Giant gallbladder cyst with acute cholecystitis: a case report.

BACKGROUND: Gallbladder cysts are rare diseases with very few reported cases, and no clinical or histological definition has been established. Furthermore, cases of giant cysts outside the gallbladder wall are extremely rare. We report a rare case of giant gallbladder cyst with acute cholecystitis. CASE PRESENTATION: An 85-year-old woman with appetite loss and right lower abdominal pain lasting 2 days presented to our hospital. At first, the patient's abdominal pain was mild to moderate with no fever. Blood tests revealed a white blood cell count of 10,950/mm3, and the C-reactive protein (CRP) level was 14.35 mg/dl. A contrast-enhanced computed tomography (CT) scan of the abdomen revealed a grossly distended gallbladder (14.5 × 14.5 × 8.7 cm) with an incarcerated stone in the cystic duct. The patient was treated by percutaneous transhepatic gallbladder drainage (PTGBD) with 735 ml of drainage fluid. Oral contrast magnetic resonance cholangiopancreatography (MRCP) revealed that gallbladder swelling remained (14.0 × 6.5 cm) 3 days after PTGBD. We performed laparoscopic cholecystectomy 6 days after PTGBD. Because of the severe adhesion around the junction of the cystic and common bile ducts, we performed open cholecystectomy. The resected specimen was 14 × 11 cm in size and consisted of a gallbladder (6 × 7 cm) with a stone (2.4 × 1.8 cm) in the gallbladder and a large cystic lesion (18 × 18 cm) outside the gallbladder wall. The cystic lesion had a wall thickness of 6 to 12 mm and internal septal structures and contained hemorrhagic and necrotic tissue. Histological examination revealed that the specimens showed a mildly swollen gallbladder and a cystic lesion on the outside of the gallbladder wall, adjacent to the gallbladder wall, with wall thickening and inflammation. The cystic lesion suggested gallbladder duplication, gallbladder diverticulum or extension of the Rokitansky-Aschoff sinus (RAS). There was no malignancy. The patient's postoperative course was uneventful, and she was discharged 5 days after the operation. CONCLUSION: We present a very rare case of giant gallbladder cyst with acute cholecystitis revealed by cholecystectomy.

A large benign struma ovarii with atypical imaging findings.

Struma ovarii is a mature ovarian teratoma characterized by the predominant presence of thyroid-tissue components. Typically, struma ovarii presents as relatively small masses (<10 cm) that often appear as multilocular cystic tumors with solid components. Herein, we report the unique case of a 44-year-old female with a large tumor including a solid mass. The solid components of the tumor comprised typical thyroid tissues with multiple small cystic structures containing colloid-like material. Given the rarity of struma ovarii, atypical imaging features can sometimes be misleading. This article highlights the unusual magnetic resonance imaging characteristics of a large struma ovarii, with a specific focus on the presence of solid components.

Motor point stimulation activates fewer Ia-sensory nerves than peripheral nerve stimulation in human soleus muscle.

Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) are noninvasive techniques used to induce muscle contraction, aiding motor function restoration in individuals with neurological disorders. Understanding sensory inputs from PNS and MPS is crucial for facilitating neuroplasticity and restoring impaired motor function. Although previous studies suggest that MPS could induce Ia-sensory inputs less than PNS, experimental evidence supporting this claim is insufficient. Here, we implemented a conditioning paradigm combining transcutaneous spinal cord stimulation (tSCS) with PNS or MPS to investigate their Ia-sensory inputs. This paradigm induces postactivation depression of spinal reflexes associated with transient decreases in neurotransmitter release from Ia-afferent terminals, allowing us to examine the Ia-sensory input amount from PNS and MPS based on the depression degree. We hypothesized that MPS would induce less postactivation depression than PNS. Thirteen individuals underwent MPS and PNS on the soleus muscle as conditioning stimuli, with tSCS applied to the skin between the spinous processes (L1-L2) as test stimuli. PNS- and MPS-conditioned spinal reflexes were recorded at five interstimulus intervals (ISIs) and four intensities. Results revealed that all PNS conditioning showed significant decreases in spinal reflex amplitudes, indicating postactivation depression. Furthermore, PNS conditioning exhibited greater depression for shorter ISIs and higher conditioning intensities. In contrast, MPS conditioning demonstrated intensity-dependent depression, but without all-conditioning depression and clear ISI dependency as seen in PNS conditioning. In addition, PNS induced significantly greater depression than MPS across most conditions. Our findings provide experimental evidence supporting the conclusion that MPS activates Ia-sensory nerves less than PNS.NEW & NOTEWORTHY Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) induce neuroplasticity, but differences in their effects on Ia-sensory inputs are unclear. We investigated their Ia-sensory inputs using a conditioning paradigm with spinal reflexes. Results showed that PNS conditioning significantly inhibited spinal reflexes than MPS conditioning, indicating greater postactivation depression due to Ia-sensory nerve activation. These findings provide experimental evidence that MPS activates Ia-sensory nerves to a lesser extent than PNS, enhancing our understanding of neuroplasticity.

