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Abstract Background Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment.

Abstract Extracorporeal blood purification with polymyxin B immobilized fiber column direct hemoperfusion (PMX-DHP), is reported to be effective in treating COVID-19 pneumonitis with oxygen demand. This multicenter prospective study evaluated the efficacy and safety of PMX-DHP in oxygen-requiring patients with COVID-19 admitted between September 28, 2020, and March 31, 2022. The primary endpoint was the percentage of clinical improvement 15 days after treatment. The secondary endpoint was the percentage of worsened disease status. Data from the COVID-19 patient registry were used for the synthetic control group. The improvement rate on Day 15 did not differ between PMX-treated patients and controls; however, the deterioration rate was 0.38 times lower in the PMX-treated group, and the death rates on Day 29 were 0 and 11.1% in the PMX-treated and control groups, respectively. The PMX group showed a 0.73 times higher likelihood for reduced intensive care demand, as 16.7% of PMX-treated patients and 22.8% of controls worsened. After treatment blood oxygenation improved, urinary β2-microglobulin and liver-type fatty acid-binding protein showed significant decreases, and IL-6 decreased once during treatment but did not persist. In this study, PMX treatment effectively prevented the worsening of COVID-19 pathology, accompanied by improved oxygenation. PMX treatment to remove activated cells may effectively improve patient outcomes.

Abstract This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien–Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54–8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23–8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78–34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83–7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14–16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.

Abstract Background Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis. Methods The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed. Results Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p

Abstract Vacuoles change their morphology in response to stress. In yeast exposed to chronically high temperatures, vacuolar membranes get deformed and invaginations are formed. We show that phase-separation of vacuolar membrane occurred after heat stress leading to the formation of the invagination. In addition, Hfl1, a vacuolar membrane-localized Atg8-binding protein, was found to suppress the excess vacuolar invaginations after heat stress. At that time, Hfl1 formed foci at the neck of the invaginations in wild-type cells, whereas it was efficiently degraded in the vacuole in the atg8Δ mutant. Genetic analysis showed that the endosomal sorting complex required for transport machinery was necessary to form the invaginations irrespective of Atg8 or Hfl1. In contrast, a combined mutation with the vacuole BAR domain protein Ivy1 led to vacuoles in hfl1Δivy1Δ and atg8Δivy1Δ mutants having constitutively invaginated structures; moreover, these mutants showed stress-sensitive phenotypes. Our findings suggest that vacuolar invaginations result from the combination of changes in the physiochemical properties of the vacuolar membrane and other cellular factors.

Abstract Background Interprofessional collaboration in the community is becoming essential in primary care, particularly collaboration between public health nurses and general practitioners. However, the precise value of such collaboration has not been sufficiently studied. The purpose of this study was to conduct a qualitative analysis of collaboration between general practitioners and public health nurses in the community to explore the details of the phenomenon and its possible impact on the community. Methods Since 2015, The University of Toyama has been implementing the Collaborative Health Activities Project, in which general practitioners and public health nurses work together to promote community health. Focus group and individual interviews were conducted with participating staff, and the data were analyzed qualitatively. Results Fifteen themes were generated, in six categories. The categories were as follows: enhanced roles of public health nurses and physicians in the community, new perspectives on the community, public health nurses' sense of trust and empathy toward physicians, bonds of solidarity between public health nurses and physicians, proactive change in residents, and supporting “hangout places”. Conclusion The collaboration between general practitioners and public health nurses familiar with the same community fostered a sense of trust and empathy and created the bonds of solidarity between staff and residents. The results also suggest the collaboration may have a positive impact on the local community by inspiring residents to change proactively and supporting “hangouts” where residents and professionals can informally connect.

