Nagasaki University Hospital

Phyllodes tumours (PTs) of the breast present diagnostic challenges due to their complex histological features and potential for malignant behaviour. The World Health Organisation (WHO) classification requires the presence of five adverse histological criteria to categorise PTs as malignant, aiming to avoid overdiagnosis and improve diagnostic consistency. However, emerging evidence suggests that these strict criteria may underdiagnose tumours with metastatic potential and histological features that would otherwise be considered malignant in soft tissue tumours, leading to significant implications for prognosis and treatment. Recent studies have highlighted cases where tumours classified as borderline PT by WHO criteria exhibited metastatic behaviour, emphasising the need to refine the diagnostic framework. Microscopic criteria used to classify PT also vary among reporting pathologists, resulting in suboptimal reproducibility. This review examines the histological parameters utilised in the classification of malignant PT, highlights existing evidence gaps and analyses international breast pathologist survey data to propose a pragmatic diagnostic approach. We recommend redefining malignant PTs to include cases meeting four of the five WHO criteria, supplemented by comprehensive sampling and clinical context. This approach balances the risk of underdiagnosis with the need for standardised, reproducible diagnostic practices. Future collaborative efforts should focus upon developing evidence‐based, biologically relevant classification systems and leveraging technological advancements to enhance diagnostic precision. These efforts aim to refine classification, improve prognostic accuracy and optimise patient management strategies.

Effective therapeutic strategies for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remain challenging, including a lack of response to therapy and post-treatment relapse. The rapid development of targeted radionuclide therapy (TRT) offers promising data for patients with somatostatin receptor (SSTR)-expressing tumors. This approach exhibits more advantages than somatostatin analog (SSA) therapy, which is primarily effective for well-differentiated and slow-growing GEP-NENs. Fortunately, some clinical studies on peptide receptor radionuclide therapy (PRRT) labeled with α-emitting radionuclides for GEP-NENs patients showed effective results for those with more advanced GEP-NENs, or those with malignant metastasis. For the improvement of clinical efficacy and the decline in the incidence of treatment-related relapse, recent progress in developing novel techniques and effective disease management strategies for optimal targeting has led to the emergence of targeted alpha therapy (TAT) in GEP-NENs patients. For instance, labeled technology and combination therapy could contribute to significantly improved long-term outcomes. However, the exact dosimetry for precision oncology, the shortage of radionuclides, and the stability of disease control are still under careful consideration. More high-quality, large-scale prospective studies are essential for obtaining valuable evidence on challenging problems and for further exploration. Graphical abstract

PURPOSE Adjuvant anti–PD-1 (adj PD-1) antibodies are extensively used to improve survival in patients with resected melanoma. Clinical trials on adj PD-1 antibodies have revealed significant improvements in recurrence-free survival (RFS); however, few of these trials have included patients with acral melanoma (AM). METHODS Clinical data were retrospectively collected from Japanese patients who underwent resection of stage III sole AM between 2014 and 2021. Survival outcomes, including RFS, distant metastasis-free survival (DMFS), and overall survival (OS), were compared between patients without adjuvant therapy (OBS group) and those receiving adj PD-1 group. RESULTS This study included 139 patients (OBS: 79; adj PD-1: 60), with a median follow-up of 2.6 years. The baseline characteristics were comparable, except for age and nodal metastasis. No significant differences in survival were observed between the OBS and adj PD-1 groups (3-year RFS: 36.7% v 27.5%, P = .13; 3-year DMFS: 51.0% v 45.3%, P = .51; 3-year OS: 65.3% v 67.4%, P = .45). Multivariate analysis showed no survival benefit of adj PD-1 (RFS: hazard ratio [HR], 1.25, P = .29; DMFS: HR, 1.03, P = .89; and OS: HR, 0.69, P = .23). Each survival outcome after propensity score matching confirmed no significant difference between the matched OBS group (n = 52) and adj PD-1 group (n = 52; 3-year RFS: 34.3% v 25.9%, P = .22; 3-year DMFS: 45.6% v 46.5%, P = .85; 3-year OS: 60.7% v 68.9%, P = .29). CONCLUSION Adj PD-1 did not improve the prognosis in sole AM. However, further studies are essential to evaluate the efficacy of the adj anti–PD-1 antibody in AM.

