Prognostic implications of tumor histology and microenvironment in surgically resected intrahepatic cholangiocarcinoma: a single institutional experience.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62 years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5 cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21 months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

Nonconventional Dysplasia is Frequently Associated With Goblet Cell Deficient and Serrated Variants of Colonic Adenocarcinoma in Inflammatory Bowel Disease.

Various subtypes of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). We hypothesized that goblet cell deficient dysplasia and serrated dysplasia may be the primary precursor lesions for goblet cell deficient (GCDAC) and serrated (SAC) variants of colonic adenocarcinoma, respectively. Clinicopathologic features of 23 GCDAC and 10 SAC colectomy cases were analyzed. All dysplastic lesions found adjacent to the colorectal cancers (n = 22 for GCDACs and n = 10 for SACs) were subtyped as conventional, nonconventional, or mixed-type dysplasia. As controls, 12 IBD colectomy cases with well to moderately differentiated adenocarcinoma that lacked any mucinous, signet ring cell, low-grade tubuloglandular, or serrated features while retaining goblet cells throughout the tumor (at least 50% of the tumor) were evaluated. The cohort consisted of 19 (58%) men and 14 (42%) women, with a mean age of 53 years and a long history of IBD (mean duration: 18 y). Twenty-seven (82%) patients had ulcerative colitis. GCDACs (57%) were more often flat or invisible than SACs (10%) and controls (25%; P= 0.023). The GCDAC and SAC groups were more likely to show lymphovascular invasion (GCDAC group: 52%, SAC group: 50%, control group: 0%, P= 0.001) and lymph node metastasis (GCDAC group: 39%, SAC group: 50%, control group: 0%, P= 0.009) than the control group. Notably, GCDACs and SACs were more frequently associated with nonconventional dysplasia than controls (GCDAC group: 77%, SAC group: 40%, control group: 0%, P< 0.001). Goblet cell deficient dysplasia (73%) was the most prevalent dysplastic subtype associated with GCDACs (P= 0.049), whereas dysplasias featuring a serrated component (60%) were most often associated with SACs (P= 0.001). The GCDAC group (75%) had a higher rate of macroscopically flat or invisible synchronous dysplasia compared with the SAC (20%) and control (33%) groups (P= 0.045). Synchronous dysplasia demonstrated nonconventional dysplastic features more frequently in the GCDAC (69%) and SAC (40%) groups compared with the control group (0%; P= 0.016). In conclusion, goblet cell deficient dysplasia and dysplasias featuring a serrated component could potentially serve as high-risk markers for GCDACs and SACs, respectively.

Can performance status mediate the relationship between therapy-related symptoms and health-related quality of life in children with cancer? A mediation model.

PURPOSE: Understanding the interplay among health-related quality of life (HRQoL), therapy-related symptoms, and performance status can offer insights into potential strategies to enhance HRQoL for pediatric cancer patients. This study aimed to examine the mediating effect of performance status on the relationship between symptom burden and HRQoL in children and adolescents with cancer. METHOD: A cross-sectional study was conducted. Participants were recruited from two tertiary hospitals located in Guangzhou, China. HRQoL, therapy-related symptoms, and performance status were assessed using the DISAKIDS Chronic Generic Measure (DCGM-37), Therapy-Related Symptom Checklist for Children (TRSC-C), and Lansky Play Performance Scale (LPPS), respectively. RESULTS: A total of 287 children with cancer (aged 11.08 ± 2.34 years) were included. The DCGM-37 scores were 59.70 ± 9.64. Emotion (56.45 ± 14.56) and physical limitations (58.59 ± 15.38) were the most affected domains. The number of symptoms experienced was 12.49 ± 5.95. The DCGM-37 demonstrated strong negative correlations with the TRSC-C (r = -0.60, P < 0.001) and number of symptoms (r = -0.62, P < 0.001), but mild-to-moderate negative correlations (r -0.16∼ -0.42, P < 0.05) with individual symptoms. The TRSC-C demonstrated an indirect effect on the DCGM-37 via the LPPS (Bootstrap-corrected standardized ß = -0.05, 95 % CI -0.10∼ -0.01; SE = 0.02). Additional analysis showed that tripping/falling (OR = 4.02, 95 % CI 2.02-7.98; P < 0.001) and sore mouth (OR = 2.38, 95 % CI 1.56-3.64; P < 0.001) were associated factors for presenting poor performance status in children undergoing acute chemotherapy. CONCLUSIONS: The accumulated symptom burden, rather than individual symptoms, weighs heavily on the HRQoL. Performance status partially mediated the relationship between symptom burdens and HRQoL among these patients.