BackgroundMycoplasma genitalium is an emerging sexually transmitted pathogen associated with increasing antibiotic resistance. The current treatment guidelines recommend moxifloxacin-sequential therapy for macrolide-resistant Mgenitalium or strains with unknown resistance profiles. However, it is unclear whether sitafloxacin, a 4th-generation fluoroquinolone antibiotic, is effective against resistant strains. ObjectiveThis study aims to assess and compare the efficacy and safety of sitafloxacin- and moxifloxacin-based treatment regimens for managing Mgenitalium infections. MethodsWe will conduct this randomized controlled trial at multiple centers in Japan. Eligible participants include adults aged 18 years or older with a confirmed Mgenitalium infection, as determined through the nucleic acid amplification test. Patients will be randomly assigned using a stratified approach based on the treatment facility and infection site. The interventions comprise oral sitafloxacin (200 mg) daily for 7 days (with optional pretreatment of oral doxycycline, 200 mg, daily for up to 7 days), with a control group receiving oral doxycycline (200 mg) daily for 7 days followed by moxifloxacin (400 mg) daily for another 7 days. The primary outcome is the treatment success rate with a superiority margin of 10%, as confirmed through the nucleic acid amplification test. Secondary outcomes encompass changes in the bacterial load at the urogenital or rectal sites and the emergence of posttreatment-resistant mutant strains. ResultsEnrollment commenced in June 2023 and will conclude in December 2024, with findings anticipated by 2025. The expected success rates fall within the range of 80% for sitafloxacin and 42% for moxifloxacin against Mgenitalium carrying the G248T (S83I) mutation, based on previous studies. Accordingly, with a 5% significance level (2-sided) and 80% statistical power, we aim to recruit 50 participants per group, factoring in a 10% expected dropout rate. ConclusionsThis study will provide valuable insights into the efficacy and safety of sitafloxacin- versus moxifloxacin-based sequential therapy in treating Mgenitalium infections. These findings have the potential to influence clinical guidelines, favoring more effective therapeutic choices. The multicenter approach enhances the robustness of this study. However, a limitation is the potential insufficiency of statistical power to detect posttreatment-resistant mutant strains in each group, rendering posttreatment-resistance mutations a notable concern. In the future, we may need to increase the sample size to enhance power. Trial RegistrationJapan Registry of Clinical Trials (jRCTs031230111); https://jrct.niph.go.jp/en-latest-detail/jRCTs031230111 International Registered Report Identifier (IRRID)DERR1-10.2196/52565

Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.

Mpox is an acute exanthematous disease caused by the monkeypox virus. Since May 2022, it has spread as a community-acquired infection, mainly in Europe and the United States, and urgent measures to prevent this infection were also required in Japan. In this study, we investigated the post-exposure prophylaxis of mpox and safety after inoculating the smallpox vaccine. Participants in close contact with patients with mpox were inoculated with “Freeze-dried cell culture Smallpox Vaccine LC16,” within 14 days after close contact. Six cases were registered, and all the participants were inoculated. No mpox symptoms or related complications were observed in the participants for 21 days after the close contact. Adverse events due to inoculation, such as rash, fever, lymphadenopathy, and local reaction at the inoculation site (comprising erythema, swelling, induration, and pain) were observed in the participants; however, all inoculation-related events were non-severe and non-serious, and the participants recovered during the 28-day observation period. The findings of this study suggest that inoculation with LC16 is an effective post-exposure prophylaxis in individuals who had close contact with patients with mpox. Further large-scale studies are warranted to validate these findings.

