Two cases of severe oral mucositis caused by atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma.

Atezolizumab is an immune checkpoint inhibitor specific for the programmed death-1 (PD-1) receptor. In this case report, we describe two cases of oral mucositis that developed following the initiation of a systemic chemotherapy regimen comprising atezolizumab and bevacizumab for recurrent hepatocellular carcinoma. After 2 or 3 cycles of treatment, each patient presented with mucosal ulcers in the mouth, oral pain, difficulty in speech and oral intake, and both were admitted to our hospital for management. Following rule out of other conditions such as pharyngeal ulcers, herpetic mucositis, denture or oral trauma, or necrotizing mucositis, both patients were diagnosed with oral mucositis as a severe immune-related adverse event. Oral candidiasis was observed in both cases and should be considered a risk factor for the development of oral mucositis. Chemotherapy was discontinued and treatment with prednisolone was started, along with supportive care. The oral mucositis improved, and prednisolone was gradually reduced; however, in one patient, discontinuation of chemotherapy led to a recurrence of hepatocellular carcinoma. The other patient was lost to follow-up. In patients with risk factors, attention must be paid to the development of oral mucositis during immune checkpoint inhibitor treatment.

Partial splenic embolization improved stomal varices in patient with decompensated liver cirrhosis: a case report.

A 63-year-old man with decompensated liver cirrhosis was admitted for treatment of stomal hemorrhage. Eighteen months earlier, he was diagnosed with rectal and sigmoid colon cancer with multiple lymph node metastases, and he underwent colostomy surgery and postoperative chemotherapy. Sixteen months after the surgery, his stoma began to bleed repeatedly, and he required frequent blood transfusions. A contrast-enhanced computed tomography revealed ectopic varices around the stoma. We considered surgical or endoscopic treatment; however, these approaches would have been technically difficult in this patient. The patient was treated with partial splenic embolization to improve thrombocytopenia and portal hypertension. After two-stage partial splenic embolization, the platelet counts increased, and the concentration of the liver fibrosis marker, Mac-2 binding protein, decreased. In addition, blood flow in the stomal varices decreased, with no recurrence of bleeding. This is a case of recurrent hemorrhage from stomal varices that was successfully treated with partial splenic embolization in a patient with liver cirrhosis. There are no guidelines for hemorrhage from ectopic varices. PSE may present potential utility as a treatment for ectopic variceal bleeding, such as stomal varices.

Disappearance of Hepatocellular Adenoma in a Patient with Cornelia de Lange Syndrome after Treatment with Transcatheter Arterial Embolization.

Cornelia de Lange syndrome (CdLS) is a congenital disorder occasionally associated with congenital portosystemic shunt (CPSSs). We herein report a patient with CdLS and CPSS who developed hepatocellular adenomas (HCAs). The patient presented to our hospital for the further investigation of newly diagnosed liver tumors. Imaging findings and pathological examination results indicated that the liver tumors were inflammatory HCAs that subsequently shrank following transcatheter arterial embolization (TAE). Patients with CdLS and CPSS are at risk of developing HCAs, and TAE may be an effective management strategy for HCA in these patients.

Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameter.

Percutaneous radiofrequency ablation (RFA) is effective for the treatment of small hepatocellular carcinoma (HCC) with a diameter ≤ 3.0 cm. The present study aimed to elucidate the prognostic factors and clarify the indication of treatment for RFA outcomes in patients with HCC with a diameter > 3.0 cm. Among 2188 patients with HCC who underwent RFA, 100 patients with HCC with a diameter > 3.0 cm were enrolled in this study between August, 2000 and August, 2021. We analyzed local therapeutic efficacy, long-term outcomes, and prognostic factors in patients with HCC with a diameter > 3.0 cm. Among all patients, 77 patients achieved complete ablation in one session. There were no treatment-related deaths or major complications. Local tumor recurrence occurred in 48% (n = 48) of the patients, and distant tumor recurrence occurred in 82% (n = 82) of the patients during the study period. The survival rates at 1-, 3-, 5-, 10-, and 15- years were 93.0%, 66.0%, 40.0%, 15.5%, and 10.2%, respectively. Cox proportional hazards regression analysis confirmed that distant tumor recurrence, Child-Pugh class B, and pre-ablation des-γ-carboxy prothrombin (DCP) levels ≥ 200 mAU/mL were independent unfavorable prognostic factors with a hazard ratio of 3.34 (95% CI, 1.57-7.11; P = 0.002), 2.43 (95% CI, 1.35-4.37; P = 0.003), and 1.83 (95% CI, 1.14-2.93; P = 0.012), respectively. In conclusion, patients with HCC with a diameter > 3.0 cm with Child-Pugh class A and DCP levels < 200 mAU/mL might be eligible for RFA treatment.

