessed by immunohistochemistry using an SP142 clone. TIL concentration was measured with hematoxylin and eosin staining. Tumor histology was classified as basal type (G1), apocrine type (G2), metaplastic change (G3), special type (G4), and adenoid cystic carcinoma (G5).

Results: The rate of PD-L1 positivity was 2.5%, 17.3%, and 58.6% for patients with TIL concentrations classified as low (TIL-L), moderate (TIL-M), and high (TIL-H) (p < 0.0001). Five-year overall survival (OS) was 78.8% among patients with PD-L1-positive tumors and 81.8% among those with PD-L1-negative tumors. Among TIL-L patients, 5-year OS in PD-L1-positive and -negative tumors was 100% and 77.4%, respectively (p = 0.9993). Among TIL-H patients, 5-year OS for PD-L1-positive and -negative tumors was 73.0% and 83.3%, respectively (p = 0.8241). In multivariate analysis, tumor size and lymphatic vessel invasion were independent prognostic factors for OS.

Conclusions: The rate of PD-L1 positivity was higher in TIL-H patients. Patients classified as TIL-H and PD-L1-positive had worse TNBC outcomes.

Extrahepatic portal vein obstruction (EHPVO) is a rare disease-causing form of portal hypertension. Myeloproliferative neoplasm (MPN) including essential thrombocythemia (ET) is a reported risk factor for EHPVO due to underlying persistent thrombophilia. A Japanese woman in her 40s was referred to our hospital with a 1-month history of gastric variceal bleeding due to EHPVO. Laboratory investigation showed thrombocytosis despite portal hypertension. She had a mutation in clonal marker JAK2V617F with EHPVO, which prompted us to consult a hematologist. A bone marrow biopsy revealed megakaryocyte lineage proliferation, which confirmed a diagnosis of ET. Esophagogastroduodenoscopy revealed esophagogastric varices (LsF2CbRC2, Lg-cF1RC1), and abdominal computed tomography and angiography revealed splenomegaly and portal vein thrombosis with cavernous transformation, which suggested EHPVO. The patient had a history of ruptured esophagogastric varices and required prophylaxis against further variceal bleeding before antithrombotic therapy for EHPVO with ET. We performed laparoscopic Hassab's operation followed by endoscopic variceal ligation (EVL) and hematological cytoreduction therapy. Laparoscopic Hassab's operation and three bi-monthly EVL procedures improved the esophagogastric varix (LmF0RC0, Lg-f F0RC0) at 6 months after surgery. Cytoreduction therapy reduced platelet count to 60.1 × 10⁴/uL, and the patient was very healthy at 7 months after surgery. Patients with EHPVO are traditionally referred to a gastroenterologist for abdominal pain, intestinal bleeding, or refractory ascites; however, hypercoagulative disease may be occult in such patients and require the attention of a hematologist. When treating patients with EHPVO, gastroenterologists should screen for hematological disease, including MPN.

Renal abscesses require prompt diagnosis and appropriate intervention, as they can be life-threatening. However, diagnosis based solely on clinical findings is often challenging. We present the case of a 69-year-old woman with left renal masses on follow-up computed tomography (CT) after surgery for pT2aN0M0 lung carcinosarcoma. The masses were localized only in the left kidney without suspected metastatic lesions at other sites. The patient was referred to our department for further evaluation and treatment under a diagnosis of suspected metastatic lung carcinosarcoma of the left kidney. On enhanced CT, the left renal masses, the largest of which had a diameter of 40×36 mm had thick irregular walls gradually enhanced by the contrast media and an internal low-attenuation area. The masses showed heterogeneous signal intensity with a pseudocapsule on T2-weighted magnetic resonance imaging. Clinical symptoms such as fever or costovertebral angle tenderness were absent, and blood and urine tests were not sufficiently inflammatory to suggest a renal abscess. Histopathological findings on CT-guided renal biopsy revealed only inflammatory tissue and no tumor cells. However, because lung carcinosarcoma metastatic nodules could not be ruled out, laparoscopic left nephrectomy was performed for a definitive diagnosis and curative intent. The pathological diagnosis was renal abscess without malignant lesions. Here, we present a case of renal abscess mimicking metastatic lesions in a patient with lung carcinosarcoma. Accurately differentiating renal abscesses from metastatic renal tumors before treatment is often difficult. Renal abscess diagnosis should be considered through a comprehensive evaluation of the clinical findings of individual cases.

Invasive neonatal infection with Group B Streptococcus (GBS) is a disease of concern that can lead to neurological sequelae. Guidelines for preventing mother-to-child transmission have been introduced to reduce the incidence of early-onset infection, but guidelines for controlling the late-onset form are lacking. Recently, the trans-breastfeeding route of transmission has been highlighted as an example of late-onset infection, but no consensus on how to manage such infections has been reached. In this report, we describe a case of late-onset bacteremia/meningitis in a neonate suspected to have been infected with GBS via breastfeeding. A vaginal culture test of the mother at 35 weeks' gestation was negative for GBS. Since she had symptoms of mastitis, breast milk and nipple cultures were also tested and found to be positive for the strain of GBS identified in the neonate on genetic analysis. Diagnosis of trans-mammary GBS infection is challenging because breastfeeding-related events are difficult to identify. In our case, the diagnosis was based on the mother's history of mastitis, and the patient was treated without escalation to sequelae. When a neonate develops a fever, physicians should consider GBS infection and examine the mother's medical history to facilitate accurate diagnosis, especially if the history includes mastitis. A breast milk culture should be performed if the mother has mastitis, especially in cases of infection in preterm infants and in recurrent cases.