BackgroundIn May 2022, a case of monkeypox (currently known as “mpox”) with no history of overseas travel was reported in the United Kingdom, followed by reports of infections reported in Europe, the United States, and other countries worldwide. Due to the significant overlap in immune responses among viruses of the genus Orthopoxvirus (including smallpox virus, mpox virus, and vaccinia virus), it is believed that cross-immunity can be achieved by administering the smallpox virus vaccine. In Japan, a smallpox vaccine (LC16m8 strain vaccine) has been approved; however, there was no regulatory approval for the mpox vaccine during the design of this study. Although it is believed that individuals exposed to the mpox virus may receive smallpox vaccination as mpox prophylaxis, the existing evidence is not clear. ObjectiveThe primary objective was to evaluate the efficacy of the LC16m8 strain vaccine, approved for smallpox in Japan, for postexposure prophylaxis against mpox when administered to close contacts of individuals with mpox. The secondary objective was to investigate the safety of the vaccine for postexposure prophylaxis against mpox. MethodsThe study aimed to enroll 100 vaccinated participants who had been identified as close contacts of individuals with mpox. Consent was obtained, and the participants are inoculated with the vaccine. Daily recordings of symptoms (body temperature, headache, rash, and side effects) were made until day 21 and then again on day 28. Furthermore, additional evaluations of adverse events were performed by the investigators on days 7, 14, 21, and 28. Considering that the maximum incubation period for mpox is 21 days, the primary end point is the presence or absence of the disease 21 days after close contact. The primary analysis focused on cases within 4 days of intense contact as it has been reported that vaccination within this timeframe can reduce the incidence of the disease. ResultsThe first trial participant was enrolled on July 28, 2022, and the research period concluded in March 2023. The study results will be published in a peer-reviewed scientific journal. ConclusionsThis study allowed us to investigate the efficacy and safety of the LC16m8 strain vaccine in postexposure prophylaxis against mpox. Trial RegistrationJapan Registry of Clinical Trials jRCTs031220137; https://jrct.niph.go.jp/en-latest-detail/jRCTs031220137 International Registered Report Identifier (IRRID)DERR1-10.2196/46955

Abstract Background The effect of enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade, which represents a patient profile similar to real-world clinical practice in Japan, remains unknown. Therefore, we investigate the efficacy and safety of enzalutamide after combined androgen blockade for recurrence following radical treatment in Japanese patients with non-metastatic castration-resistant prostate cancer. Methods We analyzed 66 patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical prostatectomy or radiation therapy who were prospectively enrolled from October 2015 to March 2018. They received enzalutamide 160 mg orally once daily until the protocol treatment discontinuation criteria were met. The primary endpoint was prostate-specific antigen-progression-free survival, defined as the time from enrollment to prostate-specific antigen-based progression or death from any cause. The secondary endpoints included overall survival, progression-free survival, metastasis-free survival, time to prostate-specific antigen progression, prostate-specific antigen response rate, chemotherapy-free survival, and safety assessment. Results The median observation period was 27.3 months. The median prostate-specific antigen-progression-free survival was 35.0 months (95% confidence interval, 17.5 to not reached). The median overall survival, median progression-free survival, median metastasis-free survival, and chemotherapy-free survival were not reached, with the corresponding 2-year rates being 91.6%, 67.1%, 72.4%, and 85.8%, respectively. The 50% prostate-specific antigen response rate was 88.9%, with the median time being 2.8 months. In total, 42.2% of the patients experienced adverse events, with malaise being the most common. Conclusions Enzalutamide effectively manages non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment. Trial registration: UMIN000018964, CRB6180007.

Abstract In the present prospective study, 225 individuals in Kumamoto General Hospital, Japan, who received two-doses of BNT162b2 vaccine were enrolled/followed up over 150 days and neutralizing activity (NT50) of their sera and antiviral activity (EC50) of IgG purified from sera on day-60 post-1st-dose were determined against wild-type SARS-CoV-2 (SARS-CoV-2Wuhan) (n = 211) and 9 variants (Alpha, Beta, Gamma, Delta, and Kappa) (n = 45). Time-dependent changes of IgG-activity (n = 25) against SARS-CoV-2Wuhan and variants were also examined. Day-60 sera showed reduced NT50 by more than 50% against all variants examined, and greatest reduction was seen with Beta. IgG fractions of high-responders and moderate-responders showed similar fold-changes in EC50 against each variant compared to SARS-CoV-2Wuhan. Evaluation of EC50 of IgG obtained at different time-points (day-28 to -150) revealed time-dependent reduction of activity against all variants. However, against Delta, relatively long-lasting favorable antiviral activity (at least 150 days) was observed. Our data strongly suggest that the successful antecedent scale-up of mRNA-based vaccine administrations in Japan was the primary contributor to the lessening of the otherwise more devastating SARS-CoV-2 pandemic wave caused by the Delta variant. The present data that the effectiveness of vaccine against the then-dominant SARS-CoV-2 variant was likely associated with the moderation of the COVID-19 pandemic wave suggest that as in the case of influenza vaccines, the development of multivalent mRNA-based vaccines represent a generalizable approach to pre-emptively respond pandemic with mutable pathogens.