Broad-spectrum antimicrobials are commonly administered for community-acquired pneumonia (CAP); however, unnecessary administration may cause adverse events and poor outcomes. This study aimed to understand the impact of broad-spectrum anti-pseudomonal β-lactam use on clinical outcomes and healthcare resource utilization (HCRU) in inpatients with CAP and a low risk of drug-resistant pathogens (DRPs). This historical cohort study reviewed Japan’s hospital claims database (January to December of 2018) and included inpatients aged ≥ 20 years who received intravenous antimicrobial therapy for CAP. Those with high DRP risk were excluded. According to the initial antimicrobial regimen, patients were divided into broad-spectrum (anti-pseudomonal β-lactam therapy) and narrow-spectrum (non-anti-pseudomonal β-lactam therapy) groups. This study evaluated 30-day hospital mortality as a primary outcome using inverse probability of treatment weighting (IPTW) to adjust for differences between both groups and HCRU as an exploratory analysis. A total of 15,617 patients were analyzed (2627 in the broad-spectrum group and 12,990 in the narrow-spectrum group). In the broad-spectrum group, the 30-day mortality rate was 10.6%, which was higher than that in the narrow-spectrum group (5.3%). Furthermore, it was associated with an increased 30-day mortality compared with the narrow-spectrum group after IPTW (adjusted odds ratio, 1.77; 95% confidence interval, 1.52–2.06; p < 0.001). The mean inpatient cost was USD 6139 and USD 5184 for the broad- and narrow-spectrum groups, respectively. The initial use of anti-pseudomonal β-lactams for CAP with low DRP risk is associated with poor outcomes, including death and high HCRU. Thus, initial antimicrobials should be judiciously selected for CAP management.

This case highlights the possibility that Immunoglobulin G4‐related disease (IgG4‐RD) lesions can also occur in the sternoclavicular joint. If a neoplastic lesion is found in the sternoclavicular joint, a biopsy should be attempted to diagnose IgG4‐RD as a differential.

Bloodstream infection caused by Pseudomonas aeruginosa with antimicrobial resistance can be difficult to treat. Herein, we investigated antimicrobial susceptibility to major antipseudomonal β-lactams and analyzed the relationship between resistance mechanisms and susceptibilities in P. aeruginosa isolates from blood. A total of 97 isolates possessing no carbapenemase gene were included in this study. The susceptibility rates to piperacillin, piperacillin/tazobactam, ceftazidime, and cefepime were in the 80% range, while 74.2% and 80.4% of the isolates showed susceptibility to imipenem and meropenem, respectively. None of the isolates showed resistance to ceftolozane/tazobactam or cefiderocol, and only one isolate each showed intermediate resistance (susceptibility rate, 99.0% each). The susceptibility rate was lowest for aztreonam (71.1%). The most prevalent susceptibility pattern was susceptible to all agents (56 isolates), followed by not susceptible only to aztreonam (nine isolates) or imipenem (seven isolates), and susceptible only to both ceftolozane/tazobactam and cefiderocol (six isolates). Multivariate logistic regression analysis revealed significant correlations between decreased oprD expression and decreased susceptibility to carbapenems; between increased ampC expression and non-susceptibility to piperacillin, piperacillin/tazobactam, and ceftazidime; and between increased mexA expression and decreased susceptibility to piperacillin, piperacillin/tazobactam, cefepime, aztreonam, and meropenem. These findings highlight the correlations between the expression of AmpC β-lactamase, OprD porin, and efflux pumps and non-susceptibility to β-lactams in P. aeruginosa isolates from blood. In contrast to traditional β-lactams, the stability of ceftolozane/tazobactam and cefiderocol against the resistance mechanisms was confirmed. IMPORTANCE Pseudomonas aeruginosa is a significant pathogen in hospital-acquired bloodstream infection (BSI) whose treatment requires the appropriate antimicrobial selection in consideration of antimicrobial resistance and resistance mechanisms. Although antipseudomonal β-lactams are key antimicrobial agents, several molecular mechanisms, including β-lactamases, OprD porin, and efflux pumps, are known to be intricately involved in β-lactam resistance. This study evaluated susceptibility profiles of P. aeruginosa to antipseudomonal β-lactams and revealed the correlations between susceptibility and the expression of genes underlying the relevant resistance mechanisms. The results demonstrate the potent in vitro activity of two new agents, ceftolozane/tazobactam and cefiderocol, against P. aeruginosa showing resistance to traditional antipseudomonal β-lactams. This study provides insights into the mechanisms underlying antipseudomonal β-lactam resistance in P. aeruginosa , highlighting the potential of ceftolozane/tazobactam and cefiderocol for use against P. aeruginosa BSI.

