Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Prognostic value of CAF marker expression in the intratumoral and marginal areas of soft tissue sarcoma.

INTRODUCTION: The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically. METHODS: We scored expression of individual CAF markers (fibroblast activating protein (FAP), CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome. RESULTS: In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with a high intratumoral CD10 score showed significantly worse local recurrence-free survival (LFS). Multivariate analysis identified intratumoral CD10/podoplanin scores and marginal FAP/podoplanin scores as independent prognostic factors for DFS, intratumoral FAP/CD10 and marginal FAP/podoplanin/CD163-positive macrophage scores as independent prognostic factors for MFS, and the intratumoral podoplanin score as an independent prognostic factor for LFS. There was a weak-to-moderate correlation between each score and CD163-positive macrophage counts. CONCLUSION: Patients with high CAF marker expression in the intratumoral and marginal areas have a poorer outcome.

Identification of uromodulin deposition in the stroma of perinephric fibromyxoid nephrogenic adenoma by mass spectrometry.

Nephrogenic adenoma (NA) is an epithelial lesion that usually occurs in the mucosa of the urinary tract. Rare cases of deep infiltrative or perinephric lesions have also been reported. Recently, NA with characteristic fibromyxoid stroma (fibromyxoid NA) has been proposed as a distinct variant. Although shedding of distal renal tubular cells due to urinary tract rupture has been postulated as the cause of NA in general, the mechanism underlying extraurinary presentation of NA and fibromyxoid stromal change in fibromyxoid NA remains unknown. In this study, we performed mass spectrometry (MS) analysis in a case of perinephric fibromyxoid NA of an 82-year-old man who underwent right nephroureterectomy for distal ureteral cancer. The patient had no prior history of urinary tract injury or radiation. Periodic acid-Schiff staining-positive eosinophilic structureless deposits in the stroma of fibromyxoid NA were microdissected and subjected to liquid chromatography/MS. The analysis revealed the presence of a substantial amount of uromodulin (Tamm-Horsfall protein). The presence of urinary content in the stroma of perinephric fibromyxoid NA suggests that urinary tract rupture and engraftment of renal tubular epithelial cells directly cause the lesion.

Nutrition Assessment and Education of Patients with Heart Failure by Cardiologists.

Although nutritional assessment and education are important for hospitalized patients with heart failure, the extent of their implementation in real-world clinical practice is unknown. Therefore, this study aimed to investigate the evaluation and management of nutrition during hospitalization for heart failure using a questionnaire survey for cardiologists.In this cross-sectional multicenter survey, 147 cardiologists from 32 institutions completed a web-based questionnaire (response rate, 95%).The survey showed that 78.2% of the respondents performed a nutritional assessment for hospitalized patients, whereas 38.3% used objective tools. In contrast, only 9.5% of the respondents evaluated the presence or absence of cardiac cachexia. Most respondents (89.8%) reported providing nutritional education to their patients before hospital discharge. However, compared with the number of respondents who provided information on sodium (97.0%) and water (63.6%) restrictions, a limited number of respondents provided guidance on optimal protein (20.5%) and micronutrient (9.1%) intake as part of the nutritional education. Less than 50% of the respondents provided guidance on optimal calorie intake (43.2%) and ideal body weight (34.8%) as a part of the nutritional education for patients identified as malnourished.Although nutritional assessment is widely performed for hospitalized patients with heart failure, most assessments are subjective rather than objective. Nutritional education, frequently provided before hospital discharge, is limited to information on water or salt intake restrictions. Therefore, more comprehensive and individualized nutritional assessments and counselling with a scientific basis are required.

Clinical and prognostic implications of hyaluronic acid in hospitalized patients with heart failure.