ABSTRACT Aims/Introduction Subcutaneous dystrophic tissue (DT) produced by insulin injection causes dysglycemia owing to inadequate absorption of insulin. However, precise techniques for measuring DT have not been established. Shear wave elastography (SWE) is an imaging technology that can quantify tissue stiffness. In this study, insulin injection‐induced DT was quantified using SWE to generate whole‐abdominal wall subcutaneous tissue by three‐dimensional (3D) imaging in patients with type 2 diabetes who were treated with multiple insulin injections. Materials and Methods Seven patients with type 2 diabetes were recruited who received long‐standing multiple insulin injections. Using SWE, the shear wave velocity (SWV) of DT and control (normal subcutaneous tissue) was measured. Furthermore, two of seven patients underwent whole‐abdominal SWE examination to calculate the proportion of DT. A subcutaneous insulin tolerance test was also performed in both the DT and control tissues. Results The SWV in DT was significantly higher than that in the control tissue (2.87 [2.66–2.98] vs 1.29 [1.23–1.44] m/s, P

Although vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) induce effective immune responses, vaccination with booster doses is necessary because of waning immunity. We conducted an open-label, non-randomized, single-arm study in adults in Japan to assess the immunogenicity and safety of a single booster dose of the KD-414 purified whole-SARS-CoV-2-virion inactivated vaccine candidate after vaccination with a primary series of BNT162b2. The primary endpoint was serum neutralizing activity at 7 days after booster injection compared with the primary series of BNT162b2. The SARS-CoV-2-structural protein-binding antibody level and T cell response against SARS-CoV-2-Spike (S) peptides were also examined as secondary endpoints, and safety profile assessments were conducted. Twenty subjects who participated in a previous study declined an injection of KD-414 (non-KD-414 group) and received a booster dose of BNT162b2 instead. The non-KD-414 group was compared to the KD-414 group as a secondary outcome. A single dose of KD-414 induced lower serum neutralizing activity against the wild-type virus within 7 days compared to after the primary series of BNT162b2 but significantly induced anti-SARS-CoV-2-S1-receptor-binding domain-binding immunoglobulin G (IgG) antibodies and SARS-CoV-2-S peptide-specific CD4+ and CD8+ T cell responses. Local or systemic symptoms were significantly lower in the participants who received KD-414 than in those who received BNT162b2 as the third COVID-19 vaccine dose. The present data indicate that a single booster dose of KD-414 induces a substantial immune response in BNT162b2-primed individuals and has a good safety profile, thereby supporting further clinical trials to identify rational targets.

Abstract Background There are several challenges in designing clinical trials for the treatment of novel infectious diseases, such as COVID-19. In particular, the definition of endpoints related to the severity, time frame, and clinical course remains unclear. Therefore, we conducted a cross-sectional analysis of phase III randomized trials for COVID-19 registered at ClinicalTrials.gov . Methods We collected the data from ClinicalTrials.gov on March 31, 2021, by specifying the following search conditions under Advanced Search: Condition or disease: (COVID-19) OR (SARS-CoV-2); Study type: Interventional Studies; Study Results: All Studies; Recruitment: Not yet recruiting, Recruiting, Enrolling by invitation, Active, Not recruiting, Suspended, Completed; Sex: All; and Phase: Phase 3. From the downloaded search results, we selected trials that met the following criteria: Primary Purpose: Treatment; Allocation: Randomized. We manually transcribed information not included in the downloaded file, such as Primary Outcome Measures, Secondary Outcome Measures, Time Frame, and Inclusion Criteria. In the analysis, we examined primary and secondary endpoints in trials with severe and non-severe patients, including the types of endpoints, time frame, clinical course, and sample size. Results A total of 406 trials were included in the analysis. The median numbers of endpoints in trials with severe and non-severe patients were 9 and 7, respectively. Approximately 25% of the trials used multiple primary endpoints. Regardless of the type of endpoint, the time frames were longer in the trials with severe patients than in the trials with non-severe patients. In the evaluation of the clinical course, worsening was often considered in binary endpoints, and improvement was considered in time-to-event endpoints. The sample size was the largest in clinical trials using binary endpoints. Conclusions Endpoints can differ with respect to severity, and the clinical course and time frame are important for defining endpoints. This study provides information that can facilitate the achievement of a consensus for the endpoints in evaluating COVID-19 treatments.