Primary spinal cord gliomas: Pathologic features associated with prognosis.

Primary spinal cord gliomas are rare and are associated with high mortality. Unlike brain tumors, the clinicopathological features of spinal cord gliomas are not well defined. We analyzed clinical, histopathology, and immunohistochemical features and overall survival (OS) of 25 patients with primary spinal cord gliomas treated between 1994 and 2023 at 4 institutions. IDH1 R132H, H3K27M, and p53 were assessed by immunohistochemistry (IHC). Four (16%), 5 (20%), 2 (8%), and 13 (52%) patients were diagnosed as having grades 1, 2, 3, and 4 gliomas according to the World Health Organization (WHO) 2021 classification, respectively. One case (4%), with a circumscribed diffuse midline glioma, H3K27-altered, had a rare molecular profile and could not be graded. IHC demonstrated H3K27M positivity, indicative of H3F3A K27M or HIST1H3B K27M mutation, in 9 (36%) patients. H3K27me3-loss was evident in 13 (52%) patients. In one patient with a grade 1 tumor that showed negative staining for H3K27M and H3K27me3 loss, numbers of EZHIP-positive cells were increased, suggesting diffuse midline glioma, H3K27-altered (WHO grade 4). H3K27me3 loss, frequency of p53 positive cells (≥10%), MIB-1 index (≥10%), and high histopathological grades significantly correlated with poor OS. These results indicate the pathological and immunohistochemical characteristics of primary spinal cord gliomas that impact prognosis.

Effects of arousal and valence on center of pressure and ankle muscle activity during quiet standing.

Emotion affects postural control during quiet standing. Emotional states can be defined as two-dimensional models comprising valence (pleasant/unpleasant) and arousal (aroused/calm). Most previous studies have investigated the effects of valence on postural control without considering arousal. In addition, studies have focused on the center of pressure (COP) trajectory to examine emotional effects on the quiet standing control; however, the relationship between neuromuscular mechanisms and the emotionally affected quiet standing control is largely unknown. This study aimed to investigate the effects of arousal and valence on the COP trajectory and ankle muscle activity during quiet standing. Twenty-two participants were instructed to stand on a force platform and look at affective pictures for 72 seconds. The tasks were repeated six times, according to the picture conditions composed of arousal (High and Low) and valence (Pleasant, Neutral, and Unpleasant). During the task, the COP, electromyogram (EMG) of the tibialis anterior and soleus muscles, and electrocardiogram (ECG) were recorded. The heart rate calculated from the ECG was significantly affected by valence; the value was lower in Unpleasant than that in Neutral and Pleasant. The 95% confidence ellipse area and standard deviation of COP in the anterior-posterior direction were lower, and the mean power frequency of COP in the anterior-posterior direction was higher in Unpleasant than in Pleasant. Although the mean velocity of the COP in the medio-lateral direction was significantly lower in Unpleasant than in Pleasant, the effect was observed only when arousal was low. Although the EMG variables were not significantly affected by emotional conditions, some EMG variables were significantly correlated with the COP variables that were affected by emotional conditions. Therefore, ankle muscle activity may be partially associated with postural changes triggered by emotional intervention. In conclusion, both valence and arousal affect the COP variables, and ankle muscle activity may be partially associated with these COP changes.

Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

The predominance of "astrocytic" intranuclear inclusions in neuronal intranuclear inclusion disease manifesting encephalopathy-like symptoms: A case series with brain biopsy.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder represented by eosinophilic intranuclear inclusions (EIIs) and GGC/CGG repeat expansion in the NOTCH2NLC gene. We report here two adult cases of NIID, genetically confirmed, with manifestation of encephalopathy-like symptoms and address the histopathologic findings obtained by brain biopsies, with a focus on "astrocytic" intranuclear inclusions (AIIs). Case 1 presented with paroxysmal restlessness, vertigo, or fever and was later involved in severe dementia and tetraparesis. Case 2 presented with forgetfulness and then with paroxysmal fever and headache. In both cases, delimited areas with gadolinium enhancement on magnetic resonance imaging and corresponding hyperperfusion were detected, leading to brain biopsies of the cortex. On histology, Case 1 showed an abnormal lamination, where the thickness of layers was different from usual. Both neurons and astrocytes showed some dysmorphologic features. Notably, astrocytes rather than neurons harbored EIIs. Case 2 showed a cortex, where neurons tended to be arrayed in a columnar fashion. Astrocytes showed some dysmorphologic features. Notably, much more astrocytes than neurons harbored EIIs. By a double-labeling immunofluorescence study for p62/NeuN and p62/glial fibrillary acidic protein, the predominance of AIIs was confirmed in both cases. Considering the physiological functions of astrocytes for the development and maintenance of the cortex, the encephalopathy-like symptoms, dynamic change of cerebral blood flow, and cortical dysmorphology can reasonably be explained by the dysfunction of EII-bearing astrocytes rather than EII-bearing neurons. This study suggests the presence of a subtype of NIID where AIIs rather than "neuronal" intranuclear inclusions are likely a key player in the pathogenesis of NIID, particularly in cases with encephalopathy-like symptoms. The importance of AIIs ("gliopathy") should be more appreciated in future studies of NIID.

Effects of finger pinch motor imagery on short-latency afferent inhibition and corticospinal excitability.

Motor imagery is a cognitive process involving the simulation of motor actions without actual movements. Despite the reported positive effects of motor imagery training on motor function, the underlying neurophysiological mechanisms have yet to be fully elucidated. Therefore, the purpose of the present study was to investigate how sustained tonic finger-pinching motor imagery modulates sensorimotor integration and corticospinal excitability using short-latency afferent inhibition (SAI) and single-pulse transcranial magnetic stimulation (TMS) assessments, respectively. Able-bodied individuals participated in the study and assessments were conducted under two experimental conditions in a randomized order between participants: (1) participants performed motor imagery of a pinch task while observing a visual image displayed on a monitor (Motor Imagery), and (2) participants remained at rest with their eyes fixed on the monitor displaying a cross mark (Control). For each condition, sensorimotor integration and corticospinal excitability were evaluated during sustained tonic motor imagery in separate sessions. Sensorimotor integration was assessed by SAI responses, representing inhibition of motor-evoked potentials (MEPs) in the first dorsal interosseous muscle elicited by TMS following median nerve stimulation. Corticospinal excitability was assessed by MEP responses elicited by single-pulse TMS. There was no significant difference in the magnitude of SAI responses between motor imagery and Control conditions, while MEP responses were significantly facilitated during the Motor Imagery condition compared to the Control condition. These findings suggest that motor imagery facilitates corticospinal excitability, without altering sensorimotor integration, possibly due to insufficient activation of the somatosensory circuits or lack of afferent feedback during sustained tonic motor imagery.

Inhibition of tibialis anterior spinal reflex circuits using frequency-specific neuromuscular electrical stimulation.

BACKGROUND: Neuromuscular electrical stimulation (NMES) can generate muscle contractions and elicit excitability of neural circuits. However, the optimal stimulation frequency for effective neuromodulation remains unclear. METHODS: Eleven able-bodied individuals participated in our study to examine the effects of: (1) low-frequency NMES at 25 Hz, (2) high-frequency NMES at 100 Hz; and (3) mixed-frequency NMES at 25 and 100 Hz switched every second. NMES was delivered to the right tibialis anterior (TA) muscle for 1 min in each condition. The order of interventions was pseudorandomized between participants with a washout of at least 15 min between conditions. Spinal reflexes were elicited using single-pulse transcutaneous spinal cord stimulation applied over the lumbar enlargement to evoke responses in multiple lower-limb muscles bilaterally and maximum motor responses (Mmax) were elicited in the TA muscle by stimulating the common peroneal nerve to assess fatigue at the baseline and immediately, 5, 10, and 15 min after each intervention. RESULTS: Our results showed that spinal reflexes were significantly inhibited immediately after the mixed-frequency NMES, and for at least 15 min in follow-up. Low-frequency NMES inhibited spinal reflexes 5 min after the intervention, and also persisted for at least 10 min. These effects were present only in the stimulated TA muscle, while other contralateral and ipsilateral muscles were unaffected. Mmax responses were not affected by any intervention. CONCLUSIONS: Our results indicate that even a short-duration (1 min) NMES intervention using low- and mixed-frequency NMES could inhibit spinal reflex excitability of the TA muscle without inducing fatigue.