We investigated the clinical and prognostic implications of hyaluronic acid, a liver fibrosis marker, in patients with heart failure. We measured hyaluronic acid levels on admission in 655 hospitalized patients with heart failure between January 2015 and December 2019. Patients were stratified into three groups according to hyaluronic acid level: low (< 84.3 ng/mL, n = 219), middle (84.3-188.2 ng/mL, n = 218), and high (≥ 188.2 ng/mL, n = 218). The primary endpoint was all-cause death. The high hyaluronic acid group had higher N-terminal pro-brain-type natriuretic peptide levels, larger inferior vena cava, and shorter tricuspid annular plane systolic excursion than the other two groups. During the follow-up period (median 485 days), 132 all-cause deaths were observed: 27 (12.3%) in the low, 37 (17.0%) in the middle, and 68 (31.2%) in the high hyaluronic acid (P < 0.001) groups. Cox proportional hazards analysis revealed that higher log-transformed hyaluronic acid levels were significantly associated with all-cause death (hazard ratio, 1.38; 95% confidence interval, 1.15-1.66; P < 0.001). No significant interaction was observed between hyaluronic acid level and reduced/preserved left ventricular ejection fraction on all-cause death (P = 0.409). Hyaluronic acid provided additional prognostic predictability to pre-existing prognostic factors, including the fibrosis-4 index (continuous net reclassification improvement, 0.232; 95% confidence interval, 0.022-0.441; P = 0.030). In hospitalized patients with heart failure, hyaluronic acid was associated with right ventricular dysfunction and congestion and was independently associated with prognosis regardless of left ventricular ejection fraction.

Prognostic impact of a reduction in the fibrosis-4 index among patients hospitalized with acute heart failure.

Although the fibrosis-4 index (FIB-4) is associated with right atrial pressure or prognosis in acute heart failure (AHF), the prognostic impact of its reduction during hospitalization remains uncertain. We included 877 patients (age, 74.9 ± 12.0 years; 58% male) hospitalized with AHF. The reduction in FIB-4 was defined as: (FIB-4 on admission-FIB-4 at discharge)/FIB-4 on admission × 100. Patients were divided into low (< 1.0%, n = 293), middle (1.0-27.4%, n = 292), and high (> 27.4%, n = 292) FIB-4 reduction groups. The primary outcome was a composite of all-cause death or heart failure rehospitalization within 180 days. The median FIB-4 reduction was 14.7% (interquartile range - 7.8-34.9%). The primary outcome was observed in 79 (27.0%), 63 (21.6%), and 41 (14.0%) patients in the low, middle, and high FIB-4 reduction groups, respectively (P = 0.001). Adjusted Cox proportional-hazards analysis revealed that the middle and low FIB-4 reduction groups were associated with the primary outcome, independent of the pre-existing risk model including baseline FIB-4 ([high vs. middle] hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.10-2,63, P = 0.017; [high vs. low] HR: 2.16, 95% CI 1.41-3.32, P < 0.001). FIB-4 reduction provided additional prognostic value to the baseline model, including well-known prognostic factors ([continuous net reclassification improvement] 0.304; 95% CI 0.139-0.464; P < 0.001; [integrated discrimination improvement] 0.011; 95% CI 0.004-0.017; P = 0.001). Additionally, the combination of the reduction in FIB-4 and brain natriuretic peptide was useful for risk stratification. In conclusion, among patients hospitalized with AHF, a greater FIB-4 reduction during hospitalization was associated with better prognoses.

Prognostic Impact of Multiple Drug Use at Discharge in Patients Hospitalized with Heart Failure.

The association between polypharmacy/multiple drug use (MDU) and prognosis in patients hospitalized with heart failure (HF) is unclear. It is also unknown whether the prognostic values of MDU vary depending on the presence/absence of a previous history of HF and preserved/reduced left ventricular ejection fraction (LVEF). We analyzed consecutive 1,034 patients hospitalized with HF (age, 74.9 ± 11.5 years; 58.7% male). MDU was defined as ≥5 drugs at discharge. The primary endpoint was a composite of all-cause death and HF readmission. MDU was observed in 695 patients (67.2%). Patients with MDU use had higher prevalences of a previous history of HF, reduced LVEF, and comorbidities than those without MDU. Cox proportional hazard analysis showed that MDU was significantly associated with the primary endpoint after adjustment for possible confounders (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.03-1.79; P = 0.030). There was significant interaction between the presence/absence of a history of HF and the prognostic impact of MDU (HF history [-]: HR, 0.86; 95% CI, 0.54-1.40; P = 0.553; HF history [+]: HR, 1.72; 95% CI, 1.16-2.55; P = 0.007; P for interaction = 0.005). However, there was no significant interaction between preserved/reduced LVEF and the prognostic impact of MDU (P for interaction = 0.274). In conclusion, MDU at discharge is an independent risk factor for the composite of death or HF readmission in patients hospitalized with HF. We observed a significant interaction between the presence of de novo versus recurrent HF and the prognostic value of MDU.

Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications.

PURPOSE: The aim of our study was to elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. MATERIALS AND METHODS: Paired bladder mucosal biopsies, 1 sample each from the Hunner lesion and nonlesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-ß, IFN-γ, TNF, TGF-ß1, HIF1α, IL-2, IL-4, IL-6, IL-10 and IL-12A. The results were compared between the lesion and nonlesion areas. RESULTS: RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (24) included HIF1α signaling pathway, PI3K-Akt signaling pathway, RAS signaling pathway and MAPK signaling pathway. By contrast, down-regulated pathways (6) included basal cell carcinoma and protein digestion and absorption. The mRNA levels of HIF1α, IFN-γ and IL-2, and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and nonlesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation and CD4/CD8 T-lymphocyte ratio. CONCLUSIONS: Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.

Prevalence and Prognostic Relevance of Isolated Tubular Dysfunction in Patients With Acute Heart Failure.

BACKGROUND: Renal dysfunction includes glomerular dysfunction (GD) and tubular dysfunction (TD); however, there is limited information regarding the prevalence, coexistence, and prognostic relevance of TD and GD among patients with acute heart failure (AHF).Methods and Results:This study reviewed 489 patients with AHF who had undergone testing at the time of their admission to identify GD (estimated glomerular filtration rate <60 mL/min/1.73 m2) and TD (urinary ß-2-microglobulin ≥300 µg/gCr). Patients were grouped according to the presence/absence of GD and TD as having neither condition (n=116), isolated TD (n=101), isolated GD (n=83), or coexisting GD plus TD (n=189). During a median follow up of 466 days (interquartile range: 170-871 days), 107 deaths were observed. Kaplan-Meier curve analysis revealed that, relative to the absence of a GD and TD group, higher mortality rates were observed in the groups with isolated TD, isolated GD, and coexisting GD plus TD (log-rank P<0.001). Similarly, the adjusted Cox regression analyses revealed that significantly higher risks of mortality were associated with isolated TD, isolated GD, and coexisting GD plus TD. Moreover, isolated GD and isolated TD were both independently associated with increased risks of all-cause mortality. CONCLUSIONS: As a significant proportion of patients with AHF had isolated TD and an increased risk of mortality, patients with AHF should be screened for TD even if they do not have GD.

Sex differences in the prevalence and prognostic impact of physical frailty and sarcopenia among older patients with heart failure.

BACKGROUND AND AIMS: Frailty and sarcopenia are common and confer poor prognosis in elderly patients with heart failure; however, gender differences in its prevalence or prognostic impact remain unclear. METHODS AND RESULTS: We included 1332 patients aged ≥65 years, who were hospitalized for heart failure. Frailty and sarcopenia were defined using the Fried phenotype model and Asian Working Group for Sarcopenia criteria, respectively. Gender differences in frailty and sarcopenia, and interactions between sex and prognostic impact of frailty/sarcopenia on 1-year mortality were evaluated. Overall, 53.9% men and 61.0% women and 23.7% men and 14.0% women had frailty and sarcopenia, respectively. Although sarcopenia was more prevalent in men, no gender differences existed in frailty after adjusting for age. On Kaplan-Meier analysis, frailty and sarcopenia were significantly associated with 1-year mortality in both sexes. On Cox proportional hazard analysis, frailty was associated with 1-year mortality only in men, after adjusting for confounding factors (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.19-3.16; P = 0.008 for men; HR, 1.63; 95% CI, 0.84-3.13; P = 0.147 for women); sarcopenia was an independent prognostic factor in both sexes (HR, 1.93; 95% CI, 1.13-3.31; P = 0.017 for men; HR, 3.18; 95% CI, 1.59-5.64; P = 0.001 for women). There were no interactions between sex and prognostic impact of frailty/sarcopenia (P = 0.806 for frailty; P = 0.254 for sarcopenia). CONCLUSIONS: Frailty and sarcopenia negatively affect older patients with heart failure from both sexes. CLINICAL TRIALS: This study was registered at the University Hospital Information Network (UMIN-CTR, unique identifier: UMIN000023929) before the first patient was enrolled.