Complete SAMD12 repeat expansion sequencing in a four-generation BAFME1 family with anticipation.

Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant, adult-onset neurological disease caused by SAMD12 repeat expansion. In BAFME1, anticipation, such as the earlier onset of tremor and/or seizures in the next generation, was reported. This could be explained by intergenerational repeat instability, leading to larger expansions in successive generations. We report a four-generation BAFME1-affected family with anticipation. Using Nanopore long-read sequencing, detailed information regarding the sizes, configurations, and compositions of the expanded SAMD12 repeats across generations was obtained. Unexpectedly, a grandmother-mother-daughter triad showed similar repeat structures but with slight repeat expansions, despite quite variable age of onset of seizures (range: 52-14 years old), implying a complex relationship between the SAMD12 repeat expansion sequence and anticipation. This study suggests that different factor(s) from repeat expansion could modify the anticipation in BAFME1.

Malnutrition and inflammation status in nonobese patients with inflammatory bowel disease are associated with nonalcoholic fatty liver disease: a retrospective study.

BACKGROUND/AIMS: The frequency and details of nonalcoholic fatty liver disease (NAFLD) complications in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to clarify characteristics of NAFLD in patients with IBD. METHODS: We retrospectively identified and enrolled patients with IBD diagnosed with or without NAFLD by undergoing abdominal computed tomography (CT) at our institution between 2005 and 2020. The primary endpoint was the complication rate of NAFLD in patients with IBD. Secondary endpoints were the clinical characteristics of nonobese patients with IBD and comorbid NAFLD and their association with nutritional and inflammatory parameters. RESULTS: Twenty-one (21.9%) of 96 eligible patients with IBD also had NAFLD. In nonobese patients (defined as patients with a body mass index <25 kg/m2), C-reactive protein (CRP; P<0.001) and alanine aminotransferase (P=0.018) levels were higher and the albumin level (P=0.005) and prognostic nutritional index (PNI; P=0.002) values were lower in patients with NAFLD than in those without NAFLD. The PNI value was positively correlated (P<0.001) and the CRP level was negatively correlated (P=0.001) with the hepatosplenic ratio. However, in the NAFLD combined group, PNI (P<0.05) and CRP values (P<0.001) were improved over time after CT imaging by continuing IBD treatment. CONCLUSIONS: Worsening nutritional and inflammatory status in IBD patients is associated with complications of NAFLD. Diagnosis of NAFLD in IBD patients using CT imaging might be useful not only for early detection of NAFLD but also in assessing the need for therapeutic intervention for IBD.

Care needs of Japanese men for sexual dysfunction associated with prostate cancer treatment.

PURPOSE: Prostate cancer (PC) treatment causes sexual dysfunction (SD) and alters fertility, male identity, and intimate relationships with partners. In Japan, little attention has been paid to the importance of providing care for SD associated with PC treatment. This study is aimed at clarifying the care needs of Japanese men regarding SD associated with PC treatment. METHODS: One-to-one semi-structured interviews were conducted with 44 PC patients to identify their care needs. Data were analyzed using thematic analysis. RESULTS: Four core categories emerged from the analysis. (1) "Need for empathy from medical staff regarding fear of SD": patients had difficulty confiding in others about their sexual problems, and medical staff involvement in their SD issues was lacking. (2) "Need for information that provides an accurate understanding of SD and coping strategies before deciding on treatment": lack of information about SD in daily life and difficulty understanding information from medical institutions, caused men to regret their treatment. (3) "Need for professional care for individuals and couples affected by SD": men faced loss of intimacy because of their partners' unwillingness to understand their SD issues or tolerate non-sexual relationships. (4) "Need for an environment that facilitates interaction among men to resolve SD issues": men felt lonely and wanted to interact with other patients about their SD concerns. CONCLUSION: These findings may help form care strategies tailored to these needs and applicable to other societies with strong traditional gender norms.

Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

Hepatitis C Virus-associated Cryoglobulinemic Livedo Reticularis Improved with Direct-acting Antivirals.

We herein report a case of hepatitis C virus (HCV)-associated cryoglobulinemic livedo reticularis in a woman in her 60s that improved with direct-acting antivirals (DAAs). Hyperpigmentation was observed in both lower legs, and a skin biopsy confirmed livedo reticularis, suggesting a relationship with cryoglobulinemia and HCV infection. DAAs with an NS5A inhibitor+NS3/4A protease inhibitor (glecaprevir/pibrentasvir) were administered for eight weeks, and a sustained virological response (SVR) was obtained. The disappearance of serum cryoglobulin was confirmed approximately two years after an SVR was obtained and livedo reticularis was improved. DAA therapy can be an effective therapeutic option for extrahepatic complications associated with HCV infection.

Two Cases of Rapidly Progressive Fatty Liver Disease due to Pancreatic Exocrine Insufficiency without a History of Surgery.

We herein report two cases of rapidly progressive fatty liver (FL) disease due to pancreatic exocrine insufficiency (PEI) without a surgical history. Two women, 59 and 72 years old, with no history of abdominal surgery presented to our hospital with severe anorexia and nausea persisting for one week. Examinations revealed progressive, marked FL disease with hepatomegaly and PEI, for which pancreatic enzyme replacement therapy was effective. Commonly known causes of PEI include chronic pancreatitis, abdominal surgery (e.g. pancreaticoduodenectomy), pancreatic cancer, and obstruction of the pancreatic duct, none of which were present in either of these two cases.

Synchronous heart rate reduction with suppression-burst pattern in KCNT1-related developmental and epileptic encephalopathies.

Suppression-burst (SB) is an electroencephalographic pattern observed in neonatal- and infantile-onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB-EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB-EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1-DEE) with neonatal- and infantile-onset DEE who presented with SB-EEG were retrospectively identified. Five-minute SB-EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1-DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (-6.1% and -7.7%) and the median duration of suppression was longer (4.0 and 8.2 s) in patients with KCNT1-DEE than the other five (range: -2.9% to 0.9% and 0.7-1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1-DEE. SB phases may influence HR regulation in patients with KCTN1-DEE.

Multipolar radiofrequency ablation via three bipolar electrodes with C-arm type X-ray fluoroscopy assistance for hepatocellular carcinoma: An observational study.

The present study aimed to investigate the therapeutic efficacy and safety of the insertion technique of 3 bipolar electrodes in patients with hepatocellular carcinoma (HCC), using C-arm type X-ray fluoroscopy-assisted ultrasonography (US) in guiding a multipolar radiofrequency ablation (RFA) system. Seventy-three patients with HCC treated with a multipolar RFA system (1 electrode, n = 2; 2 electrodes, n = 56; 3 electrodes, n = 17) were enrolled in this retrospective cohort study. To analyze their therapeutic outcome in this study, we divided among 17 patients using 3 electrodes into 2 subgroups: the C-arm type X-ray fluoroscopy-assisted (n = 7) and the US-guided alone groups (n = 10). Therapeutic efficacy and safety were analyzed between the 2 groups. Multipolar RFA treatment was performed safely in all cases, and no severe adverse events occurred. Comparing the patient background of the group treated using 1 or 2 electrodes with that treated using 3 electrodes, larger-sized HCC was treated using 3 electrodes (P < .001). The differences in overall and recurrence-free survival rates between the 1- or 2-electrode and the 3-electrode groups were not significantly different (P = .843 and P = .891). Comparing the C-arm type X-ray fluoroscopy-assisted and the US-guided alone groups among patients treated using 3 electrodes, technical factors such as total ablation time and the number of sessions were not significantly different between the 2 groups. The local tumor progression rate was not significantly different between the 2 groups (P = .942). Multipolar RFA treatment was effective for the treating HCC; using 3 electrodes was suitable for larger-sized HCCs. The technical approach with C-arm type X-ray fluoroscopy assistance using 3 electrodes was useful for operators to perform safe and appropriate insertion techniques by synchronizing the US and X-ray fluoroscopy images.