Transvaginal natural orifice endoscopic surgery for tubal ectopic pregnancy: A more suitable surgical approach for enhanced recovery after surgery.

Objective: We aimed to determine the safety of Vaginal natural orifice transluminal endoscopic surgery (vNOTES) in terms of the Enhanced Recovery after Surgery (ERAS) concept for tubal pregnancy surgery and provide a detailed process of vNOTES for tubal pregnancy surgery, including experience and key points for surgeons performing this procedure. Methods: The Longitudinal Vaginal Natural Orifice Transluminal Endoscopic Surgery Study (LovNOTESS), which was conducted in Chengdu, China. A total of 219 patients who underwent tubal ectopic pregnancy surgery between September 2021 and March 2022. The patients underwent salpingectomy or salpingostomy using transumbilical laparoendoscopic single-site surgery (LESS) or vNOTES, according to their preferences. This study prospectively collected perioperative and one-year follow-up data on tubal pregnancy outcomes after vNOTES and compared them with those after LESS. Results: The vNOTES group showed a shorter surgical duration, hospitalization duration, and postoperative exhaust time and a lower analgesic medication usage rate, but it showed a higher surgical conversion rate. The vNOTES approach reduced the postoperative exhaust time by approximately 9 h (95% confidence interval [CI]: -11.93, -5.57 h, p < .001) and the risk of postoperative analgesic drug use by 77% (odds ratio, 0.23; 95% CI: 0.10, 0.61, p = .023). Conclusion: vNOTES can shorten the exhaust time and duration of hospitalization, reduce postoperative pain, and avoid surface surgical scars in tubal pregnancy surgeries, consistent with the ERAS concept. However, more comprehensive preoperative evaluation of patients who choose vNOTES is required to reduce the occurrence of intraoperative conversion.Trial registration: ChiCTR2100053483.

Intestinal "Piggybacking Lipoma", A Unique Lipoma Composed of Lipoma and Overlying Epithelial Lesions: A Case-control Study and Review of Literature.

BACKGROUND/AIM: Lipomas are rare but the most common benign mesenchymal lesions of the gastrointestinal (GI) tract, composed of mature adipose cells. The "piggybacking lipoma" is formed by lipomas with overlying polypoid epithelial lesions, such as sessile serrated lesion, tubular adenoma, or hyperplastic polyp, and the literature on these lesions is limited. In this study, we systematically investigated the clinical, endoscopic, and pathologic characteristics of these unique lipomas. PATIENTS AND METHODS: This is a single-institution retrospective study of gastrointestinal tract lipomas diagnosed from 2016-2021. Those with concurrent polypoid epithelial or mesenchymal lesions during the same endoscopic episode were included and reviewed in this study, and the lipomas were classified as "piggybacking lipoma" or "non-piggybacking lipoma" depending on whether the concurrent lesion was overlying the lipoma or was at a different location in the intestine. Demographic, clinical, and endoscopic data were obtained from electronic medical records. RESULTS: A total of 100 lipomas with concurrent epithelial or mesenchymal lesions were included in this study. Among them, 21 cases were classified as "piggybacking lipoma" and 79 were classified as "non-piggybacking lipoma". Patients with piggybacking lipomas showed a female predilection, and were more likely to be symptomatic and less likely to exhibit classic endoscopic features of lipoma. Histologically, the piggybacking polyps showed overlying sessile serrated lesions (SSL) (76.2%) and tubular adenoma (TA) (19%), whereas the non-piggybacking group had differing characteristic lesions with TA (57.5%) and SSL (6.0%). CONCLUSION: Piggybacking lipomas are rare lipomas with overlying polypoid epithelial lesions, most commonly SSL. They present different clinical, endoscopic, and pathologic features compared to non-piggybacking lipomas.

Transvaginal natural orifice transluminal endoscopic surgery for myomectomy: A more suitable surgical approach for enhanced recovery after surgery.