Sarcopenic obesity is associated with impaired physical function and mortality in older patients with heart failure: insight from FRAGILE-HF.

BACKGROUND: The purpose of this study was to clarify the prevalence, association with frailty and exercise capacity, and prognostic implication of sarcopenic obesity in patients with heart failure. METHODS: The present study included 779 older adults hospitalized with heart failure (median age: 81 years; 57.4% men). Sarcopenia was diagnosed based on the guidelines by the Asian Working Group for Sarcopenia. Obesity was defined as the percentage of body fat mass (FM) obtained by bioelectrical impedance analysis. The FM cut-off points for obesity were 38% for women and 27% for men. The primary endpoint was 1-year all-cause death. We assessed the associations of sarcopenic obesity occurrence with the short physical performance battery (SPPB) score and 6-minute walk distance (6MWD). RESULTS: The rates of sarcopenia and obesity were 19.3 and 26.2%, respectively. The patients were classified into the following groups: non-sarcopenia/non-obesity (58.5%), non-sarcopenia/obesity (22.2%), sarcopenia/non-obesity (15.3%), and sarcopenia/obesity (4.0%). The sarcopenia/obesity group had a lower SPPB score and shorter 6MWD, which was independent of age and sex (coefficient, - 0.120; t-value, - 3.74; P < 0.001 and coefficient, - 77.42; t-value, - 3.61; P < 0.001; respectively). Ninety-six patients died during the 1-year follow-up period. In a Cox proportional hazard analysis, sarcopenia and obesity together were an independent prognostic factor even after adjusting for a coexisting prognostic factor (non-sarcopenia/non-obesity vs. sarcopenia/obesity: hazard ratio, 2.48; 95% confidence interval, 1.22-5.04; P = 0.012). CONCLUSION: Sarcopenic obesity is a risk factor for all-cause death and low physical function in older adults with heart failure. TRIAL REGISTRATION: University Hospital Information Network (UMIN-CTR: UMIN000023929 ).

Multidomain Frailty as a Therapeutic Target in Elderly Patients with Heart Failure.

Heart failure and frailty share aging as a strong risk factor. The prevalence of frailty has been shown to be particularly high in elderly patients with heart failure. Moreover, it is important not to confine frailty to physical aspects. Rather, it should be considered to consist of multiple domains, including physical disability, psychiatric disorders, cognitive impairment, depression, and social disconnection. Development of interventions that can improve frailty domains are not well established, although observational studies have evaluated the association of various frailty domains and their prognostic impact. Some interventions, including resistance exercise, functional exercise, and respiratory muscle training have been demonstrated to hold potential for improving physical frailty. In terms of cognitive dysfunction, previous studies have demonstrated that exercise therapy is also effective for cognitive dysfunction. The social domain of frailty is one of the least investigated domains, particularly in patients with heart failure. However, heart failure is also strongly associated with physical frailty and cognitive impairment and has a poor prognosis in old patients. The prevalence of social frailty in elderly patients who need hospitalization due to heart failure is higher than previously thought. Very few studies have tested interventions targeting social frailty. Frailty and heart failure affect each other, and both are becoming increasingly important in society. In this article, we review the physical, cognitive, and social domains of frailty and the possible interventions to improve them in patients with heart failure.

Prognostic Value of the FAN Score, a Combination of the Fibrosis-4 Index, Albumin-Bilirubin Score and Neutrophil-Lymphocyte Ratio, in Patients Hospitalized with Heart Failure.

The fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio are all prognostic markers in patients with heart failure. Recently, the FAN score, which includes all 3 of these markers, was developed as a useful risk stratification tool in patients with cancer. However, its cut-off values have not been validated for heart failure. We aimed to investigate the optimal cut-off and prognostic values of the FAN score in patients with heart failure. We analyzed 669 consecutive patients hospitalized with heart failure (age, 75.8 ± 11.3 years). Their median values of the fibrosis-4 index, albumin-bilirubin score, and neutrophil-lymphocyte ratio at discharge were 2.12, -2.25, and 2.41, respectively. The FAN score for heart failure (HF-FAN score) was calculated using these median values. The primary outcome was a composite of all-cause death and heart failure rehospitalization. Patients were divided into 4 groups according to HF-FAN scores of 0 (n = 112), 1 (n = 231), 2 (n = 242) and 3 (n = 84). Patients with HF-FAN scores of 3 were older, had higher brain natriuretic peptide levels, and larger inferior vena cava diameters. Kaplan-Meier analysis showed a direct correlation between higher HF-FAN scores and occurrence of the primary endpoint (log-rank P < 0.001). Cox proportional hazard analysis revealed a higher HF-FAN score was significantly associated with a worse prognosis even after adjustment for possible prognostic factors. Changing from the FAN score to HF-FAN score provided significant continuous net reclassification improvement. In conclusion, the HF-FAN score at discharge was useful for risk stratification in patients hospitalized with heart failure. The HF-FAN score might be more suitable for patients with heart failure than the FAN score.

Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis.

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at days 7-28 with a peak at day 21 tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Collision of Epstein-Barr virus-positive and -negative gastric cancer, diagnosed by molecular analysis: a case report.

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) is defined by the proliferation of GC cells with EBV infection. The co-existence of EBV-positive and -negative components in a single GC is rare. We report a case of GC with the co-existence of EBV-positive and EBV-negative components, in which we performed-for the first time-various molecular analyses to elucidate their histogenesis. CASE PRESENTATION: An 81-year-old man was diagnosed with GC based on the results of endoscopy and a pathological examination of the biopsy specimen. Systemic chemotherapy was performed, since lymph node and lung metastases were diagnosed based on computed tomography. Total gastrectomy and lymph node dissection were performed after chemotherapy, after confirming that the size of the metastatic lymph nodes had decreased and that the lung metastasis had disappeared. Grossly, a type 3 tumor was located in the middle posterior part of the stomach body. At the cut section, the tumor consisted of a white and solid part on the anal side of the tumor and a flat and elevated part on the oral side. Histologically, the former part consisted of GC with lymphoid stroma and the latter part was composed of poorly differentiated adenocarcinoma without prominent lymphocytic infiltration. The two histopathological components were clearly separated from each other. On EBV-encoded small RNA (EBER)-in situ hybridization (ISH), the part with the lymphoid stroma component was positive, while the other part was negative. Immunohistochemistry revealed that both components showed the overexpression of p53. Sequencing of TP53 using DNA extracted from the two components was conducted, and revealed different patterns. Targeted next generation sequencing revealed MYC amplification in the EBV-positive component of the tumor and HER2 amplification in the EBV-negative part. Immunohistochemistry revealed that the EBV-positive part was C-MYC( +)/HER2(-) and the EBV-negative part was C-MYC(-)/HER2( +). Correspondingly, chromogenic ISH and dual-color ISH showed amplification of C-MYC and no amplification of HER2 in the EBV-positive part, and no amplification of C-MYC and amplification of HER2 in the EBV-negative part. CONCLUSION: We presented a case of collision of two different GCs composed of EBER-ISH ( +)/C-MYC ( +) and EBER-ISH (-)/HER2 ( +) cells.

Multidomain Frailty in Heart Failure: Current Status and Future Perspectives.

PURPOSE OF REVIEW: With a worldwide aging population, frailty and heart failure (HF) have become issues that need to be addressed urgently in cardiovascular clinical practice. In this review, we outline the clinical implications of frailty in HF patients and the potential therapeutic strategies to improve the clinical outcomes of frail patients with HF. RECENT FINDINGS: Frailty has physical, psychological, and social domains, each of which is a prognostic determinant for patients with HF, and each domain overlaps with the other, although there are no standardized criteria for diagnosing frailty. Frailty can be targeted for treatment with various interventions, and recent studies have suggested that multidisciplinary intervention could be a promising option for frail patients with HF. However, currently, there is limited data, and further research is needed before its clinical implementation. Frailty and HF share a common background and are strongly associated with each other. More comprehensive assessment and therapeutic interventions for frailty need to be developed to further improve the prognosis and quality of life of frail patients with HF.

Splenic Volume Index Determined Using Computed Tomography upon Admission Is Associated with Readmission for Heart Failure Among Patients with Acute Decompensated Heart Failure.