Direction-Specific Changes in Trunk Muscle Synergies in Individuals With Extension-Related Low Back Pain.

Background Identifying altered trunk control is critical for treating extension-related low back pain (ERLBP), a common subgroup classified by clinical manifestations. The changed coordination of trunk muscles within this group during particular trunk tasks is still not clearly understood. Objectives The objective of this study is to investigate trunk muscle coordination during 11 trunk movement and stability tasks in individuals with ERLBP compared to non-low back pain (LBP) participants. Methods Thirteen individuals with ERLBP and non-LBP performed 11 trunk movement and stability tasks. We recorded the electromyographic activities of six back and abdominal muscles bilaterally. Trunk muscle coordination was assessed using the non-negative matrix factorization (NMF) method to identify trunk muscle synergies. Results The number of synergies in the ERLBP group during the cross-extension and backward bend tasks was significantly higher than in the non-LBP group (p<0.05). The cluster analysis identified the two trunk synergies for each task with strikingly similar muscle activation patterns between groups. In contrast, the ERLBP group exhibited additional trunk muscle synergies that were not identified in the non-LBP group. The number of synergies in the other tasks did not differ between groups (p>0.05). Conclusion Individuals with ERLBP presented directionally specific alterations in trunk muscle synergies that were considered as increased coactivations of multiple trunk muscles. These altered patterns may contribute to the excessive stabilization of and the high frequency of hyperextension in the spine associated with the development and persistence of ERLBP.

Inhibition of repulsive guidance molecule-a ameliorates compromised blood-spinal cord barrier integrity associated with neuromyelitis optica in rats.

The influx of pathogenic aquaporin-4 antibodies (AQP4-Abs) across the blood-spinal cord barrier (BSCB) is crucial for the development and exacerbation of neuromyelitis optica (NMO). We examined whether prophylactic intravenous administration of anti-repulsive guidance molecule-a antibodies (RGMa-Abs) has disease-modifying effects on BSCB dysfunction using an NMO model elicited by peripheral administration of AQP4-Abs to rats. RGMa-Ab treatment attenuated the acute exacerbation of perivascular astrocytopathy in the spinal cord and clinical symptoms, which were highly correlated with neurofilament light chain levels in both the cerebrospinal fluid (CSF) and serum. Additionally, RGMa-Ab treatment suppressed the expression of proinflammatory cytokines/chemokines and the infiltration of inflammatory cells into the spinal cord. CSF analysis of NMO rats revealed that RGMa-Ab treatment improved the CSF/serum albumin ratio and suppressed AQP4-Abs influx. RGMa inhibition using RGMa-Abs is suggested as a potential therapeutic option for BSCB dysfunction associated with NMO.

Neuropil-like islands are a possible pathogenetic link between glioblastoma and gangliocytoma/ganglioglioma in a case of synchronous bilateral brain tumors.

Neuropil-like islands (NIs) are a histologic hallmark of glioneuronal tumors with neuropil-like islands (GTNIs), but GTNIs are presently not considered a homogeneous entity. The essence of GTNI is likely its glial component, and NIs are now considered aberrant neuronal differentiation or metaplasia. The case we report herein is a 41-year-old woman who was synchronously affected by two brain tumors: one was a glioblastoma (glioblastoma multiforme, GBM), of isocitrate dehydrogenase (IDH)-wild type, with NIs in the left parietal lobe, and the other was histologically a composite gangliocytoma (GC)/anaplastic ganglioglioma (GG) with NIs in the right medial temporal lobe. While both tumors were genetically wild type for IDH, histone H3, and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), the former tumor, but not the latter, was mutated for telomerase reverse transcriptase promoter gene (TERT). A recent systematic study using DNA methylation profiling and next-generation sequencing showed that anaplastic GG separate into other WHO tumor types, including IDH-wild-type GBM. It suggested a diagnostic scheme where an anaplastic GG is likely an IDH-wild-type GBM if it is a BRAF wild type, IDH wild type, and TERT promoter mutant tumor. The likely scenario in this patient is that the GBM results from the progression of GC/anaplastic GG due to the superimposed TERT promoter mutation and the propagation of newly generated GBM cells in the contralateral hemisphere. A systematic analysis using DNA methylation profiling and next-generation sequencing was not available in this study, but the common presence of NIs histologically noted in the two tumors could support this scenario. Although a sufficient volume of molecular and genetic testing is sine qua non for the accurate understanding of brain tumors, the importance of histologic observation cannot be overemphasized.

