Evidence-based clinical guidelines for chronic constipation 2023.

In July 2023 the Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced frequency of bowel movement frequency type or defecation difficulty type. The first line of treatment includes improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicine, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide.

Fulminant demyelinating disease of the central nervous system effectively treated with a combination of decompressive craniectomy and immunotherapy: A case report and literature review.

Key Clinical Message: Accurately identifying fulminant demyelinating diseases is important for sudden onset of asymmetric cerebral white matter lesions with mass effect. Initially, immunotherapy should be administered; however, surgical intervention should be performed with poor response to medical management and evident signs of cerebral herniation. Abstract: A case of fulminant demyelinating disease of the central nervous system that required decompressive craniectomy 8 days after symptom onset is presented. The patient recovered without sequelae after a combination of neurosurgery and immunotherapy with steroids and has remained relapse-free for 4 years.

Successful Management of Acute Subdural Hematoma in Deep Brain Stimulation Patient: A Case Report and Literature Review.

Deep brain stimulation (DBS) has emerged as an important therapeutic option for several movement disorders; however, the management of acute complications, such as acute subdural hematoma (ASDH), remains challenging. This is the case of a 71-year-old woman with Parkinson's disease who developed ASDH 12 years after bilateral DBS placement. On admission with altered consciousness, imaging revealed significant displacement of the DBS electrodes because of the hematoma. Emergent craniotomy with endoscopic evacuation was performed with preservation of the DBS system. Postoperatively, complete evacuation of the hematoma was confirmed, and the patient experienced significant clinical improvement. ASDH causes significant electrode displacement in patients undergoing DBS. After hematoma evacuation, the electrodes were observed to return to their proper position, and the patient exhibited a favorable clinical response to stimulation. To preserve the DBS electrodes, endoscopic hematoma evacuation via a small craniotomy may be useful.

Cell-cell contact-dependent secretion of large-extracellular vesicles from EFNBhigh cancer cells accelerates peritoneal dissemination.

BACKGROUND: Large non-apoptotic vesicles released from the plasma membrane protrusions are classified as large-EVs (LEVs). However, the triggers of LEV secretion and their functions in tumors remain unknown. METHODS: Coculture system of cancer cells, peritoneal mesothelial cells (PMCs), and macrophages (MΦs) was conducted to observe cell-cell contact-mediated LEV secretion. Lineage tracing of PMCs was performed using Wt1CreERT2-tdTnu mice to explore the effects of LEVs on PMCs in vivo, and lymphangiogenesis was assessed by qRT-PCR and flow-cytometry. RESULTS: In peritoneal dissemination, cancer cells expressing Ephrin-B (EFNB) secreted LEVs upon the contact with PMCs expressing ephrin type-B (EphB) receptors, which degraded mesothelial barrier by augmenting mesothelial-mesenchymal transition. LEVs were incorporated in subpleural MΦs, and these MΦs transdifferentiated into lymphatic endothelial cells (LEC) and integrated into the lymphatic vessels. LEC differentiation was also induced in PMCs by interacting with LEV-treated MΦs, which promoted lymphangiogenesis. Mechanistically, activation of RhoA-ROCK pathway through EFNB reverse signaling induced LEV secretion. EFNBs on LEVs activated EphB forward signaling in PMC and MΦs, activating Akt, ERK and TGF-ß1 pathway, which were indispensable for causing MMT and LEC differentiation. LEVs accelerated peritoneal dissemination and lymphatic invasions by cancer cells. Blocking of EFNBs on LEVs using EphB-Fc-fusion protein attenuated these events. CONCLUSIONS: EFNBhigh cancer cells scattered LEVs when they attached to PMCs, which augmented the local reactions of PMC and MΦ (MMT and lymphangiogenesis) and exaggerated peritoneal dissemination.

Traumatic Vertebral Artery Dissection Without Cervical Spine Injury Treated by Mechanical Thrombectomy.

A 59-year-old female injured in a motor vehicle accident presented with progressively impaired consciousness, and emergent magnetic resonance imaging (MRI) revealed basilar artery occlusion (BAO). Mechanical thrombectomy (MT) was performed immediately and achieved complete recanalization. Contrast-enhanced MRI also indicated right vertebral artery dissection (VAD), and the patient was subsequently diagnosed with artery-to-artery embolism caused by traumatic VAD. Anticoagulation therapy was initiated postoperatively, and there was no VAD or BAO recurrence during the three-month follow-up. This is the first reported case of BAO caused by traumatic VAD in an adult without accompanying cervical vertebral fracture treated using MT.