The spleen is associated with inflammation, and the size of the spleen is affected by hemodynamic congestion and sympathetic stimulation. However, the association between splenic size and prognosis in patients with heart failure remains unknown. Between January 2015 and March 2017, we analyzed 125 patients with acute decompensated heart failure who were assessed by computed tomography (CT) on the day of admission. The spleen was measured by 3-dimensional CT and then the patients were assigned to groups according to their median splenic volume indexes (SpVi; splenic volume/body surface area). We then compared their baseline characteristics and rates of readmission for heart failure after one year. The median SpVi was 63.7 (interquartile range: 44.7-95.3) cm3/m2. Age did not significantly differ between the groups. Patients with a high SpVi had more significantly enlarged left atria and left ventricles. Multiple regression analysis identified significant positive correlations between SpVi and posterior wall thickness as well as left ventricular mass index. Kaplan-Meier analysis revealed lower event-free rates in the patients with a high, than a low SpVi (P = 0.041, log-rank test). After adjustment for potential cofounding factors, SpVi was independently associated with readmission for heart failure (Hazard ratio, 2.25; 95% confidence interval, 1.01-5.02; P = 0.047). In conclusion, increased splenic volume is independently associated with readmission for heart failure among patients with acute decompensated heart failure.

An extragonadal yolk sac tumor presumed to be of postmeiotic germ cell origin by genetic zygosity analysis via single nucleotide polymorphism array.

An extragonadal yolk sac tumor (YST) is a rare malignant germ cell tumor that usually occurs in childhood. The pathogenesis of extragonadal YST remains largely unknown, especially with regards to its cell of origin. Herein, we report a case of extragonadal YST arising in the uterine round ligament. A 31-year-old Japanese woman, para 2, underwent partial resection of a left-sided, 5-cm, solid inguinal mass. Intraoperative findings showed enlargement of the uterine round ligament in the inguinal canal. Pathological evaluation diagnosed the mass as YST with a mature teratoma (MT) component. The preoperative α-fetoprotein level was markedly elevated, at 24 790 ng/mL. Postoperative magnetic resonance imaging revealed a right ovarian MT and a 3-cm mass remaining in the left lower abdominal wall. The patient underwent total abdominal hysterectomy, bilateral adnexectomy, and left inguinal mass resection. We sampled three frozen tissues (YST, right ovarian MT, and left normal ovary) and performed a single nucleotide polymorphism (SNP) array. Pathological evaluation revealed remnant extragonadal YST in the left inguinal region. The SNP array demonstrated a completely homozygous YST genotype. Copy number variations were gains of 1p, 1q, 2p, 3p, 7p, 8p, 10q, 14q, 18p, 20q, Xp, and Xq and losses of 12q, 20p, and Xq. The right ovarian MT and left normal ovary were partially homozygous and heterozygous, respectively. The evidence suggests that this neoplasm is presumed to be a postmeiotic germ cell origin.

Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

Clinicopathological and molecular analyses of linearly expanded epithelial cells with ß-catenin alterations, "ß-catenin signature", in the normal fallopian tube.

AIMS: Recent advances in next-generation sequencing have made it clear that clonal expansion of cells harbouring driver gene mutations occurs in physiologically normal epithelium. Molecular analysis of tubal epithelium has been almost exclusively confined to the TP53 pathway, which is involved in serous carcinogenesis. Other oncogenic events have not been explored in detail. Here, we report the linear expansion of fallopian tubal epithelial cells exhibiting an altered ß-catenin profile (ß-catenin signature). Through molecular analyses, we determined the incidence and clinicopathological significance of ß-catenin signatures. METHODS AND RESULTS: We evaluated 64 specimens of surgically removed bilateral fallopian tubes. Thirty-three ß-catenin signatures were identified in 13 cases (20.3%); these patients were significantly younger than those without ß-catenin signatures (median ages of 44 and 57 years, respectively, P = 0.0317). No correlation between ß-catenin signature and any clinical factor was observed. CTNNB1 mutations were detected in three of eight ß-catenin signatures when tissues were microdissected and subjected to Sanger sequencing in two representative cases. CONCLUSIONS: This is the first report of the CTNNB1 mutation in clusters of morphologically bland tubal epithelial cells. The results of this study indicate that ß-catenin signatures are common, and they may be a part of diverse molecular alterations occurring in normal tubal epithelium.