OBJECTIVE: Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is widely recognized for its potential benefits, including reducing post-surgical pain and leaving no discernible scarring. However, the anatomical specificity of the vNOTES approach may elevate the risk of nearby organ damage, such as the rectum and bladder. Thus, this study aims to demonstrate the safety and relative merits of vNOTES over transumbilical laparoendoscopic single-site surgery (LESS). METHODS: The Longitudinal Vaginal Natural Orifice Transluminal Endoscopic Surgery Study (LovNOTESS), which was conducted in Chengdu, China. A total of 110 patients who underwent myomectomy in vNOTES or LESS from January 2021 to December 2022. This study prospectively collected and compared perioperative and follow-up data of the two groups. RESULTS: In the vNOTES group, patients had shorter postoperative anal exhaust time, lower pain medications use rate, shorter hospital stay but higher intraoperative conversion rate, and higher postoperative fever rate. vNOTES decreased the anal exhaust time by approximately 8.7 h (95 %CI: -16.182, -1.262, p = 0.007). Moreover, vNOTES reduces pain medication use risk by 73.1 % (OR: 0.269, 95 %CI: 0.172, 0.318, p = 0.016). CONCLUSION: Relative to LESS, vNOTES can make patients mitigate postoperative discomfort, accelerate the recovery of gastrointestinal function, curtail hospitalization duration, and enable a more rapid return to daily activities in myomectomy. However, vNOTES has a higher risk of surgical conversion and adjacent organ injury. Therefore, larger scale prospective studies are needed to prove its security and promote the widespread application of vNOTES in myomectomy.

Improving oral hygiene for better cognitive health: Interrelationships of oral hygiene habits, oral health status, and cognitive function in older adults.

OBJECTIVES: To explore the interrelationships between oral hygiene habits, oral health status and cognitive function in older adults. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: A total of 371 participants (age 76.79 [7.99] years) were enrolled from June 2020 to November 2021 in an aged care facility. METHODS: Cognitive function was screened using the mini-mental state examination (MMSE) with adjusted cut-off points for age and education. Periodontal status (Biofilm-Gingival Interface index based on periodontal probing depth and bleeding on probing), dental status (plaque, calculus, and caries), and tooth loss were assessed through full-mouth examination. Oral hygiene habits were based on self- or informant-reporting. RESULTS: Poor periodontal status was an associated factor for MCI (OR = 2.89, 95% CI = 1.20-6.95), while multiple tooth loss (OR = 4.90, 95% CI = 1.06 ~ 22.59), brushing teeth less than once a day (OR = 2.88, 95% CI = 1.12 ~ 7.45) and delayed dental visits (OR = 2.45, 95% CI = 1.05 ~ 5.68) were associated factors for cognitive impairment. An indirect effect of brushing teeth ≥2 daily on MMSE score through periodontal status was observed only in older adults without cognitive impairment (Bootstrap-corrected B = 0.17, 95%CI = 0.03 ~ 0.36, SE = 0.08, ß = 0.08). CONCLUSIONS AND IMPLICATIONS: Adequate toothbrushing might prevent cognitive decline indirectly by improving periodontal health only in older adults without cognitive impairment. Multiple tooth loss, infrequent toothbrushing, and delayed dental visits were associated factors for cognitive impairment. Nursing professionals and health care policymakers should advocate for the improvement of basic oral hygiene in older adults, and provide regular professional oral hygiene care for older adults with cognitive impairment. PATIENT OR PUBLIC CONTRIBUTION: The information on oral health habits of this study was based on an interview with the participants or their caregivers during the study period.

Histology Shift in Esophageal Cancer Between Biopsies and Resections After Neoadjuvant Therapy: A Pilot Study.