Abstract While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT50s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation seen between NT50s and adverse effects. NT50s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT50s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT50s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT50s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.

ABSTRACT Secretory immunoglobulin A (IgA) plays a crucial role in mucosal immunity for preventing the invasion of exogenous antigens; however, little is understood about the neutralizing activity of serum IgA. Here, to examine the role of IgA antibodies against COVID-19 illnesses, we determined the neutralizing activity of serum/plasma IgG and IgA purified from previously SARS-CoV-2-infected and COVID-19 mRNA vaccine-receiving individuals. We found that serum/plasma IgA possesses substantial but rather modest neutralizing activity against SARS-CoV-2 compared to IgG with no significant correlation with the disease severity. Neutralizing IgA and IgG antibodies achieved the greatest activity at approximately 25 and 35 days after symptom onset, respectively. However, neutralizing IgA activity quickly diminished to below the detection limit approximately 70 days after onset, while substantial IgG activity was observed until 200 days after onset. The total neutralizing activity in sera/plasmas of those with COVID-19 largely correlated with those in purified IgG and purified IgA and levels of anti-SARS-CoV-2-S1-binding IgG and anti-SARS-CoV-2-S1-binding IgA. In individuals who were previously infected with SARS-CoV-2 but had no detectable neutralizing IgA activity, a single dose of BNT162b2 or mRNA-1273 elicited potent serum/plasma-neutralizing IgA activity, but the second dose did not further strengthen the neutralization antibody response. The present data show that the systemic immune stimulation with natural infection and COVID-19 mRNA-vaccines elicits both SARS-CoV-2-specific neutralizing IgG and IgA responses in serum, but the IgA response is modest and diminishes faster than the IgG response. IMPORTANCE Secretory dimeric immunoglobulin A (IgA) plays an important role in preventing the invasion of foreign objects by its neutralizing activity on mucosal surfaces, while monomeric serum IgA is thought to relate to the phagocytic immune system activation. Here, we report that individuals with the novel coronavirus disease (COVID-19) developed both systemic neutralizing IgG (nIgG) and IgA (nIgA) active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the nIgA response was quick and reached the highest activity earlier than the nIgG response, nIgA activity was modest and diminished faster than nIgG activity. In individuals who recovered from COVID-19 but had no detectable nIgA activity, a single dose of COVID-19 mRNA vaccine elicited potent nIgA activity, but the second dose did not further strengthen the antibody response. Our study provides novel insights into the role and the kinetics of serum nIgA against the pathogen in both naturally infected and COVID-19 mRNA vaccine-receiving COVID-19-convalescent individuals.

We report a case of long-standing ulcerative colitis with intramucosal well- and poorly differentiated adenocarcinomas detected over a 6-month duration. A Japanese man in his sixties with a 31-year history of ulcerative colitis had a 1.1-cm-sized intramucosal well-differentiated tubular adenocarcinoma in the rectum resected by endoscopic submucosal dissection. At the follow-up colonoscopy, a biopsy near the endoscopic submucosal dissection scar revealed poorly differentiated adenocarcinoma, and a total proctocolectomy was performed 6 months after the endoscopic submucosal dissection. The whole colorectal pathological exam showed 2 flat foci of intramucosal poorly differentiated adenocarcinoma, 4 and 2 mm in size each, near the endoscopic submucosal dissection scar in the rectum, and an increased number of Paneth cells, thickened muscularis mucosa, and widening of the distance between the gland base and muscularis mucosa in the transverse colon to the rectum. Adenocarcinomas were not found in areas where architecturally severe changes of the mucosa or the highest number of Paneth cells proliferation were detected. Multiple biopsies using magnifying narrow band imaging or crystal violet staining around the initial high-grade dysplasia or intramucosal adenocarcinoma were effective to find other lesions, such as poorly differentiated adenocarcinoma foci in the mucosa in a long-standing ulcerative colitis patient.