Primary cauda equina lymphoma confirmed by autopsy: A case report.

Compared with those involving the central nervous system, lymphomas involving the peripheral nervous system, namely neurolymphomatosis, are extremely rare. Neurolymphomatosis is classified as primary or secondary; the former is much rarer than the latter. Herein, we present an autopsied case of primary cauda equina lymphoma (PCEL), a type of primary neurolymphomatosis, with a literature review of autopsied cases of PCEL as well as primary neurolymphomatosis other than PCEL (non-PCEL primary neurolymphomatosis). A 70-year-old woman presented with difficulty walking, followed by paraplegia and then bladder and bowel disturbance. On magnetic resonance imaging, the cauda equina was diffusely enlarged and enhanced with gadolinium. The brainstem and cerebellum were also enhanced with gadolinium along their surface. The differential diagnosis of the patient included meningeal tumors (other than lymphomas), lymphomas, or sarcoidosis. The biopsy of the cauda equina was planned for a definite diagnosis, but because the patient deteriorated so rapidly, it was not performed. Eventually, she was affected by cranial nerve palsies. With the definite diagnosis being undetermined, the patient died approximately 1.5 years after the onset of disesase. At autopsy, the cauda equina was replaced by a bulky mass composed of atypical B-lymphoid cells, consistent with diffuse large B-cell lymphoma (DLBCL). The spinal cord was heavily infiltrated, as were the spinal/cranial nerves and subarachnoid space. There was metastasis in the left adrenal. The patient was finally diagnosed postmortem as PCEL with a DLBCL phenotype. To date, there have been a limited number of autopsied cases of PCEL and non-PCEL primary neurolymphomatosis (nine cases in all, including ours). The diagnosis is, without exception, B-cell lymphoma including DLBCL, and the histology features central nervous system parenchymal infiltration, nerve root involvement, and subarachnoid dissemination (lymphomatous meningitis). Metastases are not uncommon. All clinicians and pathologists should be aware of lymphomas primarily involving the peripheral nervous system.

Modulation of lower limb muscle corticospinal excitability during various types of motor imagery.

Motor imagery (MI) is used for rehabilitation and sports training. Previous studies focusing on the upper limb have investigated the effects of MI on corticospinal excitability in the muscles involved in the imagined movement (i.e., the agonist muscles). The present study focused on several lower-limb movements and investigated the influences of MI on corticospinal excitability in the lower limb muscles. Twelve healthy individuals (ten male and two female individuals) participated in this study. Motor-evoked potentials (MEP) from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and soleus (SOL) muscles were elicited through transcranial magnetic stimulation (TMS) to the primary motor cortex during MI of knee extension, knee flexion, ankle dorsiflexion, and ankle plantarflexion and at rest. The results showed that the RF MEPs were significantly increased during MI in knee extension, ankle dorsiflexion, and ankle plantarflexion but not in knee flexion, compared with those at rest. The TA MEPs were significantly increased during MI in knee extension and foot dorsiflexion, while MEPs were not significantly different during MI in knee flexion and foot dorsiflexion than those at rest. For the BF and SOL muscles, there was no significant MEP modulation in either MI. These results demonstrated that corticospinal excitability of the RF and TA muscles was facilitated during MI of movements in which they are active and during MI of lower-limb movements in which they are not involved. On the contrary, corticospinal excitability of the BF and SOL muscles was not facilitated by MI of lower-limb movements. These results suggest that facilitation of corticospinal excitability depends on the muscle and the type of lower-limb MI.