We performed a laparoscopic left nephroureterectomy for a patient with primary malignant melanoma of the left ureter. Four months after the surgery, bladder metastasis was observed, and the patient underwent radical cystectomy and cutaneous ureterostomy with pelvic lymph node dissection. One month after the surgery, intra-abdominal lymph node metastasis and pelvic seeding appeared, and the patient received three courses of nivolumab, but the disease progressed. The patient died 10 months after the initial diagnosis.

Background and Aims Pediatric achalasia and peroral endoscopic myotomy (POEM) are not well investigated. This study aimed to examine the clinical characteristics of pediatric achalasia and evaluate the long‐term outcomes of POEM. Methods We conducted a multicenter study across 14 high‐volume centers, comparing the clinical characteristics of children (aged < 18 years) diagnosed with achalasia to those of adults (aged < 65 years). The POEM procedures and outcomes were also compared between the two groups. Results Of the 3421 patients with achalasia, 50 (1.5%) were children. Compared with adults, children had a shorter period to diagnosis (1.0 vs. 3.4 years; p < 0.001) and were more likely to be severely underweight (body mass index: 17.8 vs. 20.9 kg/m ² ; p < 0.001). However, children exhibited less esophageal dilation (46.0% vs. 64.1%; p = 0.013) and higher lower esophageal sphincter pressure (37.3 vs. 29.9 mmHg; p = 0.002). Notably, a significant failure to thrive was not observed in the pediatric group. The POEM procedure time was shorter for children compared to adults (58.0 vs. 83.0 min; p < 0.001). Clinical success rates were not significant between the two groups. Over the 5‐year follow‐up period, children had a lower incidence of reflux esophagitis following POEM compared to adults (11.0% vs. 26.4%; p = 0.013). Conclusions Pediatric achalasia is rare and typically presents with early‐stage manometric and esophagogastric features, along with severe systemic symptoms requiring an early diagnosis. POEM is a durable and effective treatment for pediatric achalasia, offering advantages such as shorter procedural times and a lower incidence of postprocedure reflux compared to adults.

Background : T lymphoblastic lymphoma (T-LBL) frequently manifests with a mediastinal mass and pleural effusion. We report a case of early T-cell precursor lymphoblastic lymphoma (ETP-LBL) in which pleural fluid cytology showed more than 5% basophils in a background of atypical cells. Case : A 14-year-old male patient with a past history of allergy presented with a prolonged history of cough and low-grade fever. A plain chest X-ray revealed pleural effusion and a mass lesion in the anterior mediastinum. Pleural fluid cytology showed atypical cells with fine granular chromatin, which led us to suspect a malignancy of lymphocytic origin. An increase in the number of basophils (7.3% of nucleated cells) was observed in the background. Immunohistochemical staining (IHC) of a pleural fluid cell block and mediastinal biopsy sections revealed atypical cells that showed positive staining for CD3 and CD99, and negative staining for CD4/CD8 and TdT. Bone marrow infiltration of less than 25% suggested the diagnosis of T-LBL. It was further classified as ETP-LBL because the atypical cells showed negative staining for CD1a and CD5, and weakly positive staining for CD117. Conclusion : The differential diagnosis of lymphoma using IHC staining is crucial as determining the high-risk type of lymphoma is important for selecting the appropriate treatment. On the other hand, in our present case, the finding of basophilic pleural effusion was not directly related to the T-LBL diagnosis, and we considered the possibility of local infiltration of basophils associated with the tumor.

Nutrition therapy is important in the management of critically ill patients and is continuously evolving as new evidence emerges. The Japanese Critical Care Nutrition Guideline 2024 (JCCNG 2024) is specific to Japan and is the latest set of clinical practice guidelines for nutrition therapy in critical care that was revised from JCCNG 2016 by the Japanese Society of Intensive Care Medicine. An English version of these guidelines was created based on the contents of the original Japanese version. These guidelines were developed to help health care providers understand and provide nutrition therapy that will improve the outcomes of children and adults admitted to intensive care units or requiring intensive care, regardless of the disease. The intended users of these guidelines are all healthcare professionals involved in intensive care, including those who are not familiar with nutrition therapy. JCCNG 2024 consists of 37 clinical questions and 24 recommendations, covering immunomodulation therapy, nutrition therapy for special conditions, and nutrition therapy for children. These guidelines were developed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system by experts from various healthcare professionals related to nutrition therapy and/or critical care. All GRADE-based recommendations, good practice statements (GPS), future research questions, and answers to background questions were finalized by consensus using the modified Delphi method. Strong recommendations for adults include early enteral nutrition (EN) within 48 h and the provision of pre/synbiotics. Weak recommendations for adults include the use of a nutrition protocol, EN rather than parenteral nutrition, the provision of higher protein doses, post-pyloric EN, continuous EN, omega-3 fatty acid-enriched EN, the provision of probiotics, and indirect calorimetry use. Weak recommendations for children include early EN within 48 h, bolus EN, and energy/protein-dense EN formulas. A nutritional assessment is recommended by GPS for both adults and children. JCCNG 2024 will be disseminated through educational activities mainly by the JCCNG Committee at various scientific meetings and seminars. Since studies on nutritional treatment for critically ill patients are being reported worldwide, these guidelines will be revised in 4 to 6 years. We hope that these guidelines will be used in clinical practice for critically ill patients and in future research.

High-risk Stage II may have a worse prognosis than low-risk Stage III colorectal cancer and there are limited reports examining the efficacy of adjuvant chemotherapy in Stage II and III subgroups. Using a multicenter database, 598 colorectal cancer patients who underwent laparoscopic colorectal resection and were pathologically diagnosed with high-risk Stage II (T4N0) or low-risk Stage III (T1-2N1, T1-2N2, T3N1) between April 2016 and December 2022 were retrospectively reviewed. Fewer patients received adjuvant chemotherapy in the T4N0 group (54.7/45.0/44.7/27.7%, p < 0.001). The T4N0 group had significantly worse 5-year relapse-free survival (RFS) (67.0 vs. 95.5%, p < 0.01) and than the T1-2N1 group. The T4N0 group had significantly worse 5-year RFS (67.0% vs. 95.5%, p < 0.01) than the T1-2N1 group. Five-year OS was significantly better in the T1-2N1 and T3N1 groups with than without adjuvant chemotherapy (p < 0.032, p < 0.001, respectively), but not in the T4N0 group. The present multicenter study showed that high-risk Stage II colorectal cancer may have a worse prognosis than low-risk Stage III colorectal cancer. Preoperative treatment may be considered for T4N0 colorectal cancer.

Introduction Lymphopenia is recognized as a biomarker for predicting outcomes in coronavirus disease (COVID‐19). However, the optimal timing for its observation remains uncertain. We investigated the association between early lymphopenia and COVID‐19 prognosis, as well as the relationship between lymphocyte count trends and disease outcomes. Methods We analyzed data from the J‐RECOVER study, a multicenter retrospective cohort study in Japan, encompassing patients with COVID‐19 between January and September 2020. The patients were categorized into lymphopenia (LP) (<800 cells/μL) and non‐lymphopenia (NL) (≥800 cells/μL) groups based on the lymphocyte counts between days 1 and 4 post‐onset. They were further divided into “persistent,” “recovered,” “exacerbated,” and “stable” groups based on lymphocyte counts between days 7 and 10. The primary outcome was the in‐hospital mortality. The Cox proportional hazard regression was used for the analysis. Results Of 995 enrolled patients, 212 patients (21.3%) were classified into the LP group. LP was significantly associated with in‐hospital mortality (hazard ratio [HR] 2.32, [95% CI 1.39 to 3.87], p‐value 0.001). In both the LP and NL groups, lower lymphocyte counts between 7 and 10 days—categorized as the “persistent” and “exacerbated” groups—was associated with in‐hospital mortality (HR 4.65, [95% CI 2.07 to 10.47], p‐value <0.001, and HR 5.59, [95% CI 2.24 to 13.97], p‐value <0.001, respectively). Conclusions Early lymphopenia is predictive of poor prognosis in patients with COVID‐19. A declining lymphocyte count trend post‐onset further indicates disease deterioration.

Background and Aim Injection solution is important for achieving submucosal elevation in endoscopic submucosal dissection (ESD) and various viscous solutions categorized as low‐concentration injection solution (LCS) or high‐concentration injection solution (HCS) are used. We analyzed the difference between LCS and HCS in colorectal ESD. Methods This was a prospective, randomized controlled trial at six Japanese institutions. Patients with early neoplastic lesions of ≥ 20 mm were enrolled from March 2022 to September 2023. Sodium alginate (Liftal K, Kaigen Pharma Co., Osaka, Japan) was used as the injection solution, and the concentration of HCS and LCS was set at 0.6% and 0.3%, respectively. Participants were randomized to HCS or LCS groups and the primary endpoint was the noninferiority about ESD procedure time of LCS compared to HCS. Results The LCS and HCS groups consisted of 79 and 82 cases, respectively. The ESD procedure time (min, mean ± standard deviation) was significantly noninferior between the LCS and HCS groups ( p < 0.001) and was significantly shorter in the LCS group than in the HCS group (61.9 ± 39.2 vs. 76.9 ± 67.5, p = 0.044). There were no significant differences in en bloc resection (98.7% vs. 100.0%, p = 0.985), perioperative perforation (2.5% vs. 2.4%, p = 0.639), and delayed bleeding (1.3% vs. 1.2%, p = 0.493). In the subgroup analysis, the ESD procedure times were significant for lesions of ≥ 40 mm (74.3 ± 30.4 vs. 125.3 ± 107.2, p = 0.031) and experts (51.5 ± 29.2 vs. 69.4 ± 58.9, p = 0.046). Additionally, injection volumes (mL) were not significant (38.0 ± 20.2 vs. 33.0 ± 27.0, p = 0.098) in the two groups. Conclusion LCS was noninferior to HCS in terms of procedure time and significantly reduced it. Trial Registration University Hospital Medical Information Network Clinical Trials Registry number: UMIN000048661.

Introduction: Post-COVID-19 condition (PCC) observed in some patients have emerged as a significant health concern. While knowledge regarding the characteristics of post-COVID-19 conditions and their impact on the quality of life is accumulating, the state of post-COVID-19 conditions management in Japan remains inadequately understood. We conducted a survey targeting medical institutions with infectious disease specialists to elucidate the current situation and challenges in post-COVID-19 conditions management. Materials and Methods: A web-based survey was administered from January 18 to March 9, 2024, targeting 880 infectious disease specialists nationwide regarding their respective medical institutions. The survey consisted of up to 24 questions covering respondents' attributes and backgrounds, experience in managing post-COVID-19 conditions, characteristics of post-COVID-19 conditions patients, post-COVID-19 conditions treatment status, and post-COVID-19 conditions among medical institution staff. Results: Responses were obtained from 465 specialists across 47 prefectures (response rate: 52.8%). The majority of respondents (324) were affiliated with hospitals. Among these, 69.7% had experience in managing post-COVID-19 conditions at their institutions, but only 11.2% reported having specialized outpatient clinics dedicated to these symptoms. Most respondents reported that PCC was more common in the 18-64 age group. 80.5% and 51.9% of respondents reported having patients with symptoms lasting over 3 months and 12 months, respectively. For patients with symptoms persisting over 3 months, many respondents noted neuropsychiatric symptoms such as depression and forgetfulness. Treatment approaches included not only pharmacotherapy but also rehabilitation and counseling. 27.4% of respondents reported PCC cases among staff at their medical institutions, with two-thirds of these cases requiring staff to take leave from work. Conclusion: While many medical institutions with infectious disease specialists are addressing COVID-19 treatment, the establishment of specialized outpatient clinics for PCC is limited, highlighting the need for long-term follow-up and support systems. Additionally, PCC among healthcare workers is a significant issue, necessitating the development of support systems for their return to work.

Background Although utility of composite trait‐specific polygenic risk score (multi‐trait PRS) has been examined among European ancestries, few studies investigated among East Asians and incorporated modifiable risk factors. We examined the associations of multi‐trait PRS for cardiometabolic factors with cardiovascular disease mortality by integrating nongenetic determinants. Methods A total of 14 086 Japanese participants (mean age, 55±9; 55.8% women) of the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) study were analyzed in this study. We calculated 6 PRSs for cardiometabolic traits (systolic blood pressure, body mass index, triglycerides, low‐density lipoprotein cholesterol, estimated glomerular filtration rate, and hemoglobin A1c). Based on these PRSs, we developed multi‐trait PRS and considered as a primary exposure. Three nongenetic factors (smoking, alcohol drinking, and educational attainment) from the self‐reported questionnaire were also examined. Results During a median 12.1‐year follow‐up period, a total of 472 all‐cause and 79 cardiovascular disease mortality cases were documented. Compared with 0% to 90% of multi‐trait PRSs, an adjusted hazard ratio (HR) among the top 10% of multi‐trait PRSs was 1.32 (95% CI, 1.00–1.73) for all‐cause death and 2.63 (95% CI, 1.48–4.67) for cardiovascular disease death. Incorporation of educational attainment with multi‐trait PRSs showed null associations in those who went beyond high school (HR, 2.07 [95% CI, 0.44–9.66]) even in the top 10% of multi‐trait PRS. Conclusions Our analysis combining both genetic and nongenetic determinants highlighted that lifestyle factors and educational attainment can slightly reduce an individual's composite genetic risk for cardiovascular disease death.