Preoperative neoadjuvant therapy followed by resection is the mainstay treatment for locally advanced esophageal adenocarcinoma. We recently observed the histology shift from predominant esophageal adenocarcinoma in the biopsy to neuroendocrine neoplasm with or without adenocarcinoma in the post-treatment resection. The underlying mechanism of this finding is uncertain, and there is limited information in the literature. A total of 11 patients were identified: 10 patients received presurgical chemoradiation and 1 with chemotherapy. All biopsies were diagnosed with adenocarcinoma. When neuroendocrine immunomarkers were retrospectively performed on 5 biopsies, 2 showed focal positivity, although the classic neuroendocrine morphology was not readily appreciated. All resections contained neuroendocrine neoplasm, including 8 of well-differentiated type and 3 of neuroendocrine carcinomas. Two post-treatment esophagectomies consisted of neuroendocrine neoplasm only without residual adenocarcinoma. Upon follow-up, 8 patients died of the disease (median survival = 26 months), and 3 patients were alive after a median follow-up of 14 months. The overall median survival time was better than the reported esophageal neuroendocrine carcinoma (15 months). The 5-year observed survival rate was 11.3%, which was lower than the Surveillance, Epidemiology, and End Results 5-year survival rate of adenocarcinoma (21.8%). We reported a small series of esophageal adenocarcinoma that showed histology shift between biopsy and esophagectomy after neoadjuvant therapy. Our limited data suggest that prognosis of this group is different than the conventional adenocarcinoma. Awareness of this morphological change reminds pathologists to examine the biopsy specimens thoroughly, because recognition of neuroendocrine neoplasm, especially high-grade neuroendocrine component, might potentially affect pre- and post-surgical regimens.

Assessing limb apraxia after ischemic stroke: validation of the Chinese version of the diagnostic instrument for limb apraxia-short version (DILA-S) classic subtests.

OBJECTIVE: This study aimed to translate and validate the Chinese version of the Diagnostic Instrument for Limb Apraxia-Short Version (DILA-S) classic subtests in Chinese patients after ischemic stroke. METHODS: The DILA-S was translated and adapted for use in Mandarin-speaking Chinese patients. Internal consistency, test-retest reliability, dimensionality, convergent validity, divergent validity, and concurrent validity were tested. RESULTS: A total of 112 ischemic stroke patients were included. The internal consistency (Cronbach's alpha 0.85 ~ 0.92) and test-retest reliability (ICC 0.88 ~ 0.93) were found satisfactory. Exploratory factor analysis obtained two factors for the imitation subtests and the execution scale of the pantomime of tool use. Convergent validity was supported by strong correlations (ρ > 0.7) between the scores of the DILA-S subtests and the LOTCA motor praxis subscale. Divergent validity was acceptable for weak to moderate correlations (ρ ranged from -0.25~ -0.41) between the scores of the DILA-S subtests and the NIHSS. Concurrent validity was supported by strong correlations (ρ > 0.7) between the scores of the DILA-S subtests and the MoCA, as well as strong correlations (ρ > 0.6 < 0.7) between the scores of the DILA-S subtests and the BI. CONCLUSION: The Chinese version of the DILA-S classic subtests demonstrated satisfactory psychometric properties for assessing limb apraxia in Chinese patients after ischemic stroke.

An efficient extraction method for short single-stranded DNA from agarose gels in aptamer screening.

With the rapid advancements in aptamer screening, the efficient extraction of short single-stranded DNA (ssDNA) from agarose gel has become a new requirement. However, the currently available products are primarily designed for double-stranded DNA (dsDNA) and exhibit limited efficacy when applied to the extraction of short ssDNA. In this study, we successfully developed a novel method based on amino-modified silica-coated magnetic particles (ASMPs) for the extraction of short ssDNA from agarose gel. The gel slices containing short ssDNA were subjected to centrifugation in a spin column/centrifugation tube assembly with silica wool, followed by the adsorption using ASMPs. Subsequently, reagents containing phosphate groups were employed to desorb ssDNA from the surface of ASMPs. Through optimization of each step, we realized remarkable efficiency in the extraction of short ssDNA. To assess the efficacy of our method, we utilized it in aptamer screening. The results demonstrated that our method outperformed three commercially available DNA gel extraction products (Q-kit, S-kit, and V-kit). The relative recovery rates of all methods were as follows: M-dNTP (100.00 %) > M-BB (63.38 %) > Q-kit (46.64 %) > S-kit (15.98 %) > V-kit (0.38 %). The results strongly suggest that the developed method holds promise for short ssDNA extraction from agarose gel.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.

Clinicopathologic and Molecular Characterization of Anorectal Neuroendocrine Carcinomas Reveals Human Papillomavirus, p53, and c-Myc as Alternative Mechanisms of Carcinogenesis.

Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignant neoplasms with aggressive behavior. The diagnosis remains challenging due to ever-changing terminologies and morphologic overlaps with other disease entities. Herein, we seek to better define anorectal NECs by high-risk human papillomavirus (HPV) status and molecular profiling. Fourteen cases, including 3 men and 11 women with a median age of 63 years, were included. High-risk HPV RNA in situ hybridization was diffusely positive (+) in 7 cases, focal rarely positive (+/-) in 2 cases, and completely negative (-) in 5 cases. By morphology, all HPV(-) NECs were large-cell type, 3 mixed with a tubular adenoma/dysplasia or invasive adenocarcinoma. HPV-related (+ or +/-) NECs were mostly small-cell type, 3 mixed with squamous dysplasia and/or squamous cell carcinoma. Immunohistochemically, all NECs were positive for at least 2 neuroendocrine markers. The HPV(-) NECs were also positive for CDX2, whereas all HPV-related NECs were negative or only focally positive for CDX2, p40, and p63. Overexpression of p53 was found in 3 HPV(-) and 2 HPV(+/-) NECs but not in any HPV(+) NECs. Molecular analysis revealed MYC gene amplification in 4 cases: 2 HPV(-), 1 HPV(+/-), and 1 HPV(+). This was confirmed by fluorescence in situ hybridization in all but 1 HPV(-) NEC, which showed polysomy 8 but no true MYC amplification. Interestingly, only 2 of the 4 MYC amplification-bearing cases, both p53 normal/wild-type, expressed c-Myc protein by immunohistochemistry. The other 2 cases, both p53 overexpressed, did not show c-Myc expression despite true MYC amplification. Our study demonstrates that anorectal NECs arise in HPV-dependent or -independent pathways, with heterogeneous expression of other lineage markers and different molecular signatures. Expressions of p53 and c-Myc proteins appear to be mutually exclusive regardless of HPV status, likely mediating alternative mechanisms of NEC carcinogenesis.

Non-conventional dysplasia is frequently associated with low-grade tubuloglandular and mucinous adenocarcinomas in inflammatory bowel disease.

There is limited information regarding the clinicopathological features of low-grade tubuloglandular (LGTGA) and mucinous (MAC) adenocarcinomas occurring in inflammatory bowel disease (IBD), especially with regard to their precursor lesions. METHODS AND RESULTS: Forty-six IBD colectomy specimens with LGTGA (n = 17) or MAC (n = 29) with adjacent precursor lesions were analysed. As controls, 12 IBD colectomy specimens with well- to moderately differentiated adenocarcinoma that lacked any mucinous, signet ring cell, low-grade tubuloglandular or serrated features were also analysed. Compared with MACs and controls, LGTGAs more often had a flat/invisible macroscopic appearance (LGTGAs = 88%, MACs = 34%, controls = 25%, P < 0.001). MACs were more likely to have high-grade differentiation (MACs = 31%, LGTGAs = 0%, controls = 0%, P = 0.002) and a higher pathological stage (pT3 and pT4 MACs = 76%, LGTGAs = 35%, controls = 33%, P = 0.007) than LGTGAs and controls. LGTGAs (70%) and MACs (53%) were more frequently associated with non-conventional dysplasia than controls (0%) (P < 0.001). Crypt cell (40%) and hypermucinous (34%) dysplasias were the most common non-conventional subtypes associated with LGTGAs and MACs, respectively. Synchronous dysplasia often demonstrated non-conventional features in the LGTGA (33%) and MAC (47%) groups (versus 0% for the control group, P = 0.074). Synchronous cancer frequently showed similar histological features as the main tumour (LGTGA group = 60%, MAC group = 38%, control group = 100%). CONCLUSIONS: Crypt cell and hypermucinous dysplasias are the most common precursor lesions associated with LGTGAs and MACs, respectively, and may serve as a marker of increased risk for these cancer subtypes.

Primary and secondary angiosarcomas of the liver: a multi-institutional study of 32 cases.