IgA Vasculitis as a Potential Complication of Fourth-Line Chemotherapy with Tegafur/Gimeracil/Oteracil (S-1) in Advanced Non-Small Cell Lung Cancer: A Case Report.

BACKGROUND Immunoglobulin A (IgA) vasculitis is a systemic vasculitis that involves the small vessels. It is mainly characterized by skin symptoms such as purpura, arthritis/arthralgia, abdominal symptoms, and nephropathy, which are caused by IgA adherence to the vessel walls. Herein, we report the case of an advanced non-small cell lung cancer (NSCLC) and a purpuric skin rash of the legs that developed during fourth-line chemotherapy with tegafur/gimeracil/oteracil (S-1). CASE REPORT A 68-year-old man diagnosed with NSCLC 2 years ago was undergoing S-1 as fourth-line chemotherapy when he developed purpura and edema on the lower extremities. Biopsy renal specimens were consistent with IgA vasculitis. Considering his medical history, both IgA vasculitis induced by S-1 and a paraneoplastic syndrome were considered, although the exact cause could not be identified. Subsequently, chemotherapy was discontinued because of his deteriorating general condition, and he received optimal supportive care. The purpura spontaneously disappeared; however, his ascites and renal function deteriorated. Systemic steroids improved renal function, but the ascites did not resolve. One month after being diagnosed with IgA vasculitis, the patient died due to deterioration of his general condition. CONCLUSIONS This case emphasizes the occurrence of IgA vasculitis during lung cancer treatment and its potential impact on the disease course of lung cancer. Moreover, the possible causes of IgA vasculitis in this case were paraneoplastic syndrome or S-1 adverse effects, but further case series are needed to gain a more comprehensive understanding. Refractory, steroid-unresponsive ascites may occur as an abdominal manifestation of IgA vasculitis.

The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study.

BACKGROUND: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. RESULTS: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival). CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

DUPAN-2 as a Risk Factor of Early Recurrence After Curative Pancreatectomy for Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Several patients with pancreatic ductal adenocarcinoma (PDAC) experience postoperative early recurrence (ER). We evaluated PDAC patients to identify the risk factors for postoperative ER (≤6 months), including preoperative serum DUPAN-2 level. METHODS: We retrospectively evaluated 74 PDAC patients who underwent pancreatectomy with curative intent. Clinicopathological factors including age, sex, body mass index, postoperative complications, pathological factors, preoperative C-reactive protein/albumin ratio, neutrophil/lymphocyte ratio, modified Glasgow prognostic score, preoperative tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9, SPAN-1, and DUPAN-2), and history of adjuvant chemotherapy were investigated. Early recurrence risk factors were determined using multivariate logistic regression analysis. RESULTS: Recurrence and ER occurred in 52 (70.3%) and 23 (31.1%) patients, respectively. Univariate analysis revealed that postoperative complications, C-reactive protein/albumin ratio ≥0.02, neutrophil/lymphocyte ratio ≥3.01, carbohydrate antigen 19-9 ≥ 92.3 U/mL, SPAN-1 ≥ 69 U/mL, DUPAN-2 ≥ 200 U/mL, and absence of adjuvant chemotherapy were significant risk factors for ER. In multivariate analysis, DUPAN-2 ≥ 200 U/mL (P = 0.04) and absence of adjuvant chemotherapy (P = 0.02) were identified as independent risk factors for ER. CONCLUSIONS: A higher level of preoperative DUPAN-2 was an independent risk factor for ER. For patients with high DUPAN-2 level, neoadjuvant therapies might be required to avoid ER.

Recurrent urethral tumor with neuroendocrine differentiation in a female patient after radical cystectomy for bladder cancer.

Introduction: Urethral recurrence after radical cystectomy in female patients with bladder cancer is relatively uncommon. Recurrent bladder tumors with neuroendocrine differentiation are extremely rare. Case presentation: A 71-year-old female patient who underwent radical cystectomy for bladder cancer presented with vaginal bleeding 19 months postoperatively. She was diagnosed with bladder cancer urethral recurrence. Urethral tumor en-bloc resection with the anterior vaginal wall was performed by combining abdominal and vaginal approaches. Pathological examination revealed a recurrent tumor of urothelial bladder cancer containing small-cell carcinoma components. Conclusion: This case is the first report of a recurrent tumor with small-cell carcinoma in the female urethra after radical cystectomy for pure urothelial carcinoma.