Immediate Effects, Detailed Clinical Outcomes, and Prognostic Factors of Chemonucleolysis Using Condoliase for Lumbar Disc Herniation.

Chemonucleolysis utilizing condoliase is a minimally invasive treatment for lumbar disc herniation (LDH) aimed at reducing intervertebral disc pressure and enhancing symptoms. In this study, lower limb pain was measured using the numeric rating scale (NRS) the day after treatment and 1 and 3 months after treatment. Prognostic factors were assessed, categorizing participants into an improvement group (I-group) for NRS lower limb pain scores of ≥3.5 and a non-improvement group (N-group) for scores of <3.5. This study included a total of 225 patients treated between April 2020 and March 2023. The mean age was 46.5 ± 16.5 years, with 151 males. The mean duration of illness was 6.2 ± 8.52 months. As of the day after treatment, 60 cases were classified into the I-group, 118 cases at 1 month after surgery, and 152 cases at 3 months after surgery. The disease duration before treatment was significantly shorter in the I-group at 1 (8.19 ± 8.74 [I-group] vs. 5.17 ± 8.04 [N-group] months) and 3 months (8.51 [I-group] ± 7.35 vs. 5.69 ± 8.87[N-group] months) after treatment. The comparison of baseline leg pain NRS shows a difference in leg pain NRS in the I-group when compared on the day after treatment (6.02 ± 2.64 [I-group] vs. 7.50 ± 1.79 [N-group]), 1 (5.13 ± 2.69 [I-group] vs. 7.58 ± 1.66 [N-group]), and 3 months (4.42 ± 2.70 [I-group] vs. 7.34 ± 1.77 [N-group]). Chemonucleolysis using condoliase for LDH can improve symptoms the day after treatment and can be a minimally invasive treatment to avoid surgery.

Fatal convexity and interhemispheric acute subdural hematoma from a falx meningioma: A case report.

Background: Hemorrhagic meningiomas are rare. We report a rare case of nontraumatic convexity and interhemispheric acute subdural hematoma (ASDH) caused by a falx meningioma. Case Description: An 84-year-old woman with a history of atrial fibrillation and hypertension who was taking warfarin presented to our emergency department with a sudden disorder of consciousness. The patient had no traumatic events associated with her symptoms. Computed tomography (CT) revealed right convexity and interhemispheric ASDH, mass lesions in the left frontal lobes, and brain herniation. Contrast-enhanced CT revealed vascular structures within the mass lesion. CT angiography (CTA) revealed no aneurysm or arteriovenous malformation, and the venous phase revealed occlusion in the anterior portion of the superior sagittal sinus. The patient had her right convexity and interhemispheric ASDH removed endoscopically. A mass lesion located on the falx, which was easily bleeding, soft, and suctionable, was immediately detected. Histopathological examination revealed fibrous meningioma, a benign meningioma of the World Health Organization grade 1. Despite undergoing aggressive treatment, the patient's general condition deteriorated. Conclusion: Hemorrhagic meningiomas can easily be missed with plain CT, and the enhancement effect of CTA and tumor shadow on digital subtraction angiography may not be observed during the acute phase. Surgery for nontraumatic ASDH should be performed considering the possibility that a meningioma causes it.

Usefulness of non-slip element percutaneous transluminal angioplasty scoring balloons in treating severe calcified lesions of the carotid artery for carotid artery stenting: A case report.

Background: Treatment of calcified lesions with conventional angioplasty balloons can be difficult due to insufficient lumen expansion, high dissection rates, and repeated revascularization. We report a case in which a scoring balloon was used in lesions resistant to angioplasty with a semi-compliant balloon. Case Description: A 72-year-old man presented with severe stenosis and a highly calcified lesion in the right cervical internal carotid artery. Right carotid artery stenting (CAS) was planned to prevent future ischemic stroke events. Conventional semi-compliant balloon angioplasty was unsuccessful. Three inflations of a non-slip element (NSE) percutaneous transluminal angioplasty (PTA) scoring balloon (Nipro, Osaka, Japan) successfully achieved CAS without complications. Conclusion: This is the first report to describe the use of this scoring balloon in de novo carotid artery disease. NSE PTA scoring balloon catheters can be a useful option for refractory, highly calcified stenosis.

Subarachnoid iodine leakage on dual-energy computed tomography after mechanical thrombectomy is associated with malignant brain edema.