Angiosarcomas involving the liver can be hepatic primary or metastasis from another anatomic site, which have not been systematically compared. We analyzed a series of liver biopsy or resection specimens carrying a diagnosis of angiosarcoma collected between 2005 and 2022 at 3 tertiary medical centers. The cohort included 32 patients (20 M and 12 F) with a median age of 64 years. Nineteen were primary hepatic angiosarcoma (PHA) and 13 metastatic angiosarcoma to liver (MA). Males were predominant in PHA (15/19, 78%) compared to MA (5/13, 38%, P = .025). There was no age difference between the 2 groups. Five cases had background hepatic cirrhosis, which more likely harbored PHA (4/5, 80%). Multifocality and multiorgan involvement were common in both groups. Tumor size was significantly larger in PHA than in MA (10.4 versus 4.7 cm, P < .01). Histologically, there were no differences in terms of tumor morphology (spindled versus epithelioid) and growth patterns (vasoformative versus solid) between the 2 groups. Immunohistochemically, all tumor cells were positive for CD31 (28/28, 100%) and ERG (18/18, 100%). Molecular analysis in 5 cases demonstrated different mutation profiles involving different genes, including MTOR, PIK3CA, ARID1A, CDKN2A, PTEN, TP53, ATRX, KDR/VEGFR2, and so forth. On follow-up, 30 patients (93%) died of disease, with a median survival of 114 days. Univariate and multivariate analyses revealed PHA and epithelioid morphology to be associated with worse survival (P < .05), while treatment was associated with better survival (P < .001). Our results confirmed that angiosarcoma, particularly PHA, is extremely aggressive. Epithelioid morphology is an adverse prognosticator and may be used for tumor subclassification.

Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy.

Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvß3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

Effects of multi-domain intervention on intrinsic capacity in older adults: A systematic review of randomized controlled trials (RCTs).

Intrinsic capacity is central to the maintenance of function in older adults, and maintaining optimal intrinsic capacity is of great importance to promote healthy aging. The purpose of this systematic review and meta-analysis was to analyze the impact of multi-domain interventions on intrinsic capacity in older adults, intervention components, and potential interactions between components. A total of 6740 published articles were screened until August 2022, and the review included 25 randomized controlled trials that analyzed populations, interventions, control groups, and outcomes. The meta-analysis showed improvements in the primary outcome indicators in the intervention group compared to the control group. These included increased scores on the Mini-Mental State Examination as an indicator of cognitive function, decreased scores on the Geriatric Depression Scale (GDS-15) as an indicator of psychological ability and increased scores on the Short Physical Performance Battery (SPPB) as an indicator of physical performance, with only the SPPB indicator analyzed showing greater heterogeneity. Significant improvements were also seen in the secondary indicators Time-to-Walk Test (TUG), gait speed, Chair Stand Test (CST), grip strength values and BMI. There was insufficient data for the Mini Nutritional Assessment (MNA) as an indicator of vitality to conduct a meta-analysis. Studies were of moderate to high quality. The results of this review indicate that multi-domain interventions can maintain the level of intrinsic capacity in older adults and are equally effective in older adults with declining self-care abilities.

Paget cells of the esophagus: A clinicopathologic and immunohistochemical study of 10 cases.

OBJECTIVES: Extramammary Paget's disease (EMPD) of the esophagus is very rare and the clinicopathologic features are not well characterized. DESIGN: We analyzed 10 cases with reported presence of Paget or Pagetoid tumor cells in the esophageal specimens collected between 2005 and 2018 at our institution. RESULTS: The cohort included 7 males and 3 females with a median age of 67 years. Histologically, 7 cases were secondary Pagetoid spread of tumor cells directly from an underlying invasive adenocarcinoma (pADC) located at the distal esophagus, all CK7 + with variable intracytoplasmic mucin. The clinical course of those secondary cases was dependent on the underlying malignancies. Only 3 cases were primary, including 2 Pagetoid squamous cell carcinoma in-situ (pSqCCis) and 1 Pagetoid adenocarcinoma in-situ (pADCis) with focalstromal invasion. The primary cases showed similar clinical and endoscopic presentations. Immunohistochemically, the singly dispersed Paget or Pagetoid tumor cells frequently showed loss of E-cadherin and gain of vimentin expression. Seven cases, including 5 pADC, 1 pSqCCis and the pADCis showed aberrant p53 expression. Four patients, all pADC, died of disease at a median follow-up of 10 months, while the others were alive. CONCLUSIONS: Paget or Pagetoid tumor cells in the esophagus can be primary or secondary to an invasive carcinoma. The clinical outcomes depend on the underlying malignancy and extensiveness of disease. Frequent p53 aberrancies and epithelium-mesenchymal transition likely play a role in the pathogenesis.