Abstract Background Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. Case presentation A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot’s syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. Conclusion This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot’s syndrome type 1.

Monkeypox (mpox) is an acute exanthematous disease caused by the monkeypox virus (MPXV). Since May 2022, patients with mpox have been reported worldwide, mainly in Europe and the Americas. In Japan, LC16”KMB,” which is a smallpox vaccine derived from a dried cell culture, against mpox, has been approved. Although inoculation with a smallpox vaccine has been recommended to prevent MPXV infection, the immunogenicity of the smallpox vaccine against the MPXV is unclear, and information regarding postvaccination safety is scarce. We present the protocol for a single-arm open-label study to investigate the immunogenicity and safety of LC16”KMB” against the MPXV in healthy Japanese adults. The primary endpoint is the seroconversion rate of neutralizing antibodies against the MPXV on postvaccination day 28. The secondary endpoints are the seroconversion rates against the MPXV on postvaccination days 14 and 168; the seroconversion rates against the vaccinia virus on postvaccination days 14, 28, and 168; the incidence of mpox until day 168; and adverse and serious adverse events until postvaccination days 28 and 168. These results will pave the way for larger comparative studies using other smallpox vaccines to evaluate the test vaccine’s safety and efficacy in preventing mpox.

Abstract Hepatic pseudolymphoma is a very rare benign reactive lymphoid hyperplasia associated with autoimmunity and chronic inflammatory liver diseases such as primary biliary cirrhosis and may mimic hepatocellular carcinoma. This diagnosis should be suspected in female with a suspicious single tumor. Close monitoring is needed in view of its premalignant nature.

Peritoneal metastasis (PM) is detected in 14% of gastric cancers at the time of initial diagnosis, with a median survival time of 4 months. A 66-year-old woman diagnosed with cT4a(SE) N2M1(LYN) cStage IV was treated with three lines of chemotherapy for a year. During the third line of chemotherapy, computed tomography (CT) scan revealed a large amount of ascites, periportal collar sign, and bilateral ureteral stenosis owing to PM. The tumor biomarkers (CEA and CA 19–9) remained elevated similar to the initial levels. The patient was administered 3 mg/kg nivolumab intravenously biweekly as the fourth line of chemotherapy. Three months after the nivolumab treatment, gastroscopy revealed an extreme reduction of the tumor size, while CT scan revealed the absence of ascites and a well-controlled tumor. There was no immune-related adverse event with nivolumab during and after the treatment, and performance status improved to 0. The patient has been alive for about 2.5 years since her first visit with her sixth line of chemotherapy (docetaxel). We report a case of advanced gastric cancer with PM that was treated successfully with nivolumab.

Background: The coronavirus disease 2019 (COVID-19) pandemic is currently ongoing, and there have been significant efforts in the development of COVID-19 vaccines. However, the neutralizing antibody titers in vaccinated individuals are reported to progressively decrease over time. Japanese pharmaceutical companies have published the results of Phase I and II studies on the safety and efficacy of different vaccines. Final clinical trials will be conducted with the aim of practical application by March 2023. To effectively utilize vaccines developed by Japanese companies, the efficacy and safety of a booster dose (i.e., third vaccination) must be evaluated among individuals who have received three doses of different vaccines. Methods: This protocol describes a study that aims to examine the effect of a booster dose of “KD-414”, a novel Japanese inactivated vaccine, on antibody titers among participants involved in a previous study. Volunteers in this protocol will be recruited from participants in the previous study and immunized with KD-414 after obtaining consent. The antibody titers, before and after immunization with KD-414, among participants who previously received two doses of the BNT162b2 mRNA vaccine, will be comparatively analyzed. Discussion: The reactogenicity and immunogenicity of seven different COVID-19 vaccines including an inactivated vaccine as a third dose after two doses of ChAdOx1 nCov-19 or BNT162b2, has been tested previously, and found to be superior to control (quadrivalent meningococcal conjugate vaccine) regardless of which vaccine had been received during the initial course. This suggests that many types of third booster doses are efficacious. It is anticipated that this study will provide evidence of the safety and immunogenicity of KD-414 as a booster vaccine, which will have profound public health implications.