BACKGROUND: Dual-energy computed tomography (DE-CT) can differentiate between hemorrhage and iodine contrast medium leakage following mechanical thrombectomy (MT) for acute ischemic stroke (AIS). We determined whether subarachnoid hemorrhage (SAH) and subarachnoid iodine leakage (SAIL) on DE-CT following MT were associated with malignant brain edema (MBE). METHODS: We analyzed the medical records of 81 consecutive anterior circulation AIS patients who underwent MT. SAH or SAIL was diagnosed via DE-CT performed immediately after MT. We compared the procedural data, infarct volumes, MBE, and modified Rankin scale 0-2 at 90 days between patients with and without SAH and between patients with and without SAIL. Furthermore, we evaluated the association between patient characteristics and MBE. RESULTS: A total of 20 (25%) patients had SAH and 51 (63%) had SAIL. No difference in diffusion-weighted imaging (DWI)-infarct volume before MT was observed between patients with and without SAH or patients with and without SAIL. However, patients with SAIL had larger DWI-infarct volumes 1 day following MT than patients without SAIL (95 mL vs 29 mL; p=0.003). MBE occurred in 12 of 81 patients (15%); more patients with SAIL had MBE than patients without SAIL (22% vs 3%; p=0.027). Severe SAIL was significantly associated with MBE (OR, 12.5; 95% CI, 1.20-131; p=0.006), whereas SAH was not associated with MBE. CONCLUSION: This study demonstrated that SAIL on DE-CT immediately after MT was associated with infarct volume expansion and MBE.

Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H.

Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

Prevalence of Double Incontinence and Lower Urinary Tract Symptoms in Patients with Fecal Incontinence: A Single-center Observational Study.

Objectives: Double incontinence (DI), which is the co-occurrence of fecal incontinence (FI) and urinary incontinence (UI), increases with age and has a greater negative impact on the quality of life (QOL) than either incontinence alone. We aimed to assess lower urinary tract symptoms (LUTS) in patients with FI to elucidate the prevalence and characteristics of DI. Methods: This study enrolled consecutive patients who visited our hospital with FI symptoms. FI was evaluated using the Cleveland Clinic Florida Fecal Incontinence Score (CCFIS). LUTS were assessed using the International Prostate Symptom Score (IPSS), QOL score (IPSS-QOL) and Overactive Bladder Symptom Score (OABSS). Results: This study evaluated 140 patients (96 women [mean age: 70.7 years] and 44 men [mean age: 74.4 years]). The mean IPSS was significantly higher in men than in women (12.0 vs. 7.5, p = 0.003). A positive correlation was found between IPSS and CCFIS in women (r = 0.256, p = 0.012) but not in men. For both sexes, the older group (aged ≥70 years) had higher OABSS scores and more urge UI instances than the younger group (aged ≤69 years). Of the 140 patients with FI, 78 (55.7%) had DI, and DI was more common in women than in men (63.5% vs. 38.6%, p = 0.006). Conclusions: The characteristics of LUTS and UI in patients with FI were comparable to those in the general population for both sexes; however, the prevalence of DI was much higher among patients with FI than that in the general population.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Three-Dimensional (3D) Microcatheter Shaping Using Touch Screen Devices for Cerebral Aneurysm Coil Embolization.

OBJECTIVE: In cerebral aneurysm coil embolization, proper microcatheter shaping is crucial to reduce complications and achieve sufficient embolization. Shaping a microcatheter in 3 dimensions (3D) is often required but can be challenging. We assessed the usefulness of a novel shaping on screen (SOS) method that displays real-size 3D rotational angiography (RA) images on a touch screen device during cerebral aneurysm embolization to facilitate 3D microcatheter shaping. METHODS: In this study, 18 patients with cerebral aneurysm treated with this technique were included. Real-size 3D-RA images obtained during the embolization procedure were displayed on the touch screen device, which allowed for real-time manipulation. The shape of the microcatheter was adjusted to conform to the curvature of the vessel by swiping the touch screen device and bending the mandrel accordingly. We assessed the clinical and angiographic results, along with the accuracy and stability of the microcatheter. RESULTS: No procedure-related complications were observed. The mean packing density was 41% ± 12%. In all but 1 case, microcatheters were inserted into the aneurysms without guidewire assistance. After coiling, all microcatheter forms were stable. CONCLUSIONS: Three-dimensional (3D) microcatheter shaping using touch screen devices during cerebral aneurysm coil embolization may be simple and safe and can achieve high packing density of aneurysms.