Clinicopathological spectrums and prognosis of primary appendiceal adenocarcinoma, goblet cell adenocarcinoma, and low-grade appendiceal mucinous neoplasms.

Primary appendiceal adenocarcinoma (APCA), goblet cell adenocarcinoma (GCA), and low/high-grade appendiceal mucinous neoplasms (LAMN/HAMN) are distinct entities with overlapping clinical presentation and histomorphology, leading to diagnostic challenges. We retrospectively reviewed our archived cases between 2010 and 2018 for diagnosis reappraisal and comparative analysis using updated terminology and modern parameters. A total of 87 cases (22 APCA, 40 GCA, and 25 LAMN pT≥3) were included. The entire cohort had 49 women and 38 men with a median age of 59.9 (range 26-88) years. There were no statistically significant differences in age and sex among the three groups. Clinically, patients with GCA were more likely to present with acute appendicitis (65%) and more likely to have appendectomy as initial surgery (68%). Both APCA and GCA were more likely to involve the proximal appendix while LAMN was more likely to involve the distal appendix (p<0.05). All APCAs were associated with mucosal precursor lesions, most commonly tubular, tubulovillous, or villous adenoma, flat LAMN/HAMN-pTis mucinous epithelium, or mixed, which correlated with distinct histomorphology, tumour differentiation, and stage. Although polypoid precursor lesions were rare in GCA, a significant proportion of GCA showed crypt atypia associated with neoplastic cells. Immunohistochemically, APCA had more frequent ß-catenin nuclear positivity and loss of SATB2 expression (p<0.05). KRAS mutation was more common in APCA than in GCA (8/11 vs 1/7, p<0.01). We further validated the three-tiered grading system (G1, G2, G3) in GCA, which correlated well with tumour stage and patient survival. APCA had worse progression-free and disease-specific survivals than GCA and LAMN (pT≥3) with the latter being relatively indolent even when perforated with peritoneal spread. Our study is the first comprehensive comparison between all three appendiceal neoplasms. We also describe a spectrum of previously under-recognised crypt atypia in GCA, which should trigger a diligent search for GCA if present.

Clinicopathologic characterization and assessment of prognostic factors for intraabdominal solitary fibrous tumors involving the gastrointestinal tract and liver.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms with a potential to metastasize in 10-30% of cases. Several risk models have been designed to predict tumor behavior at the pleura and extrapleural sites. Intrabdominal SFTs primarily involving the gastrointestinal tract (SFTGI) and liver (SFTL) are rare. We analyzed a series of SFTGI and SFTL to describe the clinicopathologic features and evaluate prognostic factors. The cohort included 33 males and 25 females, with a median age of 58.5 years and a mean tumor size of 15.6 cm. Patients with SFTL were predominantly older females compared to patients with SFTGI. By univariate analysis, high mitotic count (> 4/10 HPF), tumor size, tumor necrosis, and nuclear pleomorphism were associated with both disease-specific survival (DSS) and metastasis-free survival (MFS) (p < 0.05). Tumor location (SFTL vs. SFTGI) also predicted MFS (p = 0.026). Only very high mitotic count (> 9/10 HPF) predicted local recurrence-free survival (LFS, p = 0.001). Further analysis showed that all adverse histologic parameters (necrosis, hypercellularity, pleomorphism) correlated with high mitotic grade (> 4/10 HPF) (p < 0.05). On multivariate analysis, only mitosis predicted DSS (p = 0.023), MFS (p = 0.01), and LFS (p = 0.017). Validation of the 3 risk models (mDemicco, Salas, Pasquali) showed variable associations with DSS, MFS, and LFS, while a simplied 3-tiered risk model based on mitosis (0-4, 5-9, > 9/10 HPF) performed well in predicting all risks. Our results suggest that prognostication of SFTs is mainly associated with mitotic activity, supporting the use of mitosis (> 4 and/or > 9/10 HPF) for tumor grading and risk stratification at specific locations.