Long-Term Effects of Rifaximin on Patients with Hepatic Encephalopathy: Its Possible Effects on the Improvement in the Blood Ammonia Concentration Levels, Hepatic Spare Ability and Refractory Ascites.

Background and Objectives: To investigate the long-term efficacy of rifaximin (RFX) for hyperammonemia and efficacy for refractory ascites in patients with cirrhosis. Materials and Methods: We enrolled 112 patients with liver cirrhosis who were orally administered RFX in this study. Changes in the clinical data of patients were evaluated up to 36 months after RFX administration. The primary endpoint was a change in blood ammonia levels. Secondary endpoints included changes in clinical symptoms, Child−Pugh (CP) score, number of hospitalizations, degree of refractory ascites, adverse events, and the relationship between RFX administration and the renin-angiotensin-aldosterone system. Results: An improved rate of overt hepatic encephalopathy (HE) of 82.7% was observed 3 months after RFX administration, which significantly induced a progressive decrease in blood ammonia concentration and an improved CP score up to 36 months. No serious RFX treatment-related adverse events were observed. 36.5% in patients after RFX administration improved refractory ascites. After RFX administration, patients with satisfactory control of hepatic ascites without addition of diuretic had lower renin concentration than those with poor control (p < 0.01). At less than 41 pg/mL renin concentration, the control of refractory ascites was significantly satisfactory (p < 0.0001). Conclusions: RFX reduced blood ammonia concentration and improved hepatic spare ability and the quality of life of patients with long-term HE to up to 36 months. Our study revealed the effects of RFX against refractory ascites, suggesting that renin concentration may be a predictive marker for assessing ascites control.

Patients with biallelic GGC repeat expansions in NOTCH2NLC exhibiting a typical neuronal intranuclear inclusion disease phenotype.

We report two patients with autosomal dominant neuronal intranuclear inclusion disease (NIID) harboring the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype. The zygosity of the entire NOTCH2NLC GGC repeat expansion and DNA methylation were comprehensively evaluated using fluorescent amplicon length PCR (AL-PCR), Southern blotting and targeted long-read sequencing, and detailed genetic/epigenetic and clinical features were described. In AL-PCR, we could not recognize the wild-type allele in both patients. Targeted long-read sequencing revealed that one patient harbored a homozygous repeat expansion. The other patient harbored compound heterozygous repeat expansions. The GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In conclusion, the biallelic GGC repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases could be completely dominant.

Pretreatment Modified Albumin-Bilirubin Grade Is an Important Predictive Factor Associated with the Therapeutic Response and the Continuation of Atezolizumab plus Bevacizumab Combination Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (ATZ + BV) treatment is recommended as the first-line systemic therapy for patients with unresectable hepatocellular carcinoma (u-HCC). This study aimed to investigate the predictive factors of therapeutic response and the continuation of ATZ + BV treatment for u-HCC in a real-world setting. METHODS: This retrospective study was conducted between January 2021 and April 2022. Twenty-eight patients with u-HCC, who were treated with ATZ + BV, were assessed for their treatment response, continuation, and adverse events (AEs). RESULTS: Among the 28 patients, 24 were evaluated at the first imaging. The objective response rate (ORR) was 29.2% (n = 7), and 54.2% (n = 13) on the response evaluation criteria in solid tumors (RECIST 1.1) and in the modified RECIST (mRECIST) guidelines, respectively. Comparing the objective response (OR) group (n = 13) and the non-OR group (n = 11), the modified albumin-bilirubin (mALBI) grades 1 and 2a were found to be significant predictive factors for OR (p = 0.021) in the mRECIST guidelines. Among the 28 patients, 17 discontinued their treatment due to AEs. Comparing the treatment continuation (n = 11) and discontinuation groups (n = 17), a Child-Pugh score of five points (p = 0.009) and mALBI grades 1 and 2a (p = 0.020) were predictive factors with significant differences. CONCLUSIONS: Pretreatment mALBI grades 1 and 2a were the important predictive factors associated with the therapeutic response and the therapeutic continuation of ATZ + BV for patients with u-HCC.

Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants.

BACKGROUND: Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. METHODS: We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). RESULTS: We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 "plausible" candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. CONCLUSIONS: We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.

Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

Suppression of Local Tumor Progression in Perivascular Hepatocellular Carcinoma by Combination Therapy with Radiofrequency Ablation and Percutaneous Ethanol Injection: A Propensity Score Matching Analysis.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) has replaced percutaneous ethanol injection (PEI) as the treatment of choice for hepatocellular carcinoma (HCC); however, control of local tumor progression (LTP) remains a challenge in perivascular HCC. The aim of this study was to determine whether PEI added to RFA can reduce the LTP rate in perivascular HCC patients. METHODS: We retrospectively analyzed 167 patients, with 197 newly diagnosed HCC nodules with peritumoral vessels, who underwent either RFA plus PEI or RFA monotherapy as the first-line treatment between June 2001 and April 2015. Ethanol was injected inside the tumor close to the peritumoral vessels in the combination therapy group. Patients were matched 1:1 according to their propensity scores to reduce selection bias; cumulative LTP was then analyzed using log-rank tests and Cox proportional hazard regression analyses. RESULTS: The two matched groups comprised 62 tumors each. The overall median follow-up period was 34 months (range, 1-140 months). In the RFA plus PEI group, the cumulative LTP rates were 5.7%, 15.5%, and 20.4% at 1, 3, and 5 years, respectively; in the RFA monotherapy group, the rates were 13.2%, 32.0%, and 40.2%, respectively. The rates were significantly lower in the RFA plus PEI group (p = 0.032). Cox proportional hazard regression analysis showed that PEI combination treatment was significantly associated with a reduced risk of local HCC recurrence (hazard ratio, 0.44; 95% confidence interval, 0.19-0.93; p = 0.031). DISCUSSION/CONCLUSION: The risk of LTP after RFA for perivascular HCC can be significantly reduced by injecting ethanol close to the peritumoral vessels.

Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.

Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.

Sexual dysfunction associated with prostate cancer treatment in Japanese men: a qualitative research.

PURPOSE: We investigated the experiences of Japanese men with sexual dysfunction associated with various prostate cancer treatments. METHODS: We included 38 Japanese men who underwent the following initial treatments for prostate cancer: radical prostatectomy (n = 10), external beam radiotherapy (n = 12), brachytherapy (n = 5), and androgen deprivation therapy (n = 11). Semi-structured interviews were conducted regarding sexual dysfunction associated with prostate cancer treatment. Data were analyzed using a content analysis method. To obtain a unique experience for each treatment, we confirmed and organized the treatment method from which the code that constituted each category was derived. The category reliability was calculated based on Scott's formula for the matching rate of the classification by three qualitative researchers. The criterion for good reliability was set at 70%. RESULTS: Japanese men with sexual dysfunction associated with prostate cancer treatments experienced the following: a desire to maintain sexual function and conflict in decision-making concerning the initial treatment for prostate cancer; a loss of values related to sexual dysfunction; an uncertainty regarding the consequences of sexual dysfunction; a sense of calm with fewer adverse effects of sexual dysfunction at the early treatment stage; an effort to accept sexual dysfunction; and management of their changed body at the later treatment stages. The concordance rates for the categories were 70% and 78%. Additionally, there were glimpses of experiences common to all treatments and trends in treatment-specific experiences. CONCLUSION: It is necessary to provide care based on the experience of Japanese men with sexual dysfunction after prostate